WO2022017515A1 - 一种双芳香基胺类化合物及其制备方法和应用 - Google Patents

一种双芳香基胺类化合物及其制备方法和应用 Download PDF

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WO2022017515A1
WO2022017515A1 PCT/CN2021/108229 CN2021108229W WO2022017515A1 WO 2022017515 A1 WO2022017515 A1 WO 2022017515A1 CN 2021108229 W CN2021108229 W CN 2021108229W WO 2022017515 A1 WO2022017515 A1 WO 2022017515A1
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compound
formula
halogen
diarylamine
reaction
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French (fr)
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胡来兴
王天琦
周金明
刘永华
吴萌
李鑫
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中国医学科学院医药生物技术研究所
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present application relates to a compound, in particular to a diarylamine compound and a preparation method and application thereof.
  • Prostate cancer is one of the most common male malignancies, and its incidence worldwide is second only to lung cancer, ranking second among all male malignancies, and the mortality rate in developed countries is the total cancer mortality rate. the third place.
  • PCa Prostate cancer
  • the incidence of prostate cancer will show a sustained and rapid growth trend in the global region.
  • the pathogenesis and treatment techniques for prostate tumors have also received increasing attention.
  • Androgens such as androgen (Testosterone, T), dihydrotestosterone (DHT) and adrenal androgen, are an important class of steroid hormones in the human body.
  • Receptor, AR combined to promote cell differentiation and tissue growth, involved in many key physiological functions.
  • AR is a receptor protein containing 919 amino acids, encoded by the DNA sequence of the human X chromosome (q11-12), widely distributed in proliferating and non-proliferating tissues.
  • AR protein has three domains: N terminal domain (NTD), DNA binding domain (DBD) and ligand binding domain (LBD). Among them, there are three binding sites of HBP (hormone binding pocket, HBP), AF2 and BF3 on the LBD binding domain.
  • HBP hormone binding pocket
  • AF2 AF2 and BF3
  • Androgen dysregulation leads to conditions such as benign prostatic hyperplasia or prostate cancer, hypersexuality, female acne, seborrheic dermatitis, hirsutism, hair loss, and more.
  • the pathogenesis of prostate cancer is related to the abnormal activation of androgen receptor signaling pathway.
  • androgen binds to AR, AR is activated, dimerized and phosphorylated, enters the nucleus, binds to a specific DNA site (AR Response Element, ARE), recruits transcription elements such as RNA polymerase, and regulates the transcription of target genes Expression, such as up-regulation of prostate-specific antigen (PSA), TMPRSS2, FKBP5 and other genes.
  • PSA prostate-specific antigen
  • TMPRSS2 TMPRSS2
  • FKBP5 FKBP5
  • this signaling pathway can promote the differentiation of prostate epithelial cells, while under continuous activation, it will regulate cell proliferation, survival, etc., resulting in tumor formation and progression.
  • Most prostate cancer patients are androgen-dependent, and androgen castration is often used in the early stage of treatment, including surgical castration and medical castration.
  • Drug castration is currently widely used clinically, mainly by reducing androgen levels in the body and antagonizing androgen receptors.
  • Androgen receptor antagonists are currently the mainstay of treatment for prostate cancer. These drugs can be divided into steroids and non-steroids.
  • the steroid antiandrogens are represented by cyproterone acetate (CPA), and also include megestrol acetate and medroxyprogesterone acetate.
  • Nonsteroidal antiandrogens (NSAA) include hydroxyflutamide (HF), bicalutamide (BIC) and second-generation enzalutamide (ENZ), abiraterone (abiraterone) and apalutamide (aka ARN-509).
  • Enzalutamide was launched in 2012 for the treatment of advanced male castration-resistant prostate cancer that has spread or recurred, with sales exceeding $2 billion in both 2015 and 2016.
  • Enzalutamide and the first generation of bicalutamide have the same target of action, both antagonize the effect of androgen by acting on the androgen receptor, and its efficacy and side effects are significantly better than the first generation of bicalutamide.
  • the target of action since the target of action has not changed, after a period of treatment, the drug resistance phenomenon caused by the mutation of the amino acid at the hormone binding pocket (HBP) site greatly hinders the use of such antiandrogens.
  • HBP hormone binding pocket
  • the present application provides a diarylamine compound, which can inhibit the abnormally activated androgen receptor signaling pathway and play a certain positive role in the treatment of prostate cancer.
  • the present application also provides a method for preparing the above-mentioned diarylamine compound, which has a simple synthetic route and low cost.
  • the present application also provides the application of the above-mentioned diarylamine compounds in the preparation of androgen receptor antagonist drugs.
  • the present application also provides an androgen receptor antagonistic pharmaceutical composition, wherein the above-mentioned diarylamine compound is an active ingredient.
  • the present application also provides a method for treating androgen disorders, specifically, administering to a patient an androgen receptor antagonistic pharmaceutical composition comprising the diarylamine compound of the present application.
  • the application provides a diarylamine compound having the structure of formula 1:
  • R 1 is selected from C 1-12 alkyl, C 1-6 alkoxy, halogen, C 1-3 haloalkyl, -CN, -NO 2 , -NH 2 , sulfonyl or aryl
  • R 2 is selected from hydrogen, C 1-12 alkyl, C 1-6 alkoxy, halogen, C 1-3 haloalkyl, -CN, -NO 2 , -NH 2 , sulfonyl or aryl
  • R 3 is selected from substituted or unsubstituted five-membered heterocycle or six-membered heterocycle
  • Linker is selected from -SO 2 NR 4 -, -CONR 4 -, -NR 4 -, R 4 is selected from hydrogen, C 1-12 Alkyl
  • R 5 is one or more independently selected from hydrogen, C 1-12 alkyl, C 1-6 alkoxy, halogen, C 1-3 haloalkyl, -CN, -NO 2 , -NH
  • the parent structure of the bis-aromatic amine compounds provided by this application is formed by connecting a nitrogen-containing Linker group to a six-membered aromatic ring.
  • the six-membered aromatic ring can be a benzene ring or a nitrogen-containing aromatic ring, so it is called a double Aromatic amine compounds.
  • R 1 is located at the para position of Linker, and the positional relationship between R 2 , R 3 and R 5 is not particularly limited.
  • the sulfonyl group is R 6 SO 2 -, and R 6 is selected from C 1-12 alkyl groups;
  • the aryl group is C 6- C 30 monocyclic aryl groups or fused-ring aryl groups, C 5 -C 30 monocyclic heteroaryl or fused ring heteroaryl.
  • the C 1-12 alkyl group refers to a C 1-12 straight chain alkyl group (eg methyl, ethyl, propyl, allyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, etc.), C 3-12 branched chain alkyl (isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, isohexyl, etc.) or C 3-12 cycloalkyl (cyclopropyl alkoxy group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc.);
  • C 1-6 alkoxy group refers to a straight-chain alkoxy group or a branched-chain alkoxy group with 1-6 carbon atoms, for example, it can be Methoxy (-OCH 3 ), ethoxy (-OCH 2 CH 3
  • R 3 is a five-membered heterocyclic ring or a six-membered heterocyclic ring located at an appropriate position on the aromatic ring, which can be imidazole, pyrazole, thiazole, pyrrole, oxazole, isoxazole, etc., or a substituted group
  • the substituent may be a C 1-12 alkyl group, an amino group or an epoxy hexane;
  • the C 1-12 alkyl group may include a C 1-12 straight chain alkyl group (for example Methyl, ethyl, propyl, allyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, etc.), C 3-12 branched chain alkyl (isopropyl, isobutyl, sec-butyl , tert-buty
  • R 3 composed of carbon 6-membered aromatic ring or six-membered aromatic ring bonded to the nitrogen can be produced by the parent structure.
  • the six-membered aromatic ring containing V and W may include at least one substituent R 5 in addition to Linker and R 1 , that is, in the V, W-containing six-membered aromatic ring.
  • R 5 when there is R 5 in addition to Linker and R 1 , R 5 can be 1-4 same or different groups, specifically, the carbon bonded with Linker is the 1-position of the six-membered ring
  • R 1 is at the 4th position of the six-membered ring
  • R 5 can be at the 2, 3, 5, and 6 positions of the six-membered ring.
  • R 5 is independently selected from C 1-12 alkyl, C 1 -6 alkoxy group, halogen, C 1-3 halogenated alkyl group, -CN, -NO 2 , -NH 2 , sulfonyl group, aryl group, and the six-membered ring where R 5 is located is benzene. Further, R 5 is independently selected from C 1-6 alkoxy, halogen, -CF 3 , -CN, -NO 2 , -NH 2 , sulfonyl, aryl, and the six-membered ring where R 5 is located for benzene.
  • the substituent R 5 can be 1-3 substituents at the 2, 3 and 5 positions, for example, can be 3-fluoro-5-methoxy, 2,3-dimethoxy base, 2,3,5-trimethoxy, 3-trifluoromethyl-5-fluoro, 3-nitro-5-fluoro, 3-amino-5-fluoro, 3-chloro-5-cyano, 3 -Trifluoromethyl-5-cyano, etc.
  • diarylamine compound can be the structure shown in formula 1a,
  • M is -SO 2 - or -CO-
  • R 4 is selected from hydrogen or C 1-12 alkyl group
  • R 4 is preferably hydrogen or C 1-6 alkyl group, wherein, C 1-6 alkyl group The group refers to a C 1-6 straight chain alkyl group, a C 3-6 branched chain alkyl group or a C 3-6 cycloalkyl group.
  • the diarylamine compound can also be the structure shown in formula 1b,
  • the application also provides a diarylamine compound, which has the structure of formula 1:
  • R 1 is selected from substituted or unsubstituted C 1-6 alkoxy, -OR a , acyl group, amido group or substituted or unsubstituted five- or six-membered heterocycle
  • R a is selected from hydrogen, C 1 -3 haloalkyl or substituted or unsubstituted five-membered heterocycle or six-membered heterocycle, preferably, the substituent of C 1-6 alkoxy is selected from C 1-12 alkoxy
  • R 2 is selected from Hydrogen, C 1-12 alkyl, substituted or unsubstituted C 1-6 alkoxy, halogen, C 1-3 haloalkyl, -CN, -NO 2 , -NH 2 , -OR a , acyl , amide group, sulfonyl group, aryl group, substituted or unsubstituted five-membered heterocycle or six-membered heterocycle, preferably, the substituent of the C 1-6 al
  • the acyl group is R b CO-, and R b is selected from C 1-12 alkyl groups; the amide group is R c NH 2 CO-, and R c is selected from C 1-12 alkyl groups.
  • Other substituents are the same as those defined in the first aspect, and are not repeated here.
  • diarylamine compound can be the structure shown in formula 1a,
  • M is -SO 2 -, -CO- or -CH 2 -.
  • the definitions of the substituents in Formula 1a are the same as those of the substituents in Formula 1 .
  • the diarylamine compounds of the present application referred to below include the diarylamine compounds of the first aspect and the second aspect.
  • R 3 is located at the para or meta position of Linker. Wherein, R 3 and Linker are in the para position, which is the structure shown in formula 1c; R 3 and Linker are in the meta position, which is the structure shown in formula 1d.
  • the six-membered ring where R 3 is located is pyridine, and R 3 is located on the carbon that is meta-position to Linker, that is, in formula 1d, one of X, Y, and Z is nitrogen, and the other two are hydrogen.
  • the diarylamine compound of the present application may further have the structure of formula 1e, formula 1f or formula 1g.
  • the two six-membered aromatic rings bonded to Linker can be both benzene ring nitrogen-containing aromatic rings; or one of the six-membered aromatic rings is a benzene ring, and the other six-membered aromatic ring is a A nitrogen aromatic ring, that is, the six-membered aromatic ring where R 1 is located can be a benzene ring, and the six-membered aromatic ring where R 3 is located is a nitrogen-containing aromatic ring; or, the six-membered aromatic ring where R 1 is located can be a nitrogen-containing aromatic ring, The six-membered aromatic ring where R 3 is located is a benzene ring.
  • the six-membered ring where R 1 is located is a benzene ring
  • the six-membered ring where R 3 is located is a nitrogen-containing aromatic ring
  • the nitrogen-containing aromatic ring can be, for example, pyridine (one of X, Y, Z is nitrogen) , or a pyrimidine ring (X, Z are nitrogen) or a pyridazine ring (X, Y are nitrogen, or Y, Z are nitrogen).
  • diarylamine compounds of the present application can be, for example, compounds numbered 1-66:
  • the present application also provides a method for preparing a diarylamine compound according to the first aspect, comprising the following steps: causing a condensation reaction between the compound shown in formula 2 and the compound shown in formula 3 to generate the compound shown in formula 1 ,
  • L 1 and L 2 are independently selected from one of -NHR 4 , -MC1, and halogen, and M is -SO 2 - or -CO-, so as to realize the condensation reaction between the two six-membered aromatic rings and be linked by Linker bond.
  • L 1 is -NHR 4
  • L 2 is one of -MCl and halogen; or, L 1 is -MCl or halogen, and L 2 is -NHR 4 .
  • a compound of formula 1a can be prepared as follows,
  • the above synthetic route process a can be specifically as follows: under anhydrous conditions, the amine compound represented by formula 2a is dissolved in DMF, anhydrous K 2 CO 3 is added , and under ice-water bath conditions (0° C.), to this The corresponding acid chloride compound represented by formula 3a was added to the solution, and the reaction was carried out at 0-4° C. for 30 minutes and then turned to room temperature reaction until the amine compound represented by formula 2a disappeared by monitoring by TLC, and the reaction was stopped.
  • the reaction solution was diluted with ethyl acetate, the aqueous phase was tested with PH test paper, the pH was adjusted between 9-11 with saturated NaHCO 3 solution, washed with water, washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 , concentrated, and separated by column chromatography
  • the compound of formula 1a is obtained after purification.
  • the compound represented by the above formula 2a can be obtained commercially, or can be prepared by the following method.
  • R 7 is selected from halogen, preferably a halogen atom with weak electronegativity, such as bromine or iodine
  • PG is selected from the group represented by formula PG1 and formula PG2,
  • the above-mentioned synthetic route process b can be specifically: adding the compound shown in the formula 2b and the compound shown in the formula 2c into the microwave reaction tube, adding dioxane and water to dissolve the raw materials, adding 2-dicyclohexylphosphine-2', 6'-dimethoxybiphenyl Sphos, K 3 PO 4 , Pd 2 (dba) 3 , after sealing the bottle cap, put it into a microwave reactor to react at a temperature of 130° C. and a reaction time of 90 minutes.
  • the above-mentioned synthetic route process b can also be specifically as follows: adding the compound shown in formula 2b and formula 2c into a microwave reaction tube, adding DMF and water to dissolve the raw materials, adding K 3 PO 4 , and after argon bubbling for 15 min, Add Pd(PPh 3 ) 4 , seal the bottle cap, and put it into a microwave reactor to react at a temperature of 130° C. and a reaction time of 60 minutes.
  • the above-mentioned synthetic route process b can also be specifically as follows: adding the compound shown in formula 2b and formula 2c into a microwave reaction tube, adding dioxane and water to dissolve the raw materials, adding K 3 PO 4 , and argon drum Soak for 15 minutes, add Pd(PPh 3 ) 4 , seal the bottle cap, and put it into a microwave reactor for reaction at a temperature of 130° C. and a reaction time of 90 minutes.
  • the present application also provides the preparation method of the diarylamine compound of the above-mentioned second aspect, comprising the following steps:
  • L 1 and L 2 are independently selected from one of -NHR 4 , -MC1 and halogen, and M is -SO 2 -, CO- or -CH 2 -, so as to realize the connection between the two six-membered aromatic rings. Condensation reaction and linked by Linker.
  • the application also provides another preparation method of the above-mentioned first aspect diarylamine compound, comprising the following steps:
  • L 3 and L 4 are independently selected from one of -NHR 4 , -MC1 and halogen, and M is -SO 2 - or -CO-, so as to realize that the two six-membered aromatic rings are linked by Linker through condensation reaction.
  • L 5 is selected from halogen
  • PG is represented by formula PG1 and formula PG2.
  • L 3 is -NHR 4
  • L 4 is one of -MCl and halogen; or, L 3 is -MCl or halogen, and L 4 is -NHR 4 .
  • the above reaction can be completed in an appropriate condensation system, and can be controlled by using a conventional condensing agent and corresponding conditions to obtain the desired product.
  • L 3 or L 4 when L 3 or L 4 is halogen, L 3 or L 4 may be the same as L 5 , or L 5 may be more electronegative than L 3 or L 4 .
  • the above reaction can be completed in an appropriate condensation system, and can be controlled by using a conventional condensing agent and corresponding conditions to obtain the desired product.
  • a compound of formula 1b can be prepared as follows,
  • the above-mentioned synthetic route process d can be the same as the aforementioned synthetic route process b, using the compound shown in formula 6 and the compound shown in formula 7 as raw materials to obtain the compound shown in formula 1d, which will not be repeated here.
  • the application also provides another preparation method of the above-mentioned second aspect diarylamine compound, comprising the following steps:
  • L 3 and L 4 are independently selected from one of -NHR 4 , -MC1 and halogen, and M is SO 2 -, -CO- or -CH 2 -, so as to realize condensation between two six-membered aromatic rings React and be linked by Linker;
  • L 5 is selected from halogen, and the definition of PG is the same as that described above, that is, the group represented by the aforementioned PG1 and formula PG2.
  • the third aspect of the present application also provides the use of any one of the above-mentioned amine compounds in the preparation of androgen receptor antagonist drugs.
  • the inventors have studied the above-mentioned diarylamine compounds with the structure of formula 1, and surprisingly found that these compounds can inhibit the activity of androgen receptors, compounds 27, 30, 32, 43, 46-48, 54 , 56 inhibited the transcriptional activity of AR at a concentration of 1 ⁇ M, the RLU value was less than 50%; compounds 49, 51-54, 63-66 inhibited the transcriptional activity of AR at a concentration of 5 ⁇ M, the RLU value was less than 40%; Compounds 2-4, 7, 10, 11, 15, 23-25, 27, 29, 30, 32-34, 38, 39 inhibited the transcriptional activity of AR at a concentration of 10 ⁇ M, and the RLU value was less than 30%.
  • the fourth aspect of the present application also provides an androgen receptor antagonistic pharmaceutical composition, including any of the above-mentioned diarylamine compounds as an androgen receptor antagonistic active ingredient, and a pharmaceutically acceptable drug Accessories.
  • the above-mentioned substituted bisarylamine compound itself or its mixture with pharmaceutically acceptable excipients, diluents, etc. can be prepared in 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 (eg carbohydrate 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 metasilicate; Phosphate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc.), binders (eg gelatin, polyvinylpyrrolidone and polyethylene glycol), disintegrants (eg cellulose derivatives such as carboxymethyl cellulose) Sodium, polyvinylpyrrolidone), lubricants (e.g.
  • talc calcium stearate, magnesium stearate, cetyl wax, boric acid, sodium benzoate, leucine), stabilizers (methylparaben, parabens propyl ester, etc.), flavoring agents (such as commonly used sweeteners, sour agents and spices, etc.), diluents and solvents for injection (such as water, ethanol and glycerol, etc.).
  • the diarylamine compound in the androgen receptor antagonist pharmaceutical composition of the present application is a unit preparation.
  • a unit preparation is a preparation that satisfies the active ingredients required for one-time administration, such as a unit (injection) injection and the like.
  • the amount of drug required for a single administration to a patient can be conveniently obtained by calculating the product of the patient's body weight and the dose per unit body weight required for a single administration of the patient. For example, in the process of preparing medicines, it is generally considered that the weight of an adult is 50-70 kg, and the dosage can be determined by the equivalent dose conversion relationship between the doses of experimental animals and people per unit body weight.
  • the human and mouse doses can be converted using a conversion factor of 0.0026 based on the body surface area of human and mouse.
  • Examples of administration modes of the androgen receptor antagonistic pharmaceutical composition include intravenous, intraperitoneal injection, or gavage, oral administration, and the like.
  • the fifth aspect of the present application also provides a method for treating androgen disorders, specifically, administering to a patient an androgen receptor antagonistic pharmaceutical composition comprising the diarylamine compound of the present application.
  • Prostate hyperplasia or prostate cancer, hypersexuality, female acne, seborrheic dermatitis, hirsutism due to androgen imbalance can be treated by administering to a patient an androgen receptor antagonistic pharmaceutical composition comprising a bisarylamine compound of the present application ailments, hair loss, etc.
  • the diarylamine compounds provided in this application have obvious inhibitory activity on androgen receptors, some of which also have obvious inhibitory activity on prostate cancer cells, and can be used as androgen receptor antagonists to treat prostate cancer.
  • the synthetic route of the diarylamine compound is simple, the raw materials are readily available, and the cost is low, which is favorable for industrialized implementation.
  • Figure 1a is a graph showing the AR inhibitory activity of compound 23 of the present application.
  • Figure 1b shows the effect of the application compound 23 on the transcriptional activity of the 876-amino acid mutant DAR expressed in PC-3;
  • Figure 2a is a graph showing the AR inhibitory activity of compound 27 of the present application.
  • Figure 2b shows the effect of the application compound 27 on the transcriptional activity of DAR mutated at amino acid 876 expressed in PC-3.
  • Compound 1 was characterized by hydrogen nuclear magnetic resonance spectroscopy ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 2 was characterized by hydrogen nuclear magnetic resonance spectroscopy ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 3 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 4 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high-resolution mass spectrometry (HRMS) as follows:
  • Compound 5 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 6 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 7 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 8 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR), carbon nuclear magnetic resonance ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 9 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 10 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 11 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 12 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 13 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 14 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 15 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 16 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 17 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 18 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 19 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 23 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 24 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 25 was characterized by hydrogen nuclear magnetic resonance spectroscopy ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 26 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 28 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and carbon nuclear magnetic resonance ( 13 CNMR) as follows:
  • Compound 29 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and carbon nuclear magnetic resonance ( 13 CNMR) as follows:
  • Compound 33 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and carbon nuclear magnetic resonance ( 13 CNMR) as follows:
  • Compound 35-2 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and carbon nuclear magnetic resonance ( 13 CNMR) as follows:
  • Compound 35-2 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and carbon nuclear magnetic resonance ( 13 CNMR) as follows:
  • Compound 36-2 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and carbon nuclear magnetic resonance ( 13 CNMR) as follows:
  • Compound 36 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and carbon nuclear magnetic resonance ( 13 CNMR) as follows:
  • the hydrogen nuclear magnetic resonance ( 1 HNMR), carbon nuclear magnetic resonance ( 13 CNMR) and mass spectrometry of compound 37-1 are characterized as follows:
  • Compound 37-2 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and mass spectrometry as follows:
  • Compound 37 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and carbon nuclear magnetic resonance ( 13 CNMR) as follows:
  • Compound 38-1 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and mass spectrometry as follows:
  • Compound 38 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and carbon nuclear magnetic resonance ( 13 CNMR) as follows:
  • Compound 39 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and carbon nuclear magnetic resonance ( 13 CNMR) as follows:
  • Compound 40-2 was characterized by mass spectrometry as: ESIMS(+) m/z: 228.1 [M+H] + .
  • Compound 40-3 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and mass spectrometry as follows:
  • Compound 40 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and carbon nuclear magnetic resonance ( 13 CNMR) as follows:
  • Compound 41-1 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR) and carbon nuclear magnetic resonance ( 13 CNMR) as follows:
  • the hydrogen nuclear magnetic resonance ( 1 HNMR), carbon nuclear magnetic resonance ( 13 CNMR) and mass spectrometry of compound 41-2 are characterized as follows:
  • Compound 41 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR), carbon nuclear magnetic resonance ( 13 CNMR) and mass spectrometry as follows:
  • the hydrogen nuclear magnetic resonance ( 1 HNMR), carbon nuclear magnetic resonance ( 13 CNMR) and mass spectrometry of compound 42-1 are characterized as follows:
  • the hydrogen nuclear magnetic resonance ( 1 HNMR), carbon nuclear magnetic resonance ( 13 CNMR) and mass spectrometry of compound 42-2 are characterized as follows:
  • Compound 42 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR), carbon nuclear magnetic resonance ( 13 CNMR) and mass spectrometry as follows:
  • the preparation methods of compounds 43-59 and compound 30 are basically the same, except that 4-chloro-benzenesulfonyl chloride is replaced by different starting materials.
  • 4-fluoro-benzenesulfonyl chloride was used in Example 43
  • 4-cyano-benzenesulfonyl chloride was used in Example 44
  • 4-(2-methoxyethoxy)-benzenesulfonyl chloride was used in Example 45.
  • Example 46 uses 4-isopropoxy-benzenesulfonyl chloride
  • Example 47 uses 4-hydroxy-benzenesulfonyl chloride
  • Example 48 uses 4-methyl-benzenesulfonyl chloride
  • Example 49 uses 4-butoxy-benzenesulfonyl chloride Acid chloride
  • Example 50 uses 6-chloro-pyridine-3-sulfonyl chloride
  • Example 51 uses 4-trifluoromethyl-benzenesulfonyl chloride
  • Example 52 uses 4-(isoxazol-4-yl)-benzenesulfonyl Acid chloride
  • Example 53 adopts 4-(pyridin-2-yl-oxy)-benzenesulfonyl chloride
  • Example 54 adopts 4-(isoxazol-5-yl)-benzenesulfonyl chloride
  • Example 55 adopts 4-tris Fluoromethoxy-benzenesulfonyl chloride
  • Example 56 using 4-difluorometh
  • Compound 62 was characterized by hydrogen nuclear magnetic resonance ( 1 HNMR), carbon nuclear magnetic resonance ( 13 CNMR) and mass spectrometry as follows:
  • the preparation methods of compounds 63-66 and compound 30 are basically the same, except that in Example 63, 4-methoxy-benzenesulfonyl chloride is used to replace 4-chloro-benzenesulfonyl chloride, and 2-amino-5( Lin-4yl)pyridine was used instead of 4-(1H-pyrazol-3-yl)aniline; 4-methoxy-benzenesulfonyl chloride was used instead of 4-chloro-benzenesulfonyl chloride in Example 64, and 4-(thiophene was used -2-yl)aniline instead of 4-(1H-pyrazol-3-yl)aniline; 4-methoxy-benzenesulfonyl chloride was used instead of 4-chloro-benzenesulfonyl chloride in Example 65, and 4-(iso- 4-(1H-pyrazol-3-yl)aniline was replaced by thiazol-5-yl)aniline; 4-(1H-pyrazol
  • LNCaP cells were purchased from ATCC, CRL-1740;
  • DHT Dihydrotestosterone
  • Enzalutamide (ENZ) was donated by Shanghai Pharmaceuticals;
  • Biochemical reagents F-12K medium, RPMI 1640 medium, Phenol red free RPMI1640 medium, FBS, charcoal-stripped FBS, 0.25% trypsin containing EDTA, PBS were purchased from GiBCO, USA, FBS charcoal stripped The charcoal-adsorbed special grade fetal bovine serum was purchased from Biological Industries, Israel. Kit: Dual-Luciferase Assay System was purchased from Promega Corporation in the United States.
  • PSA-Jappan plasmid was donated by Prof. Hiroyuki from Japan Cancer Chemotherapy Center, which co-expresses prostate specific antigen and firefly luciferase.
  • the Renilla plasmid is owned by the immunology department of our institute and expresses Renilla luciferase.
  • Cells LNCaP cells were purchased from ATCC, CRL-1740; cultured with RPMI1640 medium containing 10% FBS. PC-3 cells were kindly provided by McGill University, Canada; cultured in F-12K medium containing 10% FBS.
  • Biochemical reagents F-12K, RPMI 1640 medium, FBS, charcoal-stripped FBS, 0.25% trypsin containing EDTA, PBS was purchased from GiBCO, USA, FBS charcoal stripped carbon-adsorbed fetal bovine serum was purchased from Israel Biological Industries Inc.
  • Microplate reader Centro XS3LB 960 was purchased from Berthold Company in Germany.
  • the diarylamine compounds of the present application all have certain anti-AR activity, especially the IC 50 values of compounds 23, 27, 30 and 32 are lower than those of enzalutamide, and they have strong anti-AR activity. activity and can therefore be used as a lead compound for further studies.
  • the cell lysates were collected into clean EP tubes, centrifuged, and 20 ⁇ L of supernatant was taken into a clean white 96-well plate. According to the instructions of the Luciferase Assay System kit, the fluorescence value was measured with a Centro XS3 LB 960 microplate reader. Three parallel groups were set up in the experiment, and statistical analysis was carried out, in which *P ⁇ 0.05, **P ⁇ 0.01 was based on the DHT group as a reference. experimental data with Graphs and statistical analyses were performed with GraphPad Prism 5.0.
  • Fig. 1a is a graph showing the AR inhibitory activity of the compound 23 of the application
  • Fig. 1b is the effect of the compound 23 of the application on the transcriptional activity of the DAR mutated at amino acid 876 expressed in PC-3
  • Fig. 2a is a graph showing the AR inhibitory activity of the compound 27 of the application
  • Fig. 2b is the effect of the compound 27 of the application on the transcriptional activity of the DAR mutated at amino acid 876 expressed in PC-3.
  • Figure 1a, Figure 1b, Figure 2a and Figure 2b show that compounds 23 and 27 also have a good inhibitory effect on the transcriptional activity of F876L mutant AR, and both have a good inhibitory effect on the transcriptional activity of AR-F876L in a dose-dependent manner relationship; IC 50 and respectively 1.05 ⁇ M 0.16 ⁇ M. And compounds 23 and 27 have a significant inhibitory effect on the transcriptional activity of AR-F876L at 0.8 ⁇ M. Compared with the effect of enzalutamide, it shows that 23 and 27 can overcome enzalutamide due to the 876 amino acid mutation of AR. The resulting drug resistance problem may solve the clinical drug resistance problem of enzalutamide androgen receptor antagonists.

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Abstract

本申请提供一种双芳香基胺类化合物及其制备方法和应用，该化合物具有式1的结构，R 1选自C1－12的烷基、C1－6的烷氧基、卤素、C1－3的卤代烷基、-CN、-NO2、-NH2、磺酰基或芳香基；R5为一个以上且R5和R2选自氢、C1－12的烷基、C1－6的烷氧基、卤素、C1－3的卤代烷基、-CN、-NO2、-NH2、磺酰基或芳香基；R3选自取代或未取代的五元杂环或六元杂环；Linker选自-SO2NR4-、-CONR4-、-NR4-，R4选自氢、C1－12的烷基；V、W、X、Y、Z独立地选自碳或者氮。本申请提供的双芳香基胺类化合物具有抑制雄激素受体的活性。

Description

一种双芳香基胺类化合物及其制备方法和应用
本申请要求于2020年7月24日提交中国专利局、申请号为202010721107.0、申请名称为“一种双芳香基胺类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。
技术领域
本申请涉及一种化合物，尤其涉及一种双芳香基胺类化合物及其制备方法和应用。
背景技术
前列腺癌(Postate cancer,PCa)是最常见的男性恶性肿瘤之一，在全球范围内的发病率仅次于肺癌，排在所有男性恶性肿瘤第二位，居发达国家死亡率为癌症总死亡率的第三位。随着生活方式、环境等因素的改变，以及人口老龄化程度的加剧，前列腺癌的发病率在全球区域都会呈现出持续快速的增长趋势。针对前列腺肿瘤的发病机理和治疗技术也日益受到重视。
雄激素(Androgen)，如雄酮(Testosterone，T)、二氢雄酮(Dihydrotestosterone，DHT)和肾上腺雄酮等，是人体内一类重要的甾体类性激素，通过与雄激素受体(Androgen Receptor，AR)结合促进细胞分化和组织生长，参与众多关键生理功能。AR是包含919种氨基酸的受体蛋白，位于人类X染色体(q11-12)的DNA序列编码，广泛分布于增殖和非增殖组织。AR蛋白具有三个结构域：N端结构域(N terminal domain，NTD)、DNA结合域(DNA binding domain，DBD)和配体结合域(Ligand binding domain，LBD)。其中LBD结合域上存在HBP(激素结合口袋Hormone binding pocket，HBP)、AF2和BF3三个结合位点。雄激素结合于HBP时，能激活或抑制靶基因表达，从而调控靶组织的生理功能。
雄激素失调导致前列腺增生症或前列腺癌、性欲亢进、女性痤疮、脂溢性皮炎、多毛症、脱发等病症。前列腺癌的致病机理与雄激素受体信号通路发生异常活化有关。具体地，雄激素与AR结合，AR被激活并二聚化磷酸化，进入细胞核中，与特异的DNA部位(AR Response Element,ARE)结合，募集RNA聚合酶等转录元件，调控靶基因的转录表达，如上调前列腺特异性抗原(PSA)、TMPRSS2、FKBP5等基因。该信号通路正常情况下可以促进前列腺上皮细胞的分化，而持续激活情况下则会调节细胞增殖、存活等，从而形成肿瘤并恶化。大部分前列腺癌患者属于雄激素依赖型的，在治疗早期常采用雄激素去势治疗，包括手术切割去势和药物去势。药物去势目前在临床上应用广泛，主要通过降低体内雄激素水平和拮抗雄激素受体。
雄激素受体拮抗剂是目前治疗前列腺癌的主体药物。这类药物可分为甾类与非甾类两种。甾类抗雄激素药物以醋酸环丙孕酮(CPA)为代表，还包括醋酸甲地孕酮和醋酸甲羟孕酮。非甾类抗雄激素药物(Nonsteroidal antiandorgens，NSAA)有羟基氟他胺(hydroxyflutamide，HF)、比卡鲁胺(bicalutamide，BIC)和二代的恩杂鲁胺(enzalutaimide，ENZ)、阿比特龙(abiraterone)和apalutamide(又名ARN-509)。恩杂鲁胺于2012上市，用于治疗已扩散或复发的晚期男性去势耐受前列腺癌，在2015年及2016销售额均突破 20亿美元。恩杂鲁胺与第一代的比卡鲁胺作用靶点相同，都是通过作用于雄激素受体来拮抗雄激素的作用，其疗效和副作用方面都明显优于第一代的比卡鲁胺作。但是由于作用靶点没有改变，在经过一段时间的治疗后，激素结合口袋(HBP)位点氨基酸的突变而产生的耐药现象极大地阻碍了此类抗雄激素药物的使用。
因此，急需开发出新型的雄激素受体拮抗剂以规避由于氨基酸突变而产生的耐药性。
发明内容
本申请提供一种双芳香基胺类化合物，能够抑制异常活化的雄激素受体信号通路而对前列腺癌的治疗起到一定的积极作用。
本申请还提供一种上述双芳香基胺类化合物的制备方法，合成线路简单，成本较低。
本申请还提供上述双芳香基胺类化合物在制备雄激素受体拮抗药物中的应用。
本申请还提供一种雄激素受体拮抗药物组合物，上述双芳香基胺类化合物为活性成分。
本申请还提供一种雄激素失调的治疗方法，具体可以是向患者施用包括本申请双芳香基胺类化合物的雄激素受体拮抗药物组合物。
第一方面，本申请提供一种双芳香基胺类化合物，其具有式1的结构：
Figure PCTCN2021108229-appb-000001
其中，R 1选自C 1－12的烷基、C 1－6的烷氧基、卤素、C 1－3的卤代烷基、-CN、-NO 2、-NH 2、磺酰基或芳香基；R 2选自氢、C 1－12的烷基、C 1－6的烷氧基、卤素、C 1－3的卤代烷基、-CN、-NO 2、-NH 2、磺酰基或芳香基；R 3选自取代或未取代的五元杂环或六元杂环；Linker选自-SO 2NR 4-、-CONR 4-、-NR 4-，R 4选自氢、C 1－12的烷基；R 5为一个以上独立地选自氢、C 1－12的烷基、C 1－6的烷氧基、卤素、C 1－3的卤代烷基、-CN、-NO 2、-NH 2、磺酰基、芳香基；V、W、X、Y、Z独立地选自碳或者氮。
本申请提供的双芳香基胺类化合物，母体结构是通过含氮的Linker基团分别键连六元芳香环而构成，该六元芳香环可以是苯环或含氮芳香环，因此称为双芳香基胺类化合物。芳香环上的各取代基中，R 1位于Linker的对位，R 2、R 3、R 5的位置关系则不做特殊限定。
本申请的化合物中，所述磺酰基为R 6SO 2-，R 6选自C 1－12的烷基；所述芳香基为C 6-C 30的单环芳基或稠环芳基、C 5-C 30的单环杂芳基或稠环杂芳基。
上述取代基的定义中，C 1－12的烷基是指C 1－12直链烷基(例如甲基、乙基、丙基、烯丙基、正丁基、正戊基、正己基、正庚基等)、C 3－12支链烷基(异丙基、异丁基、仲丁基、叔丁基、异戊基、异己基等)或C 3－12环烷基(环丙基、环丁基、环戊基、环己基等)；C 1－6的烷氧基是指碳原子个数为1-6个的直链烷氧基或支链烷氧基，例如可以是甲氧基(-OCH 3)、乙氧基(-OCH 2CH 3)、正丙氧基(-OCH 2CH 2CH 3)、异丙氧基(-OCH(CH 3) 2)等；卤素可以为-F、-Cl、-Br、-I；C 1－3的卤代烷基是指被1-3个卤素原子取代的C 1－3 的直链烷基或支链烷基(例如-CF 3、-CHF 2、-CH 2Br、-CH 2CH 2Cl等)。
根据本申请的化合物，R 3是位于芳香环上适当位置的五元杂环或六元杂环，可以为咪唑、吡唑、噻唑、吡咯、恶唑、异恶唑等，或者是含取代基的上述五元杂环或六元杂环，取代基可以是C 1－12的烷基、氨基或环氧己烷；C 1－12的烷基可以包括C 1－12直链烷基(例如甲基、乙基、丙基、烯丙基、正丁基、正戊基、正己基、正庚基等)、C 3－12支链烷基(异丙基、异丁基、仲丁基、叔丁基、异戊基、异己基等)、C 3－12环烷基(环丙基、环丁基、环戊基、环己基等)、氨基、或环氧己烷等的至少一个(即五元杂环或六元杂环可以有不止一个上述取代基)，取代基可以在五元杂环或六元杂环的任意位置。
此外，R 3可以通过组成六元芳香环的碳或氮与母体结构的六元芳香环键结。
在本申请的双芳香基胺类化合物中，含有V、W的六元芳香环上，除了连接Linker和R 1，还可以包括至少一个取代基R 5，也就是说，在含有V、W的六元环中，除了Linker和R 1外，还具有R 5时，R 5可以是1-4个相同或不同的基团，具体地，以与Linker键结的碳为六元环的1位为例，则R 1在六元环的4位，R 5可位于六元环的2,3,5,6位，进一步地，R 5独立地选自C 1－12的烷基、C 1－6的烷氧基、卤素、C 1－3的卤代烷基、-CN、-NO 2、-NH 2、磺酰基、芳香基，且R 5所在六元环为苯。更进一步地，R 5独立地选自C 1－6的烷氧基、卤素、-CF 3、-CN、-NO 2、-NH 2、磺酰基、芳香基，且R 5所在的六元环为苯。
非限定性的示例，取代基R 5可以是在2位、3位以及5位上1-3个取代基，例如，可以是3-氟-5-甲氧基,2,3-二甲氧基,2,3,5-三甲氧基,3-三氟甲基-5-氟,3-硝基-5-氟,3-氨基-5-氟,3-氯-5-氰基,3-三氟甲基-5-氰基等。
进一步地，上述双芳香基胺类化合物可以为式1a所示的结构，
Figure PCTCN2021108229-appb-000002
式1a中，M为-SO 2-或-CO-，R 4选自氢或C 1－12的烷基，R 4优选氢或C 1－6的烷基，其中，C 1－6的烷基指C 1－6直链烷基、C 3－6支链烷基或C 3－6环烷基。
该双芳香基胺类化合物还可以为式1b所示的结构，
Figure PCTCN2021108229-appb-000003
式1b中各取代基的限定与式1a中取代基的限定相同。
第二方面，本申请还提供一种双芳香基胺类化合物，其具有式1的结构：
Figure PCTCN2021108229-appb-000004
其中，
R 1选自取代或未取代的C 1－6的烷氧基、-OR a、酰基、酰胺基或取代或未取代的五元杂环或六元杂环，R a选自氢、C 1－3的卤代烷基或取代或未取代的五元杂环或六元杂环，优选地，C 1－6的烷氧基的取代基选自C 1－12的烷氧基；R 2选自氢、C 1－12的烷基、取代或未取 代的C 1－6的烷氧基、卤素、C 1－3的卤代烷基、-CN、-NO 2、-NH 2、-OR a、酰基、酰胺基、磺酰基、芳香基、取代或未取代的五元杂环或六元杂环，优选地，C 1－6的烷氧基的取代基选自C 1－12的烷氧基；R 3选自取代或未取代的五元杂环或六元杂环，优选地，R 3中的取代基选自C 1－12的烷基和/或氧；Linker选自-SO 2NR 4-、-CONR 4-、-NR 4-、-NR 4CH 2-，R 4选自氢或C 1－12的烷基中的至少一个；R 5为一个以上且选自氢、C 1－12的烷基、C 1－6的烷氧基、卤素、C 1－3的卤代烷基、-CN、-NO 2、-NH 2、磺酰基或芳香基；V、W、X、Y、Z独立地选自碳或者氮；优选地，所述磺酰基为R 6SO 2-，R 6选自C 1－12的烷基；优选地，所述芳香基为C 6-C 30的单环芳基或稠环芳基、C 5-C 30的单环杂芳基或稠环杂芳基。
本申请的化合物中，酰基为R bCO-，R b选自C 1－12的烷基；酰胺基为R cNH 2CO-，R c选自C 1－12的烷基。其他的取代基与前述第一方面中的定义相同，此处不再赘述。
进一步地，上述双芳香基胺类化合物可以为式1a所示的结构，
Figure PCTCN2021108229-appb-000005
其中，M为-SO 2-、-CO-或-CH 2-。式1a中取代基的限定与式1中取代基的限定相同。
以下所指的本申请的双芳香基胺类化合物包括前述第一方面和第二方面的双芳香基胺类化合物。
进一步地，本申请的双芳香基胺类化合物中，R 3位于Linker的对位或者间位。其中，R 3与Linker为对位，即为式1c所示的结构；R 3与Linker为间位，即为式1d所示的结构。
Figure PCTCN2021108229-appb-000006
在式1c和式1d中的双芳香基胺类化合物中，本申请不限制R 2在六元环中的位置。
进一步地，R 3所在的六元环为吡啶，且R 3位于与Linker为间位的碳上，即式1d中，X、Y、Z中的一个为氮，另外两个为氢。作为一种优选的实施方式，本申请的双芳香基胺类化合物可以进一步具有式1e、式1f或式1g的结构。
Figure PCTCN2021108229-appb-000007
本申请的双芳香基胺类化合物，与Linker键结的两个六元芳香环可以同时为苯环含氮芳香环；或者其中一个六元芳香环为苯环，另一个六元芳香环为含氮芳香环，即，R 1所在的六元芳香环可以为苯环，R 3所在的六元芳香环为含氮芳香环；或者，R 1所在的六元芳香环可以为含氮芳香环，R 3所在的六元芳香环为苯环。
在具体化合物中，R 1所在的六元环为苯环，R 3所在的六元环为为含氮芳香环，含氮芳香环例如可以是吡啶(X、Y、Z中的一个为氮)，又或者嘧啶环(X、Z为氮)或哒嗪 环(X、Y为氮，或者Y、Z为氮)。
作为非限定性实例，本申请的双芳香基胺类化合物可以例如编号为1-66的化合物：
Figure PCTCN2021108229-appb-000008
Figure PCTCN2021108229-appb-000009
本申请还提供一种上述第一方面的双芳香基胺类化合物的制备方法，包括以下步骤：使式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1所示的化合物，
Figure PCTCN2021108229-appb-000010
Figure PCTCN2021108229-appb-000011
其中，L 1和L 2独立地选自-NHR 4、-MCl、卤素中的一个，M为-SO 2-或-CO-，以实现二个六元芳香环之间经缩合反应而被Linker键结。
在具体制备过程中，L 1为-NHR 4，L 2为-MCl、卤素中的一个；或，L 1为-MCl或卤素，L 2为-NHR 4。
具体地，当制备Linker为-SO 2NR 4-的式1所示的化合物时，L 1和L 2独立地选自-NHR 4、-MCl中的一个且两者互不相同，M为-SO 2-；当制备Linker为-CONR 4-的式1所示的化合物时，L 1和L 2独立地选自-NHR 4、-MCl中的一个且两者互不相同，M为-CO-；当制备Linker为-NR 4-的式1所示的化合物时，L 1和L 2独立选自-NHR 4、卤素中的一个且两者互不相同。
上述反应可以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。例如，可以按照下述方式制备式1a所示的化合物，
Figure PCTCN2021108229-appb-000012
上述反应的实质是式2a所示的化合物与式3a所示的化合物发生酰胺化反应，因此可以采用常规的酰胺化反应的条件得到预期产物。
例如，上述合成路线过程a可以具体为：在无水条件下，将式2a所示的胺类化合物溶于DMF中，加入无水K 2CO 3，冰水浴条件(0℃)下，向该溶液中加入相应的式3a所示的酰氯化合物，0-4℃下反应30min后转为室温反应，直至通过TLC监测式2a所示的胺类化合物消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化得式1a所示的化合物。其中，式2a所示的化合物、式3a所示的化合物、K 2CO 3的摩尔比为1：(1.2-2):1.5，柱层析的洗脱液为(PE/EA＝1.5/1V/V)。
上述合成路线过程a还可以具体为：无水条件下，将式2a所示的胺类化合物溶于干燥的吡啶中，在冰水浴条件下(0℃)向反应液中加入式3a所示的酰氯化合物，室温下反应，直至通过TLC监测式2a所示的胺类化合物消失，停止反应。反应液用乙酸乙酯稀释，水洗、饱和NaCl溶液洗，无水Na 2SO 4干燥，根据实际情况进行柱层分离或者结晶纯化得到式1a所示的化合物。其中，式2a所示的化合物、式3a所示的化合物的摩尔比为1：(1.2-2)，柱层析的洗脱液为(PE/EA＝1.5/1V/V)。
一般的，上述式2a所示的化合物可以通过商购获得，或者通过下述方法制备。
具体地，式2b和式2c所示的化合物发生反应，生成式2a所示的化合物，
Figure PCTCN2021108229-appb-000013
其中，R 7选自卤素，优选电负性较弱的卤素原子，例如溴或碘，PG选自式PG1、式PG2所示的基团，
Figure PCTCN2021108229-appb-000014
上述合成路线过程b可以具体为：将式2b所示的化合物和式2c所示的化合物加入微波反应管中,加入二氧六环和水使原料溶解，加入2-双环己基膦-2',6'-二甲氧基联苯Sphos、K 3PO 4、Pd 2(dba) 3，封上瓶盖后，放入微波反应仪中反应，温度130℃，反应时间90min。反应液乙酸乙酯提取，水和饱和食盐水依次萃洗，无水硫酸钠干燥，过滤后滤液用柱层析纯化(PE/EA＝3/1-1/1V/V)，得到式2a所示的化合物。
上述合成路线过程b还可以具体为：将式2b所示的化合物和式2c所示的加入微波反应管中,加入DMF和水使原料溶解，加入K 3PO 4，氩气鼓泡15min后，加入Pd(PPh 3) 4，封上瓶盖后，放入微波反应仪中反应，温度130℃，反应时间60min。反应液乙酸乙酯提取，水和饱和食盐水依次萃洗，无水硫酸钠干燥，过滤后滤液柱层析纯化(CH 2Cl 2/MeOH＝30/1V/V)，得到式2a所示的化合物。
或者，上述合成路线过程b还可以具体为：将式2b所示的化合物和式2c所示的加入微波反应管中加入二氧六环和水使原料溶解，加入K 3PO 4，氩气鼓泡15min，加入Pd(PPh 3) 4，封上瓶盖后，放入微波反应仪中反应，温度130℃，反应时间90min。反应液乙酸乙酯提取，水和饱和食盐水依次萃取洗涤，无水硫酸钠干燥，过滤后滤液柱层析纯化(PE/EA＝4/1-2/1V/V)，得到式2a所示的化合物。
本申请还提供上述第二方面的双芳香基胺类化合物的制备方法，包括以下步骤：
使式2化合物和式3化合物发生缩合反应，生成式1所示的化合物，
Figure PCTCN2021108229-appb-000015
其中，L 1和L 2独立地选自-NHR 4、-MCl、卤素中的一个，M为-SO 2-、CO-或--CH 2-，以实现二个六元芳香环之间经缩合反应而被Linker键结。
具体地，当制备Linker为-SO 2NR 4-的式1所示的化合物时，L 1和L 2独立地选自-NHR 4、-MCl中的一个且两者互不相同，M为-SO 2-；当制备Linker为-CONR 4-的式1所示的化合物时，L 1和L 2独立地选自-NHR 4、-MCl中的一个且两者互不相同，M为-CO-；当制备Linker为-NR 4CH 2-的式1所示的化合物时，L 1和L 2独立地选自-NHR 4、-MCl中的一个且两者互不相同，M为-CH 2-；当制备Linker为-NR 4-的式1所示的化合物时，L 1和L 2独立选自-NHR 4、卤素中的一个且两者互不相同。
该制备方法和合成路线以及合成条件与前述制备方法相同，此处不再赘述。
本申请还提供另一种上述第一方面双芳香基胺类化合物的制备方法，包括以下步骤：
使式4所示的化合物和式5所示的化合物发生缩合反应，生成式6所示的化合物，
使式6所示的化合物和式3所示的化合物发生反应，生成式1所示的化合物，
Figure PCTCN2021108229-appb-000016
上述L 3和L 4独立选自-NHR 4、-MCl、卤素中的一个，M为-SO 2-或-CO-，以实现二个六元芳香环之间经缩合反应而被Linker键结；L 5选自卤素，PG为式PG1、式PG2所示。
Figure PCTCN2021108229-appb-000017
在制备中，L 3为-NHR 4，L 4为-MCl、卤素中的一个；或，L 3为-MCl或卤素，L 4为-NHR 4。
具体地，当制备Linker为-SO 2NR 4-的式1所示的化合物时，L 3和L 4独立地选自-NHR 4、-MCl中的一个且两者互不相同，M为-SO 2-；当制备Linker为-CONR 4-的式1所示的化合物时，L 3和L 4独立地选自-NHR 4、-MCl中的一个且两者互不相同，M为-CO-；当制备Linker为-NR 4-的式1所示的化合物时，L 3和L 4独立选自-NHR 4、卤素中的一个且两者互不相同。
上述反应可以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。
在第一缩合反应中，当L 3或L 4为卤素时，L 3或L 4可以和L 5相同，或者L 5的电负性强于L 3或L 4。
上述反应可以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。
例如，可以按照下述方式制备式1b所示的化合物，
Figure PCTCN2021108229-appb-000018
上述合成路线过程c可以具体为：将式5和式4所示的化合物溶于DMF，加入NaOtBu和(Cypf-tBu)PdCl 2，混合物65℃加热反应至TLC监测式5所示的化合物反应完全，停止反应。减压除去溶剂，剩余物用EtOAC提取，水和饱和食盐水依次萃取洗涤，无水硫酸钠干燥，过滤且滤液用柱层析纯化(PE/EA＝6/1-10/1V/V)，得到式6所示的化合物。
上述合成路线过程d可以与前述合成路线过程b相同，以式6所示的化合物和式7所示的化合物为原料，得到式1d所示的化合物，此处不再赘述。
本申请还提供另一种上述第二方面双芳香基胺类化合物的制备方法，包括以下步骤：
使式4所示的化合物和式5所示的化合物发生缩合反应，生成式6所示的化合物，
使式6所示的化合物和式7所示的化合物发生反应，生成式1所示的化合物，
Figure PCTCN2021108229-appb-000019
其中，L 3和L 4独立地选自-NHR 4、-MCl、卤素中的一个，M为SO 2-、-CO-或-CH 2-，以实现二个六元芳香环之间经缩合反应而被Linker键结；
L 5选自卤素，PG的定义与前述相同，即为前述PG1、式PG2所示的基团。
具体地，当制备Linker为-SO 2NR 4-的式1所示的化合物时，L 3和L 4独立地选自-NHR 4、-MCl中的一个且两者互不相同，M为-SO 2-；当制备Linker为-CONR 4-的式1所示的化合物时，L 3和L 4独立地选自-NHR 4、-MCl中的一个且两者互不相同，M为-CO-；当制备Linker为-NR 4CH 2-的式1所示的化合物时，L 3和L 4独立地选自-NHR 4、-MCl中的一个且两者互不相同，M为-CH 2-；当制备Linker为-NR 4-的式1所示的化合物时，L 3和L 4独立选自-NHR 4、卤素中的一个且两者互不相同。
本申请第三方面还提供一种上述任一所述的胺类合物在制备雄激素受体拮抗药物中的应用。发明人对上述具有式1结构的双芳香基胺类化合物进行了研究，并且惊奇的发现，该类化合物能够抑制雄激素受体的活性，化合物27，30，32，43，46-48，54，56在浓度1μM时对AR的转录活性的抑制作用，RLU值小于50％；化合物49，51-54，63-66在浓度5μM时对AR的转录活性的抑制作用，RLU值小于40％；化合物2-4，7，10，11，15，23-25，27，29，30，32-34，38，39在浓度10μM时对AR的转录活性的抑制作用，RLU值小于30％。上述这些化合均表现出强的对雄激素受体的抑制作用，并且其中编号为11、15、23、30以及32的化合物，其抑制雄激素受体的活性与恩杂鲁胺相当，编号为51、52、54、56、57、64-66的化合物，其抑制雄激素受体的活性明显优于恩杂鲁胺。此外，编号为23、27的化合物不仅对AR-F876Ld转录活性具有很好的抑制作用，而且与恩杂鲁胺相比，能够克服恩杂鲁胺由于雄激素受体的876为氨基酸突变而引起的耐药问题。因此，本申请的具有式1结构的双芳香基胺类化合物能够用于制备雄激素受体拮抗药物。
本申请第四方面还提供一种雄激素受体拮抗药物组合物，包括作为雄激素受体拮抗有效成分的上述任一所述的双芳香基胺类化合物，还包括药剂学上可接受的药物辅料。
可将上述取代的双芳香基胺类化合物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。
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；阿拉伯胶；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)。
本申请的雄激素受体拮抗药物组合物中的双芳香基胺类化合物为单位制剂。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，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》,2004Sep；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。
该雄激素受体拮抗药物组合物的给药方式例为：静脉、腹腔内注射，或灌胃、口服等。
本申请第五方面还提供一种雄激素失调的治疗方法，具体可以是向患者施用包括本申请双芳香基胺类化合物的雄激素受体拮抗药物组合物。通过向患者施用包括本申请双芳香基胺类化合物的雄激素受体拮抗药物组合物，可以治疗由于雄激素失调导致的前列腺增生症或前列腺癌、性欲亢进、女性痤疮、脂溢性皮炎、多毛症、脱发等病症。
本申请提供的双芳香基胺类化合物，对雄激素受体有明显的抑制活性，其中一些化合物对前列腺癌细胞也有明显的抑制活性，可以作为雄激素受体拮抗剂治疗前列腺癌。此外，该双芳香基胺类化合物的合成路线简单，原料易得，成本较低，有利于工业化实施。
附图说明
图1a为本申请化合物23的AR抑制活性曲线图；
图1b为申请化合物23对在PC-3中表达的876位氨基酸突变DAR转录活性的影响；
图2a为本申请化合物27的AR抑制活性曲线图；
图2b为申请化合物27对在PC-3中表达的876位氨基酸突变DAR转录活性的影响。
具体实施方式
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。
实施例1化合物1的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(100.0mg,0.63mmol)溶于无水DMF(5.0 mL)中，加入无水K 2CO 3(130.2mg,0.94mmol)，冰水浴条件(0℃)下，向该溶液中加入4-乙酰基苯磺酰氯(164.8mg,0.75mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物1(112.4mg，收率：52.3％)。
化合物1通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 12.88(s,1H),10.49(s,1H),8.08(d,J＝7.0Hz,2H),7.91(d,J＝6.5Hz,2H),7.76(s,1H),7.61(s,1H),7.45(s,1H),7.25(s,1H),7.03(d,J＝6.0Hz,1H),6.58(s,1H),2.57(s,3H)；HRMS calcd for C 17H 16O 3N 3S[M+H] +342.09069；Found 342.09061.
实施例2化合物2的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(100.0mg,0.63mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(130.2mg,0.94mmol)，冰水浴条件(0℃)下，向该溶液中加入4-氟苯磺酰氯(146.9mg,0.75mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物2(140.3mg，收率：70.2％)。
化合物2通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 12.88(s,1H),10.32(s,1H),7.83(t,J＝5.5Hz,2H),7.76(s,1H),7.59(s,1H),7.46(d,J＝7.5Hz,1H),7.39(t,J＝8.5Hz,2H),7.25(t,J＝7.5Hz,1H),7.01(d,J＝7.5Hz,1H),6.58(s,1H)；HRMS calcd for C 15H 13O 2N 3FS[M+H] +318.07070；Found 318.07101.
实施例3化合物3的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(100.0mg,0.63mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(130.2mg,0.94mmol)，冰水浴条件(0℃)下，向该溶液中加入4-氯苯磺酰氯(159.3mg,0.75mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物3(118.5mg，收率：56.4％)。
化合物3通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 12.89(s,1H),10.39(s,1H),7.77(s,1H),7.76(s,2H),7.63(d,J＝8.5Hz,2H),7.59(s,1H),7.46(d,J＝7.0Hz,1H),7.26(t,J＝7.0Hz,1H),7.01(d,J＝7.5Hz,1H),6.58(s,1H)；HRMS calcd for C 15H 13O 2N 3ClS[M+H] +334.04115；Found 334.04144.
实施例4化合物4的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(110.0mg,0.69mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(143.2mg,1.04mmol)，冰水浴条件(0℃)下，向该溶液中加入4-氰基苯磺酰氯(209.2mg,1.04mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC 显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物4(170.6mg，收率：76.3％)。
化合物4通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 12.90(s,1H),10.57(s,1H),8.04(d,J＝7.5Hz,2H),7.92(d,J＝6.5Hz,2H),7.76(s,1H),7.59(s,1H),7.48(s,1H),7.27(s,1H),7.01(d,J＝6.5Hz,1H),6.59(s,1H)；HRMS calcd for C 16H 13O 2N 4S[M+H] +325.07537；Found 325.07426.
实施例5化合物5的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(200.0mg,1.26mmol)溶于无水DMF(7.0mL)中，加入无水K 2CO 3(260.4mg,1.89mmol)，冰水浴条件(0℃)下，向该溶液中加入4-硝基苯磺酰氯(418.2mg,1.89mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物5(309.1mg，收率：71.3％)。
化合物5通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 12.89(s,1H),10.64(s,1H),8.37(d,J＝8.5Hz,2H),8.02(d,J＝8.0Hz,2H),7.76(s,1H),7.61(s,1H),7.49(d,J＝7.0Hz,1H),7.27(t,J＝7.5Hz,1H),7.04(d,J＝7.0Hz,1H),6.60(s,1H)；HRMS calcdfor C 15H 13O 4N 4S[M+H] +345.06520；Found 345.06390.
实施例6化合物6的制备
化合物5(90.0mg,0.26mmol)加入甲醇溶剂(25.0mL)中，加入Pd/C(10％,98.0mg)后通入H 2(35Psi)，室温反应2-3h，得到透明油状物6(50.4mg，收率：61.7％)。
化合物6通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,MeOD-d 6)δppm 7.64(s,1H),7.47(s,1H),7.45(m,3H),7.24(t,J＝7.5Hz,1H),7.05(d,J＝7.5Hz,1H),6.59(s,1H),6.57(s,2H),5.50(s,1H)；HRMS calcd for C 15H 15O 2N 4S[M+H] +315.09102；Found 315.08978.
实施例7化合物7的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(100.0mg,0.63mmol)溶于超干DMF(5.0mL)中，加入无水K 2CO 3(130.2mg,0.94mmol)，冰水浴条件(0℃)下，向该溶液中加入4-三氟甲基苯磺酰氯(184.6mg,0.75mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物7(153.1mg，收率：66.2％)。
化合物7通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 12.89(s,1H),10.55(s,1H),7.96(s,4H),7.76(s,1H),7.60(s,1H),7.48(d,J＝7.0Hz,1H),7.27(t,J＝7.5Hz,1H),7.02(d,J＝7.5Hz,1H),6.58(s,1H)；HRMS calcd for C 16H 13O 2N 3F 3S[M+H] +368.06751；Found 368.06818.
实施例8化合物8的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(50.0mg,0.31mmol)溶于超干DMF(2.0mL)中，加入无水K 2CO 3(65.1mg,0.47mmol)，冰水浴条件(0℃)下，向该溶液中加入4-异丙氧基苯磺酰氯(88.6mg,0.38mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物8(73.1mg，收率：66.0％)。
化合物8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：
1HNMR(500MHz,DMSO-d 6)δppm 12.87(s,1H),10.15(s,1H),7.76(s,1H),7.67(d,J＝8.0Hz,2H),7.58(s,1H),7.42(s,1H),7.23(s,1H),7.01(d,J＝8.5Hz,3H),6.56(s,1H),4.66(t,J＝7.5Hz,1H),1.23(d,J＝5.5Hz,6H)； 13CNMR(101MHz,DMSO-d 6)δppm160.9,149.6,138.4,134.8,130.8,130.0,129.4,129.0,121.0,118.7,116.5,115.5,101.8,70.0,21.7；HRMS calcdfor C 18H 20O 3N 3S[M+H] +358.12199；Found 358.12268.
实施例9化合物9的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(113.0mg,0.71mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(196.7mg,1.43mmol)，冰水浴条件(0℃)下，向该溶液中加入1,1’-二基苯-4-磺酰氯(270.1mg,1.07mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物9(193.6mg，收率：72.7％)。
化合物9通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 12.88(s,1H),10.39(s,1H),7.85(s,4H),7.75(s,1H),7.69(d,J＝7.0Hz,2H),7.65(s,1H),7.46(m,3H),7.42(d,J＝7.0Hz,1H),7.26(s,1H),7.07(d,J＝7.5Hz,1H),6.58(s,1H)；HRMS calcd for C 21H 18O 2N 3S[M+H] +376.11142；Found 376.11041.
实施例10化合物10的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(100.0mg,0.63mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(130.2mg,0.94mmol)，冰水浴条件(0℃)下，向该溶液中加入4-甲氧基苯磺酰氯(156.0mg,0.75mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物10(155.1mg，收率：74.8％)。
化合物10通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 12.87(s,1H),10.16(s,1H),7.76(s,1H),7.71(d,J＝8.5Hz,2H),7.59(s,1H),7.42(d,J＝7.0Hz,1H),7.23(t,J＝7.5Hz,1H),7.05(d,J＝8.5Hz,2H),7.01(d,J＝8.0Hz,1H),6.57(s,1H),3.77(s,3H)；HRMS calcd for C 16H 16O 3N 3S[M+H] +330.09069；Found 330.09143.
实施例11化合物11的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(100.0mg,0.63mmol)溶于无水二氯甲烷(5.0mL)中，加入无水K 2CO 3(130.2mg,0.94mmol)，冰水浴条件(0℃)下，向该溶液中加入3-氟-4-甲氧基苯磺酰氯(169.5mg,0.75mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(DCM/甲醇＝45/1V/V)得白色絮状物11(70.9mg，收率：32.4％)。
化合物11通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 12.89(s,1H),10.28(s,1H),7.73(s,1H),7.57(m,3H),7.45(d,J＝7.5Hz,1H),7.28(dt,J＝18.5,8.0Hz,2H),7.02(d,J＝7.5Hz,1H),6.58(s,1H),3.86(s,3H)；HRMS calcd for C 16H 15O 3N 3FS[M+H] +348.08127；Found 348.08170.
实施例12化合物12的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(100.0mg,0.63mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(130.2mg,0.94mmol)，冰水浴条件(0℃)下，向该溶液中加入2，4-二甲氧基苯磺酰氯(178.6mg,0.75mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物12(96.2mg，收率：42.5％)。
化合物12通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
HNMR(500MHz,DMSO-d 6)δppm 12.85(s,1H),9.87(s,1H),7.75(s,1H),7.69(d,J＝8.5Hz,1H),7.58(s,1H),7.36(d,J＝7.0Hz,1H),7.18(t,J＝7.1Hz,1H),6.99(d,J＝8.0Hz,1H),6.62(s,1H),6.56(d,J＝10.0Hz,1H),6.53(s,1H),3.87(s,3H),3.77(s,3H)；HRMS calcd for C 17H 18O 4N 3S[M+H] +360.10125；Found 360.10187.
实施例13化合物13的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(105.0mg,0.66mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(136.7mg,0.99mmol)，冰水浴条件(0℃)下，向该溶液中加入2，3，4-三甲氧基苯磺酰氯(229.0mg,0.86mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物13(175.4mg，收率：68.3％)。
化合物13通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 12.91(s,1H),10.23(s,1H),7.77(s,1H),7.66(s,1H),7.46(d,J＝6.3Hz,1H),7.27(s,1H),7.06(s,3H),6.59(s,1H),3.75(s,6H),3.66(s,3H)；HRMS calcd for C 18H 20O 5N 3S[M+H] +390.11182；Found 390.11027.
实施例14化合物14的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(100.0mg,0.63mmol)溶于无水二氯甲烷(5.0mL)中，加入无水K 2CO 3(130.2mg,0.94mmol)，冰水浴条件(0℃)下，向该溶液中加入3-三氟甲基-4-氟苯磺酰氯(198.2mg,0.75mmol)，0-4℃下反应30min后转为室温反应， 6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(DCM/甲醇＝50/1V/V)得白色絮状物14(53.2mg，收率：21.9％)。
化合物14通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 12.91(s,1H),10.48(s,1H),8.09(d,J＝4.5Hz,2H),7.73(t,J＝9.5Hz,2H),7.57(s,1H),7.51(d,J＝7.5Hz,1H),7.29(t,J＝8.0Hz,1H),7.01(d,J＝7.5Hz,1H),6.59(s,1H)；HRMS calcd for C 16H 12O 2N 3F 4S[M+H] +386.05809；Found 386.05847.
实施例15化合物15的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(100.2mg,0.63mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(130.2mg,0.94mmol)，冰水浴条件(0℃)下，向该溶液中加入3-硝基-4-三氟苯磺酰氯(180.8mg,0.75mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得黄色絮状物15(95.6mg，收率：41.9％)。
化合物15通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm12.90(s,1H),10.59(s,1H),8.48(d,J＝4.5Hz,1H),8.11(d,J＝6.0Hz,1H),7.78(m,2H),7.61(s,1H),7.51(d,J＝4.5Hz,1H),7.29(s,1H),7.05(d,J＝7.5Hz,1H),6.60(s,1H)；HRMS calcd for C 15H 12O 4N 4FS[M+H] +363.05578；Found 363.05591.
实施例16化合物16的制备
化合物15(50.0mg,0.14mmol)加入甲醇溶剂(15.0mL)中，加入Pd/C(10％,60.0mg)后通入H 2(35Psi)，室温反应3-4h，得到透明油状物16(27.6mg，收率：59.4％)。
化合物16通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,MeOD-d 6)δppm 7.64(s,1H),7.48(s,1H),7.47(d,J＝8.0Hz,1H),7.27(d,J＝8.0Hz,1H),7.24(d,J＝6.5Hz,1H),7.07(d,J＝7.5Hz,1H),7.02–6.98(m,2H),6.58(s,1H),5.49(s,1H)；HRMS calcd for C 15H 14O 2N 4FS[M+H] +333.08160；Found 333.08075.
实施例17化合物17的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(107.3mg,0.67mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(139.3mg,1.01mmol)，冰水浴条件(0℃)下，向该溶液中加入3-氯-4-氰苯磺酰氯(206.5mg,0.87mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色固体粉末17(202.2mg，收率：84.3％)。
化合物17通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 12.93(s,1H),10.68(s,1H),8.18(d,J＝8.0Hz,1H), 8.04(s,1H),7.84(d,J＝7.5Hz,1H),7.78(s,1H),7.60(s,1H),7.52(d,J＝6.0Hz,1H),7.30(s,1H),7.03(d,J＝7.5Hz,1H),6.62(s,1H)；HRMS calcd for C 16H 12O 2N 4ClS[M+H] +359.03640.Found 359.03510.
实施例18化合物18的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(100.3mg,0.63mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(130.2mg,0.94mmol)，冰水浴条件(0℃)下，向该溶液中加入3-三氟甲基-4-氰苯磺酰氯(220.5mg,0.82mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色固体粉末18(196.6mg，收率：79.6％)。
化合物18通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 12.93(s,1H),10.71(s,1H),8.37(d,J＝7.5Hz,1H),8.21(s,1H),8.18(d,J＝7.5Hz,1H),7.77(s,1H),7.58(s,1H),7.53(d,J＝6.5Hz,1H),7.30(s,1H),7.01(d,J＝7.0Hz,1H),6.60(s,1H)；HRMS calcd for C 17H 12O 2N 4F 3S[M+H] +393.06276；Found 393.06146.
实施例19化合物19的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(103.3mg,0.65mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(134.1mg,0.97mmol)，冰水浴条件(0℃)下，向该溶液中加入6-氯-吡啶-3-磺酰氯(178.6mg,0.84mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色固体粉末19(163.1mg，收率：75.1％)。
化合物19通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 12.91(s,1H),10.59(s,1H),8.73(s,1H),8.13(d,J＝7.5Hz,1H),7.77(s,1H),7.74(d,J＝8.5Hz,1H),7.60(s,1H),7.52(d,J＝5.5Hz,1H),7.30(s,1H),7.03(d,J＝7.5Hz,1H),6.61(s,1H)；HRMS calcd for C 14H 12O 2N 4ClS[M+H] +335.03640；Found 335.03543.
实施例20化合物20的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(103.3mg,0.65mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(134.1mg,0.97mmol)，冰水浴条件(0℃)下，向该溶液中加入4-甲基氨基甲酰基苯磺酰氯(196.0mg,0.84mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色固体粉末20(169.0mg，收率：73.0％)。
化合物20通过核磁共振氢谱( 1HNMR)表征如下：
1HNMR(500MHz,DMSO-d 6)δ12.88(s,1H),10.41(s,1H),8.58(s,1H),7.92(d,J＝8.0Hz,2H),7.85(s,2H),7.76(s,1H),7.60(s,1H),7.45(d,J＝6.7Hz,1H),7.25(d,J＝7.3Hz, 1H),7.01(d,J＝6.8Hz,1H),6.58(s,1H),2.75(d,J＝4.1Hz,3H).
实施例21化合物21的制备
在无水条件下，将3-(1H-吡唑-5-基)苯胺(103.3mg,0.65mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(134.1mg,0.97mmol)，冰水浴条件(0℃)下，向该溶液中加入4-甲基-苯磺酰氯(160.0mg,0.84mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色固体粉末21(172.0mg，收率：85.0％)。
化合物21通过核磁共振氢谱( 1HNMR)表征如下：
1H NMR(500MHz,DMSO-d 6)δ12.85(s,1H),10.25(s,1H),7.72(s,1H),7.67(d,J＝7.5Hz,2H),7.57(s,1H),7.42(d,J＝7.0Hz,1H),7.33(d,J＝7.5Hz,1H),7.24(m,1H),7.01(d,J＝7.5Hz,1H),6.55(s,1H),2.31(s,3H).
实施例22化合物22的制备
在无水条件下，将3-(1H-吡唑-4-基)苯胺(103.3mg,0.65mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(134.1mg,0.97mmol)，冰水浴条件(0℃)下，向该溶液中加入4-甲氧基-苯磺酰氯(173.0mg,0.84mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示3-(1H-吡唑-4-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色固体粉末22(171.0mg，收率：80.0％)。
化合物22通过核磁共振氢谱( 1HNMR)表征如下：
1H NMR(500MHz,DMSO-d 6)δ12.96(s,1H),10.12(s,1H),8.05(s,1H),7.72(d,J＝8.5Hz,3H),7.24(d,J＝13.5Hz,2H),7.19(m,1H),7.06(d,J＝7.5Hz,2H),6.88(d,J＝7.0Hz,1H),3.78(s,3H).
实施例23化合物23的制备
在无水条件下，将4-(1H-吡唑-5-基)苯胺(132.4mg,0.83mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(172.3mg,1.25mmol)，冰水浴条件(0℃)下，向该溶液中加入4-甲氧基-苯磺酰氯(190.6mg,1.08mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示4-(1H-吡唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1/1V/V)得白色固体粉末23(192.8mg，收率：70.6％)。
化合物23通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 12.81(s,1H),10.17(s,1H),7.73(s,1H),7.69(d,J＝5.0Hz,2H),7.65(s,2H),7.10(s,2H),7.05(d,J＝6.5Hz,2H),6.59(s,1H),3.77(s,3H)；HRMS calcd for C 16H 16O 3N 3S[M+H] +330.09069；Found 330.08942.
实施例24化合物24的制备
在无水条件下，将4-(1H-咪唑-1-基)苯胺(105.0mg,0.66mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(136.7mg,0.99mmol)，冰水浴条件(0℃)下，向该溶液中加入4-甲氧基-苯磺酰氯(177.4mg,0.86mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC 显示4-(1H-咪唑-1-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色固体粉末24(149.6mg，收率：68.9％)。
化合物24通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 10.35(s,1H),8.13(s,1H),7.71(d,J＝8.0Hz,2H),7.63(s,1H),7.51(d,J＝8.0Hz,2H),7.18(d,J＝8.0Hz,2H),7.08(s,1H),7.06(s,2H),3.78(s,3H)；HRMS calcd for C 16H 16O 3N 3S[M+H] +330.09069；Found 330.08980.
实施例25化合物25的制备
在无水条件下，将4-(噻唑-2-基)苯胺(115.0mg,0.65mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(135.1mg,0.98mmol)，冰水浴条件(0℃)下，向该溶液中加入4-甲氧基-苯磺酰氯(175.3mg,0.85mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示4-(噻唑-2-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物25(183.8mg，收率：81.7％)。
化合物25通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
1HNMR(500MHz,DMSO-d 6)δppm 10.52(s,1H),7.85(s,1H),7.81(d,J＝8.0Hz,2H),7.74(d,J＝8.0Hz,2H),7.71(s,1H),7.21(d,J＝7.5Hz,2H),7.07(d,J＝8.0Hz,2H),3.78(s,3H)；HRMS calcd for C 16H 15O 3N 2S 2[M+H] +347.05186；Found 347.05060.
实施例26化合物26的制备
在无水条件下，将4-(异恶唑-5-基)苯胺(160.0mg,1.0mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(204.0mg,1.5mmol)，冰水浴条件(0℃)下，向该溶液中加入4-甲氧基-苯磺酰氯(247.0mg,1.2mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示4-(异恶唑-5-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝3/1V/V)得白色絮状物26(201.0mg，收率：61.0％)。
化合物26通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下：
11H NMR(500MHz,DMSO-d 6)δ10.54(s,1H),8.59(d,J＝1.5Hz,1H),7.74(d,J＝8.5Hz,4H),7.23(d,J＝8.5Hz,2H),7.07(d,J＝8.5Hz,2H),6.86(d,J＝1.5Hz,1H),3.79(s,3H)；HRMS calcd for C 16H 15N 2O 4S[M+H] +331.07450；Found 331.07470.
实施例27化合物27的制备
在无水条件下，将4-(1H-吡唑-4-基)苯胺(159.0mg,1.0mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(166.0mg,1.2mmol)，冰水浴条件(0℃)下，向该溶液中加入4-甲氧基-苯磺酰氯(247.0mg,1.2mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示4-(1H-吡唑-4-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物27(223.0mg，收率：68.0％)。
化合物27通过核磁共振氢谱( 1HNMR)表征如下：
1H NMR(500MHz,DMSO-d 6)δ12.86(s,1H),10.04(s,1H),8.06(s,1H),7.81(s,1H), 7.68(d,J＝8.5Hz,2H),7.45(d,J＝8.0Hz,2H),7.05(d,J＝8.5Hz,4H),3.78(s,3H).
实施例28化合物28的制备
在无水条件下，将4-(N-甲基-吡唑-3-基)苯胺(120.0mg,0.69mmol)溶于无水DMF(5.0mL)中，加入无水K 2CO 3(190.0mg,1.38mmol)，冰水浴条件(0℃)下，向该溶液中加入4-甲氧基-苯磺酰氯(186.0mg,1.30mmol)，0-4℃下反应30min后转为室温反应，6-8h后，TLC显示4-(N-甲基-吡唑-3-基)苯胺消失，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物28(192.0mg，收率：56.0％)。
化合物28通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下：
1HNMR(CDCl 3,500MHz)δppm 3.78(3H,s),3.91(3H,s),6.45(1H,d,J＝2.0Hz),6.85(2H,d,J＝9.0Hz),6.99(1H,s),7.08(2H,d,J＝9.0Hz),7.34(1H,s),7.63(2H,d,J＝9.0Hz),7.69(2H,d,J＝9.0Hz)； 13CNMR(CDCl 3,125Hz)δppm 39.1,55.6,102.8,114.2,122.1,126.5,129.5,136.0,150.8,163.2.
实施例29化合物29的制备
Figure PCTCN2021108229-appb-000020
1、在无水条件下，将3-氨基-5-(4-氨基苯基)1H-吡唑-1-羧酸叔丁基酯(180.0mg,0.65mmol)溶于无水吡啶(5.0mL)中，冰水浴条件(0℃)下，向该溶液中加入4-甲氧基-苯磺酰氯(135.0mg,0.62mmol)，0-4℃下反应30min后转为室温反应，6-8h后，停止反应。反应液用乙酸乙酯稀释，水相用PH试纸测试，用NaHCO 3饱和溶液调PH在9-11之间，水洗，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物29-1(125.0mg，收率：43.0％)。
2、将化合物29-1溶于二氯甲烷(3.0mL)中，0℃下加入三氟乙酸(1.0mL)，搅拌30min，减压除溶剂，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物29(89.0mg，收率：92.0％)。
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：
1HNMR(CDCl 3,500MHz)δppm 3.78(3H,s),3.91(3H,s),6.45(1H,d,J＝2.0Hz),6.85(2H,d,J＝9.0Hz),6.99(1H,s),7.08(2H,d,J＝9.0Hz),7.34(1H,s),7.63(2H,d,J＝9.0Hz),7.69(2H,d,J＝9.0Hz)； 13CNMR(CDCl 3,125Hz)δppm 39.1,55.6,102.8,114.2,122.1,126.5,129.5,136.0,150.8,163.2.
实施例30化合物30的制备
无水条件下，将4-(1H-吡唑-3-基)苯胺(159.0mg,1.0mmol)溶于干燥的吡啶(5.0mL)中，在冰水浴条件下(0℃)向反应液中加入4-氯-苯磺酰氯(300.0mg,1.0mmol)，室温下反应6-8h，停止反应。反应液用乙酸乙酯稀释，水洗、饱和NaCl溶液洗，无水Na 2SO 4干燥，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物30(289.0mg，收率：87.0％)。
化合物30通过核磁共振氢谱( 1HNMR)表征如下：
1HNMR(500MHz,DMSO-d6)δ12.81(s,1H),10.35(s,1H),7.75(d,J＝8.5Hz,2H),7.67(m,2H),7.63(d,J＝8.5Hz,2H),7.11(d,J＝6.5Hz,2H),6.60(s,1H).
实施例31化合物31的制备
无水条件下，将4-(1H-吡唑-3-基)苯胺(159.0mg,1.0mmol)溶于干燥的吡啶(5.0mL)中，在冰水浴条件下(0℃)向反应液中加入3-氟-4-甲氧基-苯磺酰氯(224.0mg,1.0mmol)，室温下反应6-8h，停止反应。反应液用乙酸乙酯稀释，水洗、饱和NaCl溶液洗，无水Na 2SO 4干燥，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物31(301.0mg，收率：87.0％)。
化合物31通过核磁共振氢谱( 1HNMR)表征如下：
1H NMR(500MHz,DMSO-d 6)δ12.81(s,1H),10.22(s,1H),7.73(s,1H),7.68(s,2H),7.56(s,2H),7.30(s,1H),7.12(s,2H),6.60(s,1H),3.87(s,3H).
实施例32化合物32的制备
无水条件下，将4-(1H-吡唑-3-基)苯胺(159.0mg,1.0mmol)溶于干燥的吡啶(5.0mL)中，在冰水浴条件下(0℃)向反应液中加入3-硝基-4-氟-苯磺酰氯(239.0mg,1.0mmol)，室温下反应6-8h，停止反应。反应液用乙酸乙酯稀释，水洗、饱和NaCl溶液洗，无水Na 2SO 4干燥，柱层析分离纯化(PE/EA＝1.5/1V/V)得黄色絮状物31(322.0mg，收率：89.0％)。
化合物32通过核磁共振氢谱( 1HNMR)表征如下：
1H NMR(500MHz,DMSO-d 6)δ12.80(s,1H),10.22(s,1H),8.28(s,1H),7.74(m,4H),7.62(d,J＝7.0Hz,2H),7.23(s,1H),6.64(s,1H).
实施例33化合物33的制备
无水条件下，将4-甲基-3-(1H-吡唑-3-基)苯胺(173.0mg,1.0mmol)溶于干燥的吡啶(5.0mL)中，在冰水浴条件下(0℃)向反应液中加入3-氟-4-甲氧基-苯磺酰氯(224.0mg,1.0mmol)，室温下反应6-8h，停止反应。反应液用乙酸乙酯稀释，水洗、饱和NaCl溶液洗，无水Na 2SO 4干燥，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物33(259.0mg，收率：72.0％，有近0.3的异构体)。
化合物33通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下：
1HNMR(DMSO,500MHz)δppm 2.32(3H,s),3.86(3H,s),6.39(1H,s),6.97(1H,d,J＝9.0Hz),7.12(1H,d,J＝9.0Hz),7.30(2H,m),7.55(2H,m),7.78(1H,s),10.10(1H,s),12.92(1H,s)； 13CNMR(DMSO,125Hz)δppm 20.5,56.3,104.4,113.9,114.2,114.3,119.2,124.4,128.9,131.4,135.1,149.7,150.7.
实施例34化合物34的制备
无水条件下，将4-甲氧基-3-(1H-吡唑-3-基)苯胺(189.0mg,1.0mmol)溶于干燥的吡啶(5.0mL)中，在冰水浴条件下(0℃)向反应液中加入3-氟-4-甲氧基-苯磺酰氯(224.0mg,1.0mmol)，室温下反应6-8h，停止反应。反应液用乙酸乙酯稀释，水洗、饱和NaCl溶液洗，无水Na 2SO 4干燥，柱层析分离纯化(PE/EA＝1.5/1V/V)得白色絮状物34(2110mg，收率：56.0％)。
化合物34通过核磁共振氢谱( 1HNMR)表征如下：
1HNMR(DMSO,500MHz)δppm 3.78(3H,s),3.86(3H,s),6.67(1H,s),6.97(2H,m),7.30(1H,t,J＝9.0Hz),7.49(2H,m),7.71(1H,d,J＝10.0Hz),9.89(1H,s),12.84(1H,s).
实施例35化合物35的制备
Figure PCTCN2021108229-appb-000021
1、将2-氟-4-碘苯胺(237mg,1.0mmol)和化合物A(278mg,1.0mmol)加入微波反应管(20mL)中,加入二氧六环(3mL)和水(0.3mL)使样品溶解，加入2-双环己基膦-2',6'-二甲氧基联苯(16mg,0.04mmol),K 3PO 4(424mg,2.0mmol),Pd 2(dba) 3(18mg,0.02mmol),封上瓶盖后，放入微波反应仪中反应，温度130℃，反应时间90min后停止反应。反应液乙酸乙酯提取，水和饱和食盐水依次萃洗，无水硫酸钠干燥，柱层析纯化(PE/EA＝3/1-1/1V/V),得化合物35-1(223mg，86％)。
化合物35-1通过核磁共振氢谱( 1HNMR)表征如下：
1HNMR(CDCl 3,500MHz)δppm 1.54(2H,m),1.56(1H,m),1.57(1H,m),1.60(1H,d,J＝9.0Hz),2.05(1H,m),2.55(1H,m),3.60(1H,t,J＝11.0Hz),3.89(3H,s),4.12(1H,t,J＝7.5Hz),5.17(1H,d,J＝10.0Hz),6.25(1H,s),6.83(1H,d,J＝7.5Hz),7.09(1H,J＝6.5Hz),7.28(1H,s),7.56(1H,s).
2、化合物35-1(261mg,1.0mmol)溶于无水吡啶(5.0mL)，0℃下加入4-甲氧基-苯磺酰氯(207mg,1.0mmol)，室温反应8h，减压除去溶剂，剩余物乙酸乙酯提取，盐酸溶液、水和饱和食盐水依次萃洗，无水硫酸钠干燥，柱层析纯化(PE/EA＝2/1)，得白色絮状物35-2(350mg，收率：81％)。
化合物35-2通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下：
1HNMR(CDCl 3,500MHz)δppm 1.58(2H,m),1.74(1H,m),1.83(1H,d,J＝9.0Hz),2.06(1H,m),2.55(1H,m),3.56(1H,t,J＝11.0Hz),3.84(3H,s),4.11(1H,t,J＝7.5Hz),5.10(1H,d,J＝10.0Hz),6.28(1H,s),6.89(1H,s),6.93(2H,d,J＝9.0Hz),7.22(2H,t,J＝6.5Hz),7.56(1H,s),7.64(1H,t,J＝8.5Hz),7.79(2H,d,J＝8.5Hz)； 13CNMR(CDCl 3,100Hz)δppm23.0,24.9,29.6,55.7,67.7,84.4,106.9,114.4,116.0,116.2,122.3,125.2,128.0,129.5,130.4,139.6,142.4,152.0,154.5,163.6；
3、化合物35-2(200mg，0.46mmol)溶于无水乙醇中(5mL),0℃加入HCl/EtOAc溶液(1.0M，1.5mL),搅拌12h至反应完全，减压除去溶剂，加入CH 2Cl 2,出现白色固体，过滤得化合物35(146mg，收率：92％)。
化合物35-2通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下：
1HNMR(DMSO,500MHz)δppm 3.80(3H,s),6.72(1H,s),7.07(2H,d,J＝7.5Hz),7.26(1H,t,J＝8.0Hz),7.56(2H,d,J＝10.0Hz),7.66(2H,d,J＝7.5Hz),7.74(1H,s),10.02(1H,s)； 13CNMR(DMSO-d 6,150Hz)δppm 55.7,102.4,112.3,112.4,114.3,121.2,123.4,123.5,126.6,131.5,154.9,156.6,162.5.
实施例36化合物36的制备
Figure PCTCN2021108229-appb-000022
1、将3-氯-5-硝基吡啶(200mg,1.26mmol)和化合物B(155mg,1.39mmol)加入微波反应管中,加入DMF(3mL)和水(0.3mL)使样品溶解，加入K 3PO 4(535mg,2.52mmol),氩气鼓泡15min后，加入Pd(PPh 3) 4(146mg,0.126mmol),封上瓶盖后，放入微波反应仪中在130℃反应60min。反应液乙酸乙酯提取，水和饱和食盐水依次萃洗，无水硫酸钠干燥，柱层析纯化(CH 2Cl 2/MeOH＝30/1V/V),得化合物36-1(150mg，收率：63％)。
化合物36-1通过核磁共振氢谱( 1HNMR)表征如下：
1HNMR(DMSO-d 6,500MHz)δppm 7.08(1H,s),7.92(1H,s),8.85(1H,s),9.27(1H,s),9.42(1H,s),13.30(1H,s).
2、将化合物36-1(150mg,0.79mmol)溶于MeOH/EtOAc(2:1,30mL)，加入Pd/C(10％,25mg)，H 2(20psi)氢化还原2h，减压除去溶剂得化合物36-2(120mg,收率：95％)。
化合物36-2通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下：
1HNMR(CD 3OD,500MHz)δppm 4.92(2H,br s),6.64(1H,s),7.44(1H,s),7.66(1H,s),7.92(1H,s),8.22(1H,s)； 13CNMR(CD 3OD,100Hz)δppm 103.6,119.4,129.9,133.0,133.7,135.9,136.3,146.4.
3、化合物36-2(110mg,0.68mmol)溶于无水吡啶(3.0mL)，0℃下加入3-氟-4-甲氧基-苯磺酰氯(154mg,0.68mmol)，室温反应8h，减压除去溶剂，剩余物用C18柱纯化(MeOH/H 2O＝2％-95％)，得白色固体36(75mg，收率：32％)。
化合物36通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下：
1HNMR(CD 3OD,500MHz)δppm 3.87(3H,s),6.71(1H,d,J＝3.0Hz),7.17(1H,t,J＝10.0Hz),7.53(2H,m),7.72(1H,s),7.98(1H,s),8.19(1H,d,J＝3.0Hz),8.66(1H,s)； 13CNMR(CD 3OD,100Hz)δppm 56.9,103.7,114.3,114.4,115.7,115.9,125.8,126.3,131.4,136.7,141.5,143.3,151.6,153.1,153.2,154.1.
实施例37化合物37的制备
Figure PCTCN2021108229-appb-000023
1、将2-溴-3-甲基-4-硝基吡啶(217mg,1.0mmol)和化合物B(168mg,1.50mmol)加入微波反应管中,加入DMF(3mL)和水(0.3mL)使样品溶解，加入K 3PO 4(535mg,2.52mmol),氩气鼓泡15min后，加入Pd(PPh 3) 4(146mg,0.126mmol),封上瓶盖后，放入微波反应仪中在130℃反应60min。反应液乙酸乙酯提取，水和饱和食盐水依次萃取洗涤，无水硫酸钠干燥，柱层析纯化(PE/EtOAc＝1.5/1),得化合物37-1(120mg，收率：59％)。
化合物37-1的核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和质谱表征如下：
1HNMR(DMSO-d 6,500MHz)δppm 2.51(3H,s),6.88(1H,s),7.88(1H,s),8.33(1H,s),8.78(1H,s),13.24(1H,s)； 13CNMR(DMSO-d 6,100Hz)δppm 103.4,111.8,124.3,130.5,149.4,152.6,153.9,154.9；ESIMS(+)m/z:205.1[M+H] +；
2、将化合物37-1(240mg,1.18mmol)溶于MeOH/EtOAc(2:1,30mL)，加入Pd/C(10％,25mg)，H 2(30psi)氢化还原2h，减压除去溶剂得化合物37-2(196mg,收率：95％)。
化合物37-2通过核磁共振氢谱( 1HNMR)和质谱表征如下：
1HNMR(CD 3OD,500MHz)δppm 2.02(3H,s),5.78(2H,br s),6.62(1H,s),7.17(1H,s),7.68(1H,s),7.90(1H,s),12.77(1H,s)；ESIMS(+)m/z:175.1[M+H] +.
3、将化合物37-2(170mg,0.97mmol)溶于无水吡啶(3.0mL)，0℃下加入4-甲氧基苯磺酰氯(201mg,0.97mmol)，室温反应8h，减压除去溶剂，剩余物柱层析纯化(MeOH/CH 2Cl 2＝1％-5％)，得白色固体37(283mg，收率：85％)。
化合物37通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下：
1HNMR(DMSO,500MHz)δppm 3.01(3H,s),3.84(3H,s),5.96(2H,s),6.94(1H,s),7.17(3H,m),7.93(3H,m),8.44(1H,s)； 13CNMR(DMSO,125Hz)δppm 14.0,55.9,104.2,107.7,115.2,116.8,127.5,130.0,133.4,147.5,149.2,153.1,157.5,164.2.
实施例38化合物38的制备
Figure PCTCN2021108229-appb-000024
1、将2-氨基-3-氯-4-碘-吡啶(250mg,1.0mmol)和化合物B(123mg,1.10mmol)加入微波反应管中,加入DMF(3mL)和水(0.3mL)使样品溶解，加入K 3PO 4(535mg,2.52mmol),氩气鼓泡15min后，加入Pd(PPh 3) 4(146mg,0.126mmol),封上瓶盖后，放入微波反应仪中在100℃反应60min。反应液乙酸乙酯提取，水和饱和食盐水依次萃取洗涤，无水硫酸钠干燥，柱层析纯化(PE/EtOAc＝1/1),得化合物38-1(78mg，收率：40％)。
化合物38-1通过核磁共振氢谱( 1HNMR)和质谱表征如下：
1HNMR(DMSO-d 6,500MHz)δppm 6.28(1H,s),6.84(1H,s),6.98(1H,s),7.86(1H,s),13.20(1H,s)；ESIMS(+)m/z:195.0[M+H] +
2、将化合物38-1(78mg,0.40mmol)溶于无水吡啶(2.0mL)，0℃下加入3-氟-4甲氧基苯磺酰氯(90mg,0.40mmol)，室温反应8h，减压除去溶剂，剩余物柱层析纯化(MeOH/CH 2Cl 2＝1％-5％)，得白色固体38(40mg，收率：26％)。
化合物38通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下：
1HNMR(CDCl 3,500MHz)δppm 3.95(3H,s),5.04(2H,s),6.94(1H,s),7.04(1H,s),7.07(1H,d,J＝8.0Hz),7.76(1H,d,J＝10.0Hz),7.86(1H,d,J＝8.0Hz),7.98(1H,s),8.14(1H,s)； 13CNMR(CDCl 3,100Hz)δppm 56.7,110.0,110.2,112.9,113.1,113.2,115.1,126.2,126.3,128.1,128.2,131.4,146.0,150.4,152.9,155.8.
实施例39化合物39的制备
将化合物38-1(78mg,0.40mmol)溶于无水吡啶(2.0mL)，0℃下加入4甲氧基苯磺酰氯(83mg,0.40mmol)，室温反应8h，减压除去溶剂，剩余物柱层析纯化(MeOH/CH 2Cl 2＝1％-5％)，得白色固体39(30mg，收率：21％)。
化合物39通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下：
1HNMR(DMSO,500MHz)δppm 3.85(3H,s),6.45(2H,s),6.76(1H,d,J＝5.0Hz),7.03(1H,s),7.18(2H,d,J＝9.0Hz),7.93(1H,d,J＝5.0Hz),7.99(2H,d,J＝9.0Hz),8.56(1H,d,J＝5.0Hz)； 13CNMR(DMSO,125Hz)δppm 56.0,110.2,110.9,112.7,115.2,127.0,130.4,132.8,137.4,146.0,152.6,156.6,164.4
实施例40化合物40的制备
Figure PCTCN2021108229-appb-000025
1、将2-溴-3-氯-5-硝基吡啶(237mg,1.0mmol)和化合物A(333mg,1.2mmol)加入微波反应管中,加入二氧六环(3mL)和水(0.3mL)使样品溶解，加入K 3PO 4(424mg,2.0 mmol),氩气鼓泡15min,加入Pd(PPh 3) 4(23mg,0.02mmol),封上瓶盖后，放入微波反应仪中在130℃反应90min。反应液乙酸乙酯提取，水和饱和食盐水依次萃取洗涤，无水硫酸钠干燥，柱层析纯化(PE/EA＝4/1-2/1),得化合物40-1(274mg，收率：89％)。
化合物40-1通过核磁共振氢谱( 1HNMR)表征如下：
1HNMR(CDCl 3,500MHz)δppm 1.64(3H,m),1.98(1H,d,J＝13.0Hz),2.07(1H,d,J＝10.5Hz),2.48(1H,m),3.45(1H,t,J＝11.0Hz),4.00(1H,d,J＝11.0Hz),5.04(1H,d,J＝8.5Hz),6.55(1H,s),7.67(1H,s),8.72(1H,s),9.56(1H,s).
2、将化合物40-1(240mg,0.78mmol)溶于MeOH/EtOAc(2:1,30mL)，加入Pd/C(10％,25mg)，H 2(20psi)氢化还原3h，减压除去溶剂得化合物40-2(227mg,收率：93％)。
化合物40-2通过质谱表征为：ESIMS(+)m/z:228.1[M+H] +.
3、将化合物40-2(200mg,0.72mmol)溶于无水吡啶(3.0mL)，0℃下加入4-甲氧基苯磺酰率(148mg,0.72mmol)，室温反应8h，减压除去溶剂，剩余物柱层析纯化(PE/EtOAc＝3/1)，得油状物40-3(170mg，收率：53％)。
化合物40-3通过核磁共振氢谱( 1HNMR)和质谱表征如下：
1HNMR(CDCl 3,500MHz)δppm 1.56(2H,m),1.71(1H,m),1.83(1H,d,J＝9.0Hz),2.04(1H,m),2.50(1H,m),3.53(1H,t,J＝11.0Hz),3.81(3H,s),4.00(1H,t,J＝7.5Hz),5.08(1H,d,J＝10.0Hz),6.86(2H,d,J＝8.5Hz),7.04(1H,s),7.55(2H,d,J＝8.5Hz),7.72(1H,s),7.99(1H,s),8.68(1H,s)；ESIMS(+)m/z:449.1[M+H] +.
4、将化合物40-3(150mg，0.34mmol)溶于无水乙醇中(5mL),0℃加入HCl/EtOAc溶液(1.0M，1.5mL),搅拌12h至反应完全，减压除去溶剂，加入CH 2Cl 2,出现白色固体，过滤得化合物40(110mg，收率：89％)。
化合物40通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下：
1HNMR(CDCl 3,500MHz)δppm 3.81(3H,s),6.84(1H,s),7.09(2H,d,J＝8.5Hz),7.47(2H,d,J＝8.5Hz),7.88(1H,s),7.95(1H,s),8.14(1H,s),11.42(1H,s),13.25(1H,s)； 13CNMR(DMSO,125Hz)δppm 55.8,105.6,114.4,123.1,128.7,129.8,131.4,131.5,139.0,141.6,144.7,145.0,163.9.
实施例41化合物41的制备
Figure PCTCN2021108229-appb-000026
1、将4-甲氧基苯胺(148mg,1.2mmol)和1,4-二溴苯(236mg,1.0mmol)溶于DMF(3.0mL),加入NaOtBu(144mg,1.5mmol)和(Cypf-tBu)PdCl 2(10mg,0.01mmol),混合物65℃加热反应3h至TLC监测原料点消失。减压除去溶剂，剩余物用EtOAC提取，水和饱和食盐水依次萃取洗涤，无水硫酸钠干燥，柱层析纯化(PE/EA＝6/1),得化合物41-1(78mg，收率：28％)。
化合物41-1通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下：
1HNMR(CDCl 3,500MHz)δppm 3.80(3H,s),6.76(2H,br s),6.87(2H,d,J＝8.5Hz),7.04(2H,br s),7.28(2H,d,J＝8.5Hz)； 13CNMR(DMSO,125Hz)δppm 55.6,111.0,114.2,117.0,122.7,124.4,132.1,135.0,144.5,155.7.ESIMS(+)m/z:278.0[M+H] +.
2、将化合物41-1(152mg,0.55mmol)和化合物A(229mg,0.85mmol)加入微波反应管中,加入二氧六环(3mL)和水(0.3mL)使样品溶解，加入K 3PO 4(234mg,1.1mmol),氩气鼓泡15min,加入Pd(PPh 3) 4(13mg,0.01mmol),封上瓶盖后，放入微波反应仪中反应，温度100℃，反应时间60min。反应液乙酸乙酯提取，水和饱和食盐水依次萃取洗涤，无水硫酸钠干燥，柱层析纯化(PE/EA＝4/1-2/1),得化合物41-2(130mg，68％)。
化合物41-2的核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和质谱表征如下：
1HNMR(CDCl 3,500MHz)δppm 1.53(2H,m),1.75(1H,m),1.85(1H,m),2.07(1H,m),2.57(1H,m),3.60(1H,t,J＝11.0Hz),3.81(3H,s),4.12(1H,d,J＝7.5Hz),5.23(1H,d,J＝10.0Hz),6.25(1H,s),6.91(1H,d,J＝8.0Hz),6.92(2H,br s),7.13(2H,br s),7.34(2H,s),7.58(1H,s)； 13CNMR(DMSO,125Hz)δppm 23.2,24.9,25.0,29.9,55.6,67.9,84.2,105.9,114.8,123.5,130.2,139.6；ESIMS(+)m/z:350.2[M+H] +.
3、将化合物41-2(130mg，0.37mmol)溶于无水乙醇中(2.0mL),0℃加入HCl/EtOAc溶液(1.0M，1.0mL),搅拌12h至反应完全，减压除去溶剂，加入CH 2Cl 2,出现白色固体，过滤得化合物41(98mg，收率：98％)。
化合物41通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和质谱表征如下：
1HNMR(DMSO,500MHz)δppm 3.72(3H,s),6.77(1H,m),6.90(2H,d,J＝10.5Hz),6.96(2H,d,J＝9.5Hz),7.10(2H,d,J＝9.5Hz),7.68(2H,m),7.95(1H,m)； 13CNMR(DMSO-d 6,150Hz)δppm 55.3,101.7,114.7,121.3,127.1,135.2,146.1,154.4；ESIMS(+)m/z:266.2[M+H] +.
实施例42化合物42的制备
Figure PCTCN2021108229-appb-000027
1、将N-甲基-对茴香胺(200mg,1.45mmol)和1,4-二溴苯(413mg,1.75mmol)溶于DMF(3.0mL),加入NaOtBu(209mg,2.17mmol)和(Cypf-tBu)PdCl 2(11mg,0.014mmol),混合物65℃加热反应5h至TLC监测原料点消失。减压除去溶剂，剩余物用EtOAC提取，水和饱和食盐水依次萃取洗涤，无水硫酸钠干燥，柱层析纯化(PE/EA＝10/1),得化合物42-1(110mg，收率26％)。
化合物42-1的核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和质谱表征如下：
1HNMR(CDCl 3,500MHz)δppm 3.21(3H,s),3.81(3H,s),6.62(2H,d,J＝8.5Hz),6.90(2H,d,J＝9.0Hz),7.06(2H,J＝9.0Hz),7.25(2H,d,J＝8.5Hz)； 13CNMR(CDCl 3,125Hz)δppm 40.6,55.6,110.1,114.8,116.8,126.8,131.7,141.7,148.9,156.9；ESIMS(+)m/z:292.0[M+H] +.
2、将化合物42-1(190mg,0.65mmol)和化合物A(278mg,0.97mmol)加入微波反应管中,加入二氧六环(3mL)和水(0.3mL)使样品溶解，加入K 3PO 4(275mg,1.3mmol),氩气鼓泡15min,加入Pd(PPh 3) 4(15mg,0.013mmol),封上瓶盖后，放入微波反应仪中反应，温度100℃，反应时间60min。反应液乙酸乙酯提取，水和饱和食盐水依次萃取洗涤，无水硫酸钠干燥，柱层析纯化(PE/EA＝4/1-2/1),得化合物42-2(170mg，收率：73％)。
化合物42-2的核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和质谱表征如下：
1HNMR(CDCl 3,500MHz)δppm 1.58(2H,m),1.74(1H,m),1.84(1H,d,J＝13.0Hz),2.06(2H,m),2.58(1H,m),3.30(3H,s),3.60(1H,t,J＝11.0Hz),3.82(3H,s),4.12(1H,d,J＝13.5Hz),5.24(1H,d,J＝9.5Hz),6.23(1H,s),6.80(2H,d,J＝8.5Hz),6.94(2H,d,J＝9.0Hz),7.16(2H,d,J＝9.0Hz),7.33(2H,d,J＝9.0Hz),7.56(1H,s)； 13CNMR(CDCl 3,100Hz)δppm 23.0,24.9,29.8,40.3,55.4,67.7,84.0,105.6,114.0,114.9,119.1,127.5,129.6,139.4,141.1,144.5,149.8,157.1；ESIMS(+)m/z:364.2[M+H] +.
3、将化合物42-2(170mg，0.46mmol)溶于无水乙醇中(2.0mL),0℃加入HCl/EtOAc溶液(1.0M，1.0mL),搅拌12h至反应完全，减压除去溶剂，加入CH 2Cl 2,出现白色固体，过滤得化合物42(98mg，收率：98％)。
化合物42通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和质谱表征如下：
1HNMR(DMSO,500MHz)δppm 3.72(3H,s),6.77(1H,m),6.90(2H,d,J＝10.5Hz),6.96(2H,d,J＝9.5Hz),7.10(2H,d,J＝9.5Hz),7.68(2H,m),7.95(1H,m)； 13CNMR(DMSO-d 6,150Hz)δppm 55.3,101.7,114.7,121.3,127.1,135.2,146.1,154.4；ESIMS(+)m/z:266.2[M+H] +.
实施例43-59化合物43-59的制备
化合物43-59与化合物30的制备方法基本相同，不同之处包括采用不同的原料对4-氯-苯磺酰氯进行替换。其中，实施例43采用4-氟-苯磺酰氯，实施例44采用4-氰基-苯磺酰氯，实施例45采用4-(2-甲氧基乙氧基)-苯磺酰氯，实施例46采用4-异丙氧基-苯磺酰氯，实施例47采用4-羟基-苯磺酰氯，实施例48采用4-甲基-苯磺酰氯，实施例49采用4-丁氧基-苯磺酰氯，实施例50采用6-氯-吡啶-3-磺酰氯，实施例51采用4-三氟甲基-苯磺酰氯，实施例52采用4-(异恶唑-4-基)-苯磺酰氯，实施例53采用4-(吡啶-2-基-氧基)-苯磺酰氯，实施例54采用4-(异恶唑-5-基)-苯磺酰氯，实施例55采用4-三氟甲氧基-苯磺酰氯，实施例56采用4-二氟甲氧基-苯磺酰氯，实施例57采用6-甲氧基-吡啶-3-磺酰氯，实施例58采用4-甲氧基-苯磺酰氯且采用4-(呋喃-2-基)苯胺替换4-(1H-吡唑-3-基)苯胺，实施例59采用4-甲氧基-苯磺酰氯替换4-氯-苯磺酰氯且采用6-(4-氨基苯基)-4,5-二氢-5-甲基-3(2H)-哒嗪酮替换4-(1H-吡唑-3-基)苯胺。
化合物43核磁共振氢谱： 1H NMR(500MHz,DMSO-d 6)δ12.80(s,1H),10.31(s,1H),7.81(s,2H),7.69(m,3H),7.39(m,2H),7.10(s,2H),6.59(s,1H).
化合物44核磁共振氢谱： 1H NMR(600MHz,DMSO-d 6)δ12.82(s,1H),10.55(s,1H),8.04(d,J＝8.4Hz,2H),7.90(d,J＝8.4Hz,2H),7.70(m,3H),7.11(d,J＝6.6Hz,2H),6.60(s,1H).
化合物45核磁共振氢谱： 1H NMR(500MHz,DMSO-d 6)δ12.79(s,1H),10.14(s,1H),7.68(m,5H),7.08(m,4H),6.59(s,1H),4.12(s,2H),3.62(s,2H),3.27(s,3H).
化合物46核磁共振氢谱： 1H NMR(500MHz,DMSO-d 6)δ12.79(s,1H),10.14(s,1H),7.65(m,5H),7.10(d,J＝7.0Hz,2H),7.02(d,J＝8.5Hz,2H),6.59(s,1H),4.66(m,1H),1.24(d,J＝5.0Hz,6H).
化合物47核磁共振氢谱： 1H NMR(500MHz,DMSO-d 6)δ12.78(s,1H),10.41(s,1H),10.05(s,1H),7.61(m,5H),7.10(m,2H),6.83(d,J＝8.5Hz,2H),6.58(m,1H).
化合物48核磁共振氢谱： 1H NMR(500MHz,DMSO-d 6)δ12.79(s,1H),10.21(s,1H),7.67(m,5H),7.33(d,J＝7.5Hz,2H),7.10(d,J＝7.0Hz,2H),6.59(s,1H),2.32(s,3H).
化合物49的核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和质谱表征如下： 1HNMR(600MHz,DMSO-d 6)δppm 13.12(m,1H),10.09(m,1H),7.68(m,5H),7.10(d,J＝7.2Hz,2H),7.04(d,J＝9.0Hz,2H),6.58(s,1H),3.99(m,2H),1.66(m,2H),1.39(m,2H),0.90(m,3H)； 13CNMR(101MHz,DMSO-d 6)δppm 161.8,130.9,129.7,128.8,125.8,120.1,114.6,101.4,67.6,30.4,18.5,13.5；HRMS calcd for C 19H 21O 3N 3NaS[M+Na] +394.11958；Found 394.11887.
化合物50的核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和质谱表征如下： 1HNMR(600MHz,DMSO-d 6)δppm 12.82(m,1H),10.54(s,1H),8.71(s,1H),8.12(d,J＝7.8Hz,1H),7.72(m,4H),7.13(m,2H),6.62(s,1H)； 13CNMR(101MHz,DMSO-d 6)δppm 154.1,149.3,147.8,138.0,135.1,130.8,129.8,126.1,125.2,121.3,101.6；HRMS calcd for C 14H 12ClO 4N 2S[M+H] +335.03640；Found 335.03580.
化合物51的核磁共振氢谱( 1HNMR)和质谱表征如下： 1HNMR(600MHz,DMSO-d 6)δppm 12.80(m,1H),10.50(s,1H),7.96(m,4H),7.67(m,3H),7.13(d,J＝7.8Hz,2H),6.60(s,1H)；HRMS calcd for C 16H 13O 2N 3F 3S[M+H] +368.06751；Found 368.06799.
化合物52的核磁共振氢谱( 1HNMR)和质谱表征如下： 1HNMR(600MHz,DMSO-d 6)δppm 12.77(s,1H),10.28(s,1H),8.73(s,1H),8.50(s,1H),7.93(d,J＝8.4Hz,2H),7.82(d,J＝7.8Hz,2H),7.66(m,3H),7.13(m,2H),6.58(s,1H)；HRMS calcd for C 18H 15O 3N 4S[M+H] +367.08594；Found367.08664.
化合物53的核磁共振氢谱( 1HNMR)和质谱表征如下： 1HNMR(600MHz,DMSO-d 6)δppm 12.78(m,1H),10.27(m,1H),8.18(dd,J＝1.2,1.8Hz,1H),7.90(m,1H),7.80(d,J＝8.4Hz,2H),7.73(s,1H),7.69(m,2H),7.27(d,J＝9.0Hz,2H),7.19(m,1H),7.15(m,2H),7.11(d,J＝8.4Hz,1H),6.60(s,1H)；HRMS calcd for C 20H 17N 4O 3S[M+H] +393.10159；Found393.10092.
化合物54的核磁共振氢谱( 1HNMR)和质谱表征如下： 1HNMR(600MHz,DMSO-d 6)δppm 12.78(s,1H),10.32(s,1H),8.51(s,1H),7.88(m,2H),7.83(m,3H),7.68(m,3H),7.13(s,2H),6.59(s,1H)；HRMS calcd for C 18H 15O 3N 4S[M+H] +367.08594；Found 367.08615.
化合物55的核磁共振氢谱( 1HNMR)和质谱表征如下： 1HNMR(600MHz,DMSO-d 6)δppm 12.78(m,1H),10.20(m,1H),8.28(d,J＝1.8Hz,1H),7.73(m,4H),7.62(m,2H),7.23(d,J＝7.8Hz,1H),6.64(m,1H)；HRMS calcd for C 16H 13F 3N 3O 3S[M+H] +384.06242；Found384.06256.
化合物56的核磁共振氢谱( 1HNMR)和质谱表征如下： 1HNMR(600MHz,DMSO-d 6)δppm 12.78(s,1H),10.32(s,1H),7.82(m,2H),7.65(d,J＝7.8Hz,3H),7.32(m,3H),7.12(d,J＝9.0Hz,2H),6.59(d,J＝1.8Hz,1H)；HRMS calcd for C 16H 14N 3O 3F 2S[M+H] +366.07184；Found 366.07248.
化合物57的核磁共振氢谱( 1HNMR)和质谱表征如下： 1HNMR(600MHz,DMSO-d 6)δppm 12.80(m,1H),10.30(s,1H),8.50(s,1H),7.97(d,J＝8.4Hz,1H),7.70(m,3H),7.13(d,J＝7.8Hz,2H),6.97(d,J＝8.4Hz,1H),6.61(s,1H),3.88(s,3H)；HRMS calcd for C 15H 15N 4O 3S[M+H] +331.08594；Found331.08563.
化合物58的核磁共振氢谱( 1HNMR)和质谱表征如下： 1HNMR(600MHz,DMSO-d 6)δppm 10.21(s,1H),7.69(d,J＝9.0Hz,2H),7.67(m,1H),7.54(d,J＝9.0Hz,2H),7.13(d,J＝9.0Hz,2H),7.05(d,J＝9.0Hz,2H),6.79(dd,J＝3.6,0.6Hz,1H),6.54(dd,J＝3.6,1.8Hz,1H),3.78(s,3H)；HRMS calcd for C 17H 16O 4NS[M+H] +330.07946；Found330.07901.
化合物59的核磁共振氢谱( 1HNMR)和质谱表征如下： 1HNMR(600MHz,DMSO-d 6)δppm 10.85(s,1H),10.36(s,1H),7.72(d,J＝9.0Hz,2H),7.64(d,J＝9.0Hz,2H),7.14(d,J＝9.0Hz,2H),7.06(d,J＝9.0Hz,2H),3.79(s,3H),2.62(dd,J＝16.8,7.2Hz,1H),2.19(d,J＝16.8Hz,1H),1.02(d,J＝7.2Hz,3H)；HRMS calcd for C 18H 20O 4N 3S[M+H] +374.11690；Found 374.11713.
实施例60化合物60的合成
无水条件下，4-(1H-吡唑-3-基)苯胺(150.3mg,0.94mmol)，4-甲氧基苯甲醛(160.8mg,1.17mmol)溶于无水四氢呋喃(4.0mL)，加入硼氢化钠(54.8mg,1.43mmol)，室温下反应6-8h，TLC监测，待原料胺反应尽，停反应。反应液用EtOAc萃取，水洗2次，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析(PE/EA＝1.5/1)，得白色粉末状固体E34(104.6mg，收率：39.9％)。通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和质谱表征如下： 1HNMR(600MHz,DMSO-d 6)δppm 12.85(s,1H),12.52(s,1H),7.45(m,3H),7.28(d,J＝9.0Hz,2H),6.88(d,J＝8.4Hz,2H),6.61(d,J＝6.0Hz,2H),6.39(m,1H),4.22(s,2H),3.72(s,3H)； 13CNMR(101MHz,DMSO-d 6)δppm 158.1,128.3,125.9,113.6,112.2,100.3,54.9,45.8；HRMS calcd for C 17H 18N 3O[M+H] +280.14444；Found280.14395.
实施例61化合物61的合成
无水条件下，4-(1H-吡唑-3-基)苯胺(134.3mg,0.84mmol)，4-甲氧基苯甲酸(156.8mg,1.02mmol)溶于无水二氯甲烷(3.0mL)，加入EDCI(220.8mg,1.15mmol)和DMAP(23.8mg,0.19mmol)，室温下反应6-8h，TLC监测，待原料胺反应尽，停反应。反应液用EtOAc萃取，水洗2次，饱和NaCl溶液洗，无水Na 2SO 4干燥，浓缩，柱层析(PE/EA＝1.5/1)，得白色粉末状固体E35(75.8mg，收率：30.8％)。通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和质谱表征如下： 1HNMR(600MHz,DMSO-d 6)δppm 13.19(s,1H),10.23(s,1H),8.00(m,2H),7.88(m,3H),7.83(m,2H),7.06(m,2H),6.81(d,J＝2.4Hz,1H),3.84(s,3H)； 13CNMR(151MHz,DMSO-d 6)δppm 164.9,161.9,146.8,139.5,133.4,129.6,126.8,125.9,120.3,113.5,102.2,55.4；HRMS calcd for C 17H 16O 2N 3[M+H] +294.12370；Found 294.12436.
实施例62化合物62的制备
Figure PCTCN2021108229-appb-000028
1、将4-碘苯胺(220mg,1.0mmol)和化合物A(278mg,1.0mmol)加入微波反应管(20mL)中,加入二氧六环(3mL)和水(0.3mL)使样品溶解，加入2-双环己基膦-2',6'-二甲氧基联苯(16mg,0.04mmol),K 3PO 4(424mg,2.0mmol),Pd 2(dba) 3(18mg,0.02mmol),封上瓶盖后，放入微波反应仪中反应，温度130℃，反应时间90min后停止反应。反应液乙酸乙酯提取，水和饱和食盐水依次萃洗，无水硫酸钠干燥，柱层析纯化(PE/EA＝3/1-1/1V/V),得化合物62-1(208mg，收率：86％)。
2、化合物62-1(261mg,1.0mmol)溶于无水吡啶(5.0mL)，0℃下加入4-甲氧基-苯磺酰氯(207mg,1.0mmol)，室温反应8h，减压除去溶剂，剩余物乙酸乙酯提取，盐酸溶液、水和饱和食盐水依次萃洗，无水硫酸钠干燥，柱层析纯化(PE/EA＝2/1)，得白色絮状物62-2(330mg，收率：81％)。
3、化合物62-2(180mg,0.43mmol)溶于无水四氢呋喃(3mL)，冰水浴，滴加碘甲烷(0.2mL,d＝2.28g/mL,7.4mmol),室温反应8h，减压除去溶剂，剩余物乙酸乙酯提取，盐酸溶液、水和饱和食盐水依次萃洗，无水硫酸钠干燥，柱层析纯化(PE/EA＝2/1)，得黄色油状物62-3(147mg，收率：80％)。
4、化合物62-3(130mg,0.35mmol)溶于无水乙醇中(5mL),0℃加入HCl/EtOAc溶液(1.0M,1.5mL),搅拌12h至反应完全，减压除去溶剂，加入CH 2Cl 2,出现白色固体，过滤得化合物62(105mg，收率：72％)。
化合物62通过核磁共振氢谱( 1HNMR)，核磁共振碳谱( 13CNMR)和质谱表征如下：
1H NMR(600MHz,DMSO-d 6)δ12.91(s,1H),7.75(m,3H),7.45(d,J＝9.0Hz,2H),7.13(d,J＝8.4Hz,2H),7.09(d,J＝9.0Hz,2H),6.70(d,J＝2.4Hz,1H),3.83(s,3H),3.12(s,3H)； 13CNMR(151MHz,DMSO-d 6)δppm 162.7,140.2,131.4,129.6,128.6,127.5,126.2,125.4,114.3,102.1,55.6,37.6.HRMS calcd for C 17H 18N 3O 3S[M+H] +344.10634；Found344.10568.
实施例63-66化合物63-66的制备
化合物63-66与化合物30的制备方法基本相同，不同之处包括：实施例63中采用4-甲氧基-苯磺酰氯替换4-氯-苯磺酰氯，且采用2-氨基-5(吗啉-4基)吡啶替换4-(1H-吡唑-3-基)苯胺；实施例64中采用4-甲氧基-苯磺酰氯替换4-氯-苯磺酰氯，且采用4-(噻吩-2-基)苯胺替换4-(1H-吡唑-3-基)苯胺；实施例65中采用4-甲氧基-苯磺酰氯替换4-氯-苯磺酰氯，且采用4-(异噻唑-5-基)苯胺替换4-(1H-吡唑-3-基)苯胺；实施例66中采用4-(1H-吡唑-1-基)-苯磺酰氯替换4-氯-苯磺酰氯。
化合物63的核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和质谱表征如下： 1HNMR(500MHz,DMSO-d 6)δppm 10.62(s,1H),7.80(s,1H),7.75(d,J＝8.5Hz,2H),7.36(d,J＝8.0Hz,1H),7.04(d,J＝7.5Hz,3H),3.79(s,3H),3.69(m,4H),3.02(m,4H)； 13CNMR(151MHz,DMSO-d 6)δppm162.1,132.5,128.8,114.1,113.7,65.8,55.5,48.2；HRMS calcd for C 16H 19O 4N 3NaS[M+Na] +372.09885；Found 372.09814.
化合物64的核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和质谱表征如下： 1HNMR(500MHz,DMSO-d 6)δppm 10.25(s,1H),7.71(d,J＝8.5Hz,2H),7.51(d,J＝8.0Hz,2H),7.47(d,J＝5.0Hz,1H),7.38(m,1H),7.12(d,J＝8.5Hz,2H),7.07(m,3H),3.78(s,3H)； 13CNMR(151MHz,DMSO-d 6)δppm162.4,142.7,137.2,131.1,129.4,128.8,128.3,126.1,125.1,123.1,120.2,114.3,55.5；HRMS calcd for C 17H 15O 3NNaS 2[M+Na] +368.03856；Found 368.03763.
化合物65的核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和质谱表征如下： 1HNMR(500MHz,DMSO-d 6)δppm 10.49(s,1H),8.53(s,1H),7.74(d,J＝9.0Hz,2H),7.65(s,1H),7.62(d,J＝8.5Hz,2H),7.20(d,J＝8.5Hz,2H),7.07(d,J＝9.0Hz,2H),3.78(s,3H)； 13CNMR(151MHz,DMSO-d 6)δppm165.8,162.5,159.1,139.3,130.9,128.8,127.5,125.3,120.2,119.6,114.4,55.6；HRMS calcd for C 16H 15O 3N 2S 2[M+H] +347.05186；Found 347.05106.
化合物66的核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和质谱表征如下： 1HNMR(500MHz,DMSO-d 6)δppm 10.57(s,1H),8.58(s,1H),8.02(d,J＝8.0Hz,2H),7.88(d,J＝7.0Hz,3H),7.79(s,1H),7.74(d,J＝7.5Hz,2H),7.20(d,J＝7.5Hz,2H),6.76(s,1H),6.57(s,1H). 13CNMR(151MHz,DMSO-d 6)δppm 146.6,142.4,142.1,137.7,136.3,133.1,128.5,128.4,126.6,120.3,118.4,108.8,102.4.HRMS calcd for C 18H 16O 2N 5S[M+H] +366.10192；Found 366.10269.
生物活性评价
1、双荧光素酶报告基因检测
1.1细胞系及药品：
(1)LNCaP细胞购于ATCC，CRL-1740；
(2)二氢睾酮(dihydrotestosterone,DHT)由加拿大麦吉尔大学惠赠；
恩杂鲁胺(enzalutamide,ENZ)由上海药物所惠赠；
IMB-A6
Figure PCTCN2021108229-appb-000029
1.2试剂与仪器
(1)生化试剂：F-12K培养基、RPMI 1640培养基、Phenol red free RPMI1640培养基、FBS、charcoal-stripped FBS、含EDTA的0.25％胰酶，PBS均购自美国GiBCO公司，FBS charcoal stripped炭吸附特级胎牛血清购自以色列Biological Industries公司。试剂盒：双荧光素酶活性测定试剂盒Dual-Luciferase Assay System购自美国Promega公司。
(2)质粒：PSA-Jappan质粒由日本癌症化疗中心Hiroyuki教授惠赠，共表达前列腺特异性抗原和萤火虫荧光素酶。Renilla质粒是本所免疫室所有，表达海肾荧光素酶。
(3)仪器：酶标仪Centro XS3 LB 960购自德国Berthold公司。
1.3实验方法：在24孔板中，接种1.6×10 5个/mL的LNCaP细胞悬液，每孔接种500μL。待细胞长至80％时，每孔共转染100ng PSA-luc和1ng pCMV-Renilla质粒,转染后6h将培 养基换成含10％charcoal-stripped FBS的phenol red-free RPMI 1640培养基；转染24h后，每孔按照1nM DHT和相应浓度药物(化合物1-42、阳性对照恩杂鲁胺、IMB-A6)各加入1μL，继续培养24h，并以DHT做空白对照，最后将培养基吸掉，每孔加入100μL的1×PLB裂解20min，收集细胞裂解物到干净的EP管中，离心,取上清20μL到干净的白色96孔板中，按照Dual-luciferase protocol，用960酶标仪测定荧光值，以校准后的萤光虫荧光素酶活性(相对荧光值，RLU)反应药物对AR的转录活性的抑制作用，RLU值越低，抑制活性越强，结果见表1。
表1
Figure PCTCN2021108229-appb-000030
Figure PCTCN2021108229-appb-000031
由表1可知：本申请大部分的双芳香基胺类化合物都具有较为突出的抗AR活性，化合物15、23、30以及32的抗AR活性与恩杂鲁胺相当，化合物51、52、54、56、57、64-66的化合物的抗AR活性明显优于恩杂鲁胺，可作为AR拮抗剂的先导化合物进行研究。
2、MTT法检测化合物抑制细胞增殖活性实验
2.1材料:(1)细胞：LNCaP细胞购于ATCC，CRL-1740；用含有10％FBS的RPMI1640培养基培养。PC-3细胞由加拿大麦吉尔大学惠赠；用含有10％FBS的F-12K培养基进行培养。(2)生化试剂：F-12K、RPMI 1640培养基、FBS、charcoal-stripped FBS、含EDTA的0.25％胰酶，PBS均购自美国GiBCO公司，FBS charcoal stripped炭吸附特级胎牛血清购自以色列Biological Industries公司。
2.2仪器：酶标仪Centro XS3LB 960均购自德国Berthold公司。
2.3实验方法：分别取生长良好的LNCaP、PC-3细胞，制成2×10 4个/mL的细胞悬液，接种于96孔板中，每孔接种200μL。培养24h后，每孔加入1μL相应的药物(本申请的部分双芳香基胺类化合物、阳性对照恩杂鲁胺、IMB-A6)，每组药物做三组平行，同时设好空白组。接着培养72h，每孔加入20μL用PBS配制的5g/L的MTT溶液，继续培养2-4h后，小心地弃掉上清，每孔用100μL异丙醇溶解沉淀物，96孔板振荡器上混匀30min，最后用多功能酶标仪在570nm波长下测定其吸光度值，以IC 50进一步评价本申请的双芳香基胺类化合物的细胞毒活性以及对AR的选择性，具体结果见表2。
表2
Figure PCTCN2021108229-appb-000032
Figure PCTCN2021108229-appb-000033
根据表2可知：本申请的双芳香基胺类化合物都具有一定的抗AR活性，尤其是化合物23，27，30和32的IC 50值低于恩杂鲁胺，具有较强的抑制AR的活性，因此可以作为先导化合物进行进一步研究。
3、可抑制突变型激素受体的活性
目前，研究发现一些系列AR关键位点的突变，包括741位色氨酸(W)→亮氨酸(L)或者半胱氨酸(C)，877位苏氨酸(T)→丙氨酸(A)，876位苯丙氨酸(F)→亮氨酸(L)。其中F876L针对恩杂鲁胺产生耐药性。
将1.4×10 5个/mL的PC-3细胞悬液，按照每孔500μL接种于24孔板中。待细胞长至80％时，每孔共转染100ng PSA-luc、20ngAR-F876L和1ng pCMV-Renilla质粒。转染后6h将培养基换成含10％charcoal-stripped FBS的phenol red-free RPMI 1640培养基；转染24h后，继续培养24h。最后将培养基吸掉，每孔加入100μL的1×PLB裂解20min，收集细胞裂解物到干净的EP管中，离心，取上清20μL到干净的白色96孔板中，按照Promega公司的
Figure PCTCN2021108229-appb-000034
Luciferase Assay System试剂盒的说明书，用Centro XS3 LB 960酶标仪测定荧光值。实验设置了三组平行，并进行了统计学分析，其中*P<0.05，**P<0.01是以DHT组为参照。实验数据以
Figure PCTCN2021108229-appb-000035
表示，并用GraphPad Prism 5.0进行作图和统计学分析。实验结果见图1a、图1b、图2a和图2b(图1b以及图2b中分别表示仅含有DMSO、DMSO+DHT以及DMSO+DHT+相应浓度的化合物或恩杂鲁胺各加入1μL)。
图1a为本申请化合物23的AR抑制活性曲线图，图1b为申请化合物23对在PC-3中表达的876位氨基酸突变DAR转录活性的影响。图2a为本申请化合物27的AR抑制活性曲线图，图2b为申请化合物27对在PC-3中表达的876位氨基酸突变DAR转录活性的影响。图1a、图1b、图2a和图2b显示，化合物23和27对F876L突变AR的转录活性也有很好的抑制作用，对AR-F876L的转录活性均具有很好的抑制作用，并呈现剂量依赖关系；IC 50分别为1.05μM和0.16μM。并且化合物23和27在0.8μM时对AR-F876L的转录活性的抑制作用很显著，其与恩杂鲁胺的作用结果比较，表明23和27可以克服恩杂鲁胺由于AR的876位氨基酸突变而引起的耐药问题，有可能解决临床上针对恩杂鲁胺类雄激素受体拮抗剂出现的耐药问题。
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。

Claims (23)

  1. 一种双芳香基胺类化合物，其具有式1的结构：
    Figure PCTCN2021108229-appb-100001
    其中，
    R 1选自C 1－12的烷基、C 1－6的烷氧基、卤素、C 1－3的卤代烷基、-CN、-NO 2、-NH 2、磺酰基或芳香基；R 2选自氢、C 1－12的烷基、C 1－6的烷氧基、卤素、C 1－3的卤代烷基、-CN、-NO 2、-NH 2、磺酰基或芳香基；R 3选自取代或未取代的五元杂环或六元杂环，优选地，R 3中的取代基选自C 1－12的烷基、氨基或环氧己烷中的至少一个；Linker选自-SO 2NR 4-、-CONR 4-、-NR 4-，R 4选自氢、C 1－12的烷基；R 5为一个以上且独立地选自氢、C 1－12的烷基、C 1－6的烷氧基、卤素、C 1－3的卤代烷基、-CN、-NO 2、-NH 2、磺酰基或芳香基；V、W、X、Y、Z独立地选自碳或者氮；优选地，所述磺酰基为R 6SO 2-，R 6选自C 1－12的烷基；优选地，所述芳香基为C 6-C 30的单环芳基或稠环芳基、C 5-C 30的单环杂芳基或稠环杂芳基。
  2. 根据权利要求1所述的双芳香基胺类化合物，所述双芳香基胺类化合物具有式1a的结构：
    Figure PCTCN2021108229-appb-100002
    其中，M为-SO 2-或-CO-。
  3. 一种双芳香基胺类化合物，其具有式1的结构：
    Figure PCTCN2021108229-appb-100003
    其中，R 1选自取代或未取代的C 1－6的烷氧基、-OR a、酰基、酰胺基或取代或未取代的五元杂环或六元杂环，R a选自氢、C 1－3的卤代烷基或取代或未取代的五元杂环或六元杂环，优选地，C 1－6的烷氧基的取代基选自C 1－12的烷氧基；R 2选自氢、C 1－12的烷基、取代或未取代的C 1－6的烷氧基、卤素、C 1－3的卤代烷基、-CN、-NO 2、-NH 2、-OR a、酰基、酰胺基、磺酰基、芳香基、取代或未取代的五元杂环或六元杂环，优选地，C 1－6的烷氧基的取代基选自C 1－12的烷氧基；R 3选自取代或未取代的五元杂环或六元杂环，优选地，R 3中的取代基选自C 1－12的烷基和/或氧；Linker选自-SO 2NR 4-、-CONR 4-、-NR 4-、-NR 4CH 2-，R 4选自氢或C 1－12的烷基中的至少一个；R 5为一个以上且选自氢、C 1－12的烷基、C 1－6的烷氧基、卤素、C 1－3的卤代烷基、-CN、-NO 2、-NH 2、磺酰基或芳香基；V、W、X、Y、Z独立地选自碳或者氮；优选地，所述磺酰基为R 6SO 2-，R 6选自C 1－12的烷基；优选地，所述芳香基为C 6-C 30的单环芳基或稠环芳基、C 5-C 30的单环杂芳基或稠环杂芳基。
  4. 根据权利要求3所述的双芳香基胺类化合物，所述双芳香基胺类化合物具有式1a的结构：
    Figure PCTCN2021108229-appb-100004
    其中，M为-SO 2-、-CO-或-CH 2-。
  5. 根据权利要求1-4任一项所述的双芳香基胺类化合物，其中，R 3位于Linker的对位或者间位。
  6. 根据权利要求1-5任一项所述的双芳香基胺类化合物，其中，R 3所在的六元环为吡啶，且R 3位于与Linker为间位的碳上。
  7. 根据权利要求6所述的双芳香基胺类化合物，其中，R 1所在的六元环为苯。
  8. 根据权利要求1-4任一项所述的双芳香基胺类化合物，其中，R 5独立地选自C 1－6的烷氧基、卤素、-CF 3、-CN、-NO 2、-NH 2、磺酰基、芳香基，且R 5所在的六元环为苯。
  9. 根据权利要求1-4任一项所述的双芳香基胺类化合物，其中，与Linker相连的二个六元环均为苯；或者，其中一个六元环为苯，另一个六元环为含氮芳香环。
  10. 根据权利要求9所述的双芳香基胺类化合物，其中，R 1所在的六元环为苯，R 3所在的六元环为吡啶。
  11. 根据权利要求1-10任一项所述的双芳香基胺类化合物，其中，R 3为吡唑、咪唑、恶唑、吡咯、异恶唑或噻唑。
  12. 一种权利要求1-11任一项所述的双芳香基胺类化合物的制备方法，包括以下步骤：使式2化合物和式3化合物发生缩合反应，生成式1所示的化合物，
    Figure PCTCN2021108229-appb-100005
    其中，L 1和L 2独立地选自-NHR 4、-MCl、卤素中的一个，M为-SO 2-或-CO-，以实现二个六元芳香环之间经缩合反应而被Linker键结。
  13. 一种权利要求1-11任一项所述的双芳香基胺类化合物的制备方法，包括以下步骤：使式2化合物和式3化合物发生缩合反应，生成式1所示的化合物，
    Figure PCTCN2021108229-appb-100006
    其中，L 1和L 2独立地选自-NHR 4、-MCl、卤素中的一个，M为SO 2-、-CO-或-CH 2-，以实现二个六元芳香环之间经缩合反应而被Linker键结。
  14. 根据权利要求12或13所述的双芳香基胺类化合物的制备方法，其中，
    L 1为-NHR 4，L 2为-MCl、卤素中的一个；或，L 1为-MCl或卤素，L 2为-NHR 4。
  15. 根据权利要求14所述的双芳香基胺类化合物的制备方法，包括使式2a的化合物和式3a的化合物发生缩合反应，生成式1a化合物的过程：
    Figure PCTCN2021108229-appb-100007
  16. 根据权利要求15所述的双芳香基胺类化合物的制备方法，还包括以下步骤：
    使式2b的化合物和式2c的化合物发生反应，生成式2a所示的化合物，
    Figure PCTCN2021108229-appb-100008
    其中，R 7选自卤素，PG独立地选自式PG1、式PG2所示的基团，
    Figure PCTCN2021108229-appb-100009
  17. 一种权利要求1-11任一项所述的双芳香基胺类化合物的制备方法，包括以下步骤：使式4所示的化合物和式5所示的化合物发生缩合反应，生成式6所示的化合物，
    使式6所示的化合物和式7所示的化合物发生反应，生成式1所示的化合物，
    Figure PCTCN2021108229-appb-100010
    其中，L 3和L 4独立地选自-NHR 4、-MCl、卤素中的一个，M为-SO 2-或-CO-，以实现二个六元芳香环之间经缩合反应而被Linker键结；L 5选自卤素，PG选自式PG1、式PG2所示的基团，
    Figure PCTCN2021108229-appb-100011
  18. 一种权利要求1-11任一项所述的双芳香基胺类化合物的制备方法，包括以下步骤：
    使式4所示的化合物和式5所示的化合物发生缩合反应，生成式6所示的化合物，
    使式6所示的化合物和式7所示的化合物发生反应，生成式1所示的化合物，
    Figure PCTCN2021108229-appb-100012
    Figure PCTCN2021108229-appb-100013
    其中，L 3和L 4独立地选自-NHR 4、-MCl、卤素中的一个，M为SO 2-、-CO-或-CH 2-，以实现二个六元芳香环之间经缩合反应而被Linker键结；
    L 5选自卤素，PG选自式PG1、式PG2所示的基团，
    Figure PCTCN2021108229-appb-100014
  19. 根据权利要求17或18所述的双芳香基胺类化合物的制备方法，其中，
    L 3为-NHR 4，L 4为-MCl、卤素中的一个；或，
    L 3为-MCl或卤素，L 4为-NHR 4。
  20. 根据权利要求17-19任一项所述的双芳香基胺类化合物的制备方法，其中，L 3和
    L 4独立地选自-NHR 4或卤素。
  21. 一种权利要求1-11任一所述的双芳香基胺类化合物在制备雄激素受体拮抗药物中的应用。
  22. 一种雄激素受体拮抗药物组合物，其包括作为雄激素受体拮抗有效成分的权利要求1-11任一项所述的双芳香基胺类化合物，还包括药剂学上可接受的药物辅料。
  23. 一种使用权利要求22所述的雄激素受体拮抗药物组合物治疗雄激素失调的方法。
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