WO2022007168A1 - 一种苯并五元氮杂环化合物及其应用 - Google Patents

一种苯并五元氮杂环化合物及其应用 Download PDF

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WO2022007168A1
WO2022007168A1 PCT/CN2020/113949 CN2020113949W WO2022007168A1 WO 2022007168 A1 WO2022007168 A1 WO 2022007168A1 CN 2020113949 W CN2020113949 W CN 2020113949W WO 2022007168 A1 WO2022007168 A1 WO 2022007168A1
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phenyl
benzo
ethylsulfonyl
methyl
acetamide
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French (fr)
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许�永
吴锡山
张岩
王蕊
沈慧
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中国科学院广州生物医药与健康研究院
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    • C07D513/04—Ortho-condensed systems

Definitions

  • the present application relates to the technical field of chemical medicine, in particular to a benzo five-membered nitrogen heterocyclic compound and its application.
  • ROR Retinoic acid receptor-related orphan receptor
  • the receptor family includes three members, namely ROR ⁇ (NR1F1), ROR ⁇ (NR1F2) and ROR ⁇ (NR1F3), which are distributed in different tissues and organs of the body, respectively.
  • ROR ⁇ is widely expressed in skeletal muscle, liver, lung, skin, adipocyte tissue, kidney, thymus, and brain.
  • the expression site of ROR ⁇ is very limited, and it is only expressed in the central nervous system.
  • ROR ⁇ 1 is highly expressed in skeletal muscle, liver, kidney and adipose tissue.
  • ROR ⁇ t is only highly expressed in immune tissues including the thymus.
  • TH17 cells are a subset of TH cells that can secrete interleukin 17 (IL-17).
  • IL-17 interleukin 17
  • IL-17 as a pro-inflammatory factor, plays an important role in the development of inflammation and autoimmune diseases, thus regulating TH17 cells. Differentiation and IL-17 secretion can modulate immune system responses.
  • Professor Littman of New York University first discovered that ROR ⁇ can directly promote the differentiation and development of TH17 cells.
  • ROR ⁇ directly regulates the production and secretion of IL-17 cytokines and is a key factor in the development of TH17 cells. Therefore, inhibition of ROR ⁇ transcription is promising as a new strategy of choice in the treatment of autoimmune diseases.
  • ROR ⁇ nuclear receptor ROR ⁇ is highly expressed in metastatic castration-resistant prostate cancer (CRPC), and can act on the upstream of Androgen Receptor (AR) gene and regulate the correlation between AR and AR regulation. gene expression.
  • the ROR ⁇ inhibitor SR2211 and XY011, XY018 and XY101 obtained by structure-based drug design method can significantly inhibit the expression of AR and AR-V7, and show a good inhibitory effect on cells resistant to the second-generation drug enzalutamide.
  • ROR ⁇ inhibitors also inhibited tumor growth in a mouse xenograft CRPC model. In summary, inhibiting the target ROR ⁇ can interfere with AR gene expression and downstream signaling pathways, providing a new treatment for prostate cancer and its clinical drug resistance.
  • the present application provides a benzo five-membered nitrogen heterocyclic compound.
  • the benzofive-membered nitrogen heterocyclic compound is used as a compound of ROR ⁇ receptor inhibitor, and the compound can effectively inhibit ROR ⁇ protein and has good selectivity to other nuclear receptor family proteins.
  • the application provides a benzofive-membered nitrogen heterocyclic compound, the benzofive-membered nitrogen heterocyclic compound has the structure shown in formula I;
  • the X is selected from The wavy line represents the bond of the group
  • the Y is selected from CR 5 or N atom
  • Z is selected from S atom or NR 10 ;
  • the R 1 and R 10 are each independently selected from 0 to 3 R 11 is C1 ⁇ C10 alkyl group substituted with 0 to 3 R 11 substituents of C6 ⁇ C10 aryl group, 0 to 3 R 11 Substituted C6-C10 aryl C1-C3 alkyl, 0-3 R 11 substituted C2-C10 heteroaryl, 0-3 R 11 substituted C2-C20 heterocyclyl, 0-3 R 11 substituted C2 ⁇ C10 heteroaryl C1-C3 alkyl, 0 ⁇ 3 R 11 substituted C2 ⁇ 20 heterocyclyl C1-C3 alkyl, 0 ⁇ 3 R 11 substituted C3 ⁇ C10 cycloalkyl, 0 ⁇ Any one of the 3 R 11- substituted C3-C10 cycloalkyl C1-C3 alkyl groups;
  • the R 11 is selected from halogen, cyano, nitro, carboxyl, hydroxyl, amino, C1-C10 alkyl sulfone, at least one halogen-substituted C1-C10 alkyl sulfone, C1-C10 alkyl ester, at least One halogen-substituted C1-C10 alkyl ester group, C1-C10 alkyl group, at least one halogen-substituted C1-C10 alkyl group, C1-C10 alkoxy group, at least one halogen-substituted C1-C10 alkoxy group, C3- Any one of C10 cycloalkyl and at least one halogen-substituted C3-C10 cycloalkyl;
  • the R 2 -R 9 are each independently selected from hydrogen, halogen, C1-C10 alkyl, at least one halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, at least one halogen-substituted C1 ⁇ C10 alkoxy, C1 ⁇ C10 alkylamide, at least one halogen substituted C1 ⁇ C10 alkylamide, C1 ⁇ C10 cycloalkylamide, at least one halogen substituted C1 ⁇ C10 cycloalkylamide, Any one of C1-C10 alkylamino groups, C1-C10 alkylamino groups substituted with at least one halogen, C3-C10 cycloalkylamino groups, and C3-C10 cycloalkylamino groups substituted with at least one halogen.
  • substituted refers to the replacement of one or more hydrogens on one or more of the designated atoms with the choice of the indicated group, provided that the normal valences of the designated atom under the present circumstances are not exceeded, and that the substitution results in a stable compound .
  • halogen includes fluorine, chlorine, bromine, and iodine.
  • C2-C20 heterocyclic group refers to a monoheterocyclic group containing 2-10 Cs and a fused heterocyclic group containing 10-20 Cs.
  • the mono-heterocyclic group of 2-10 C refers to a saturated or partially saturated and non-aromatic monocyclic cyclic group containing 1-4 heteroatoms (N, O or S).
  • the fused heterocyclic group of 10-20 C refers to a fused heterocyclic group containing 10-20 C atoms and 1-4 heteroatoms (N, O or S) saturated or partially saturated, non-aromatic cyclic group, the condensed ring may have an aromatic ring, but the condensed ring as a whole does not have aromaticity.
  • ring atoms (eg, C, N or S) in the ring structure can be oxo.
  • 2-10 C monoheterocyclyl groups include, but are not limited to, 2H-aziridine, diaziridine, azetidinyl, 1,4-dioxanyl, , 1 , 3-dioxolane, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5 -Dihydrothienyl, 4,5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyridyl, piperidonyl, tetrahydropyridone, dihydropiperyl Iridonyl, piperazin
  • 10-20 C fused heterocyclic groups include but are not limited to benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzimidazolidinyl, benzo oxazolidinyl, benzothiazolidinyl, benzisoxazolidinyl, benzisothiazolidinyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, chroman pyrrolidinocyclopropyl, pyrrolidinocyclopropyl, pyrrolidinocyclobutyl, pyrrolidinopyrrolidino, pyrrolidinopiperidinyl, pyrrolidinopiperazine base, pyrrolidinomorpholinyl, piperidinomorpholinyl, pyridocyclopentyl, pyridocyclohexyl, pyri
  • C1-C10 alkyl refers to a branched or unbranched chain alkyl group with 1-10 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n- Butyl, tert-butyl, n-pentyl, n-hexyl, etc.; all carbon atoms may be optionally substituted with one or more halogens.
  • C1 ⁇ C10 alkoxy refers to -O-C1 ⁇ C10 alkyl group, said C 1 ⁇ C 10 alkyl is as defined above.
  • C1-C10 alkylamide group refers to -CO-NH-C1-C10 alkyl group or C1-C10 alkyl group-CO-NH-, and C1-C10 alkyl group is as defined above.
  • C3-C10 cycloalkyl refers to a saturated cyclic hydrocarbon having 3-10 carbon atoms; including but not limited to cyclobutyl, cyclopentyl, cyclohexyl and the like. wherein all carbon atoms of the alkyl group are optionally substituted with one or more halogens.
  • C3-C10 cycloalkyl C1-C3 alkyl refers to C1-C3 cycloalkyl connected to C3-C10 alkyl, both of which have the same meaning as defined above, C6-C10 aryl C1- C3 alkyl, C2-C10 heteroaryl C1-C3 alkyl, and C2-20 heterocyclic C1-C3 alkyl all have the same meaning, and represent a group formed by connecting two or three groups.
  • C3-C10 cycloalkylamide group refers to -CO-NH-C3-C10 cycloalkyl or C3-C10 cycloalkyl-CO-NH-, and C3-C10 cycloalkyl is as defined above.
  • C2-C10 heteroaryl group refers to containing 2-10 carbon atoms and 1-4 heteroatoms selected from N, O and S, and containing aromatic 5-6 membered monocyclic heteroaryl and aromatic A 7-11 membered heteroaryl bicyclic or fused ring wherein at least one of the rings is an aromatic ring heteroaryl ring system.
  • 5 to 6 membered monocyclic heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, triazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl , pyrrolyl, thienyl.
  • heteroaryl bicyclic or fused rings including but not limited to benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, thienopyrimidinyl, indolyl, isoindyl dolyl, indazolyl, benzotriazolyl, benzofuranyl, benzopyranyl, benzoxazolyl, benzothiazolyl, pyrrolopyridyl and imidazopyridyl.
  • the C1-C10 alkyl sulfone group refers to -SO 2 -C1-C10 alkyl group, and the C1-C10 alkyl group is as defined above.
  • C1-C10 alkyl ester group refers to -COO-C1-C10 alkyl group
  • C1-C10 alkyl group is as defined above.
  • C1-C10 alkylamine group refers to -NH-C1-C10 alkyl group, and C1-C10 alkyl group is as defined above.
  • the C2-C20 heterocyclic group substituted with 0-3 R 11 is The wavy lines represent the linkages of the groups.
  • R 1 is R 11 is selected from C1 ⁇ C10 alkyl, halo, trifluoromethoxy, nitro, cyano, carboxyl, methyl ester, ethyl ester group, an amino group, a methyl sulphone group, Any one or a combination of at least two ethyl sulfone groups, preferably any one or at least two combinations of a cyano group, an ethyl ester group, and an ethyl sulfone group.
  • the R 2 -R 5 are all hydrogen.
  • the R 6 , R 7 , R 8 and R 9 are not simultaneously hydrogen.
  • the R 6 and R 9 are hydrogen.
  • the R 7 and R 8 are not simultaneously hydrogen.
  • one and only one of said R 7 and R 8 is hydrogen.
  • the R 7 and R 8 are each independently selected from any one or a combination of at least two of hydrogen, methyl, methoxy, halogen, trifluoromethyl, and C2-C10 alkylamide.
  • the C2-C10 alkyl amido group is an isopropyl amido group or a cyclopentyl amido group.
  • the R 10 is selected from C1-C10 alkyl, cyclobutyl, cyclobutylmethyl, cyclohexylmethyl, pyridinemethyl, 0-3 R 11- substituted phenylethyl, 0-3 R Any of 11 substituted benzyl groups.
  • any one of R 10 R 11 is selected from methyl, carboxyl, trifluoromethyl, methyl ester, halogen, cyano, methyl sulfone group or a combination of at least two.
  • the benzofive-membered nitrogen heterocyclic compound has the structure shown in formula II;
  • R 1 is selected from 0 to 3 R 11 is C1 ⁇ C10 alkyl group substituted with 0 to 3 R 11 substituents of C6 ⁇ C10 aryl group, 0 to 3 R 11 substituents of C6-C10 aryl C1-C3 alkyl group, 0-3 R 11 substituted C2-C20 heterocyclic group (for example );
  • R 11 is selected from halogen, cyano, nitro, carboxyl, hydroxyl, amino, C1-C10 alkyl sulfone, at least one halogen-substituted C1-C10 alkyl sulfone, C1-C10 alkane C1-C10 alkyl ester group, at least one halogen-substituted C1-C10 alkyl ester group, C1-C10 alkyl group, at least one halogen-substituted C1-C10 alkyl group, C1-C10 alkoxy group, at least one
  • the R 2 to R 9 are each independently selected from hydrogen, halogen, C1-C10 alkyl, C1-C10 alkyl substituted with at least one halogen, C1-C10 alkoxy, and C1 substituted with at least one halogen Any of ⁇ C10 alkoxy.
  • said R 2 is selected from hydrogen or chlorine.
  • the R 8 is selected from any one of methyl, methoxy or fluorine.
  • the R 7 is hydrogen
  • the benzofive-membered nitrogen heterocyclic compound has the structure shown in formula II-2;
  • R 1 , R 7 and R 8 all have the same selection range as in formula II.
  • the benzofive-membered nitrogen heterocyclic compound has the structure shown in formula III;
  • Y is selected from CR 5 or N atom
  • R 2 to R 9 are each independently selected from hydrogen, halogen, C1-C10 alkyl, C1-C10 alkyl substituted with at least one halogen, C1-C10 alkoxy, C1-C10 substituted with at least one halogen Any of alkoxy, C1-C10 alkylamide, C1-C10 alkylamide substituted with at least one halogen, C1-C10 cycloalkylamide, and C1-C10 cycloalkylamide substituted with at least one halogen A sort of;
  • R 10 is selected from the 0 to 3 R 11 is C1 ⁇ C10 alkyl group substituted with 0 to 3 R 11 substituents of C6-C10 aryl C1-C3 alkyl group, 0 to 3 R 11 substituents C2-C10 heteroaryl C1-C3 alkyl (such as pyridylmethylene), 0-3 R 11 substituted C3-C10 cycloalkyl, 0-3 R 11 substituted C3-C10 cycloalkyl Any one of C1-C3 alkyl groups; the R 11 is selected from hydrogen, halogen, cyano, carboxyl, C1-C10 alkyl, at least one halogen-substituted C1-C10 alkyl, C1-C10 alkylsulfone , at least one halogen-substituted C1-C10 alkyl sulfone group, C1-C10 alkyl ester group, at least one halogen-substi
  • R 12 and R 13 are each independently selected from hydrogen, an amino group, 0 to 3 R 14 is C1-10 alkyl substituted with 0 to 3 R 14 is C1 ⁇ C10 alkyl group substituted with an amide group, Or R 12 and R 13 together with the carbon to which they are attached form a C3-C6 carbocyclic ring; the R 14 is selected from halogen, carboxyl, hydroxyl, amino, C1-C10 alkylamide, C1-C10 alkylamino, C1 Any of ⁇ C10 alkyl ester groups.
  • the R 7 is selected from any one of methyl, methoxy, isopropylamido or cyclopentylamido.
  • the R 8 is selected from any one of methyl, methoxy, trifluoromethyl, isopropylamido or cyclopentylamido.
  • the R 12 and R 13 are each independently selected from any one of hydrogen, amino or methylamido (CH 3 -CO-NH-).
  • the benzofive-membered nitrogen heterocyclic compound has the structure shown in formula III-2;
  • the present application provides a pharmaceutically acceptable salt, isomer, racemate, prodrug, co-crystal complex or solvate of the benzofive-membered nitrogen heterocyclic compound described in the first aspect thing.
  • the pharmaceutically acceptable salts of the present application can be synthesized by conventional chemical methods from the compounds of the present application containing either a basic moiety or an acidic moiety.
  • salts of basic compounds are prepared by reaction with a suitable inorganic or organic acid in a suitable solvent or combination of solvents.
  • salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the present application include compounds of the present application by the basicity of the compounds of the present application and inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid) or organic acids (eg, acetic acid, propionic acid, Succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-amino acid Benzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid) formed by the reaction of
  • non-toxic bases including inorganic bases (including aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts salts, manganous salts, potassium salts, sodium salts, zinc salts) and salts prepared from organic bases (salts of primary, secondary and tertiary amines).
  • inorganic bases including aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts salts, manganous salts, potassium salts, sodium salts, zinc salts
  • organic bases salts prepared from organic bases (salts of primary, secondary and tertiary amines).
  • isomers refers to compounds that have the same chemical composition, but differ in the arrangement of atoms or groups in space. There are mainly diastereomers and enantiomers.
  • diastereomers refers to stereoisomers that have two or more asymmetric centers and whose molecules are not mirror images of each other.
  • enantiomers refers to two non-superimposable mirror image stereoisomers of a compound.
  • An equimolar mixture of two enantiomers is called a “racemic mixture” or “racemate”.
  • prodrug includes compounds having moieties that are metabolized in vivo. Typically, prodrugs are metabolized to the active drug in vivo by esterases or other mechanisms. These prodrugs can be prepared in situ upon final isolation and purification of the compound, or the purified compound can be reacted with a suitable esterifying agent in the acid form or hydroxyl, respectively.
  • the present application provides the benzofive-membered nitrogen heterocyclic compound described in the first aspect or the pharmaceutically acceptable salts, isomers, racemates, prodrugs, co- Application of crystalline complex or solvate in the preparation of ROR ⁇ receptor inhibitor.
  • the ROR ⁇ receptor inhibitor is used to prepare a drug for the treatment of cancer, cell proliferative disorders, inflammatory diseases and autoimmune diseases, sepsis, viral infections or neurodegenerative diseases.
  • the ROR ⁇ receptor inhibitor is used for the preparation of a medicament for the treatment of cancer.
  • the ROR ⁇ receptor inhibitor is used to prepare a medicament for the treatment of prostate cancer.
  • the present application provides a pharmaceutical composition, the active ingredient of which comprises the benzofive-membered azacyclic compound described in the first aspect or the pharmaceutically acceptable salt described in the second aspect , isomers, racemates, prodrugs, co-crystallized complexes or solvates.
  • the application provides the pharmaceutical composition of the fourth aspect in the preparation of treatment, prevention or amelioration of inflammation, autoimmune disease, cell proliferative disorder disease, sepsis, cancer, viral infection or neurodegenerative disease.
  • the medicine prepared by the ROR ⁇ receptor inhibitor, and the cancers that can be treated by the pharmaceutical composition include adrenal tumor, acoustic neuroma, acral melanoma, acral hidradenoma, acute eosinophilic leukemia, acute erythroleukemia, acute lymphoid leukemia blastocytic leukemia, acute megakaryocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adipose tissue tumor, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft sarcoma, ameloblastoma fibroma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, angiomyolipoma, angiosarcoma, astro
  • the medicine prepared by the ROR ⁇ receptor inhibitor, and the inflammatory diseases treatable by the pharmaceutical composition include inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, bone marrow inflammation, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, pancreatitis, psoriasis, allergies, Crohn's disease, intestinal syndrome, ulcerative colitis, tissue transplant rejection, organ transplant rejection, asthma, allergies Rhinitis, chronic obstructive pulmonary disease, autoimmune disease, autoimmune alopecia, anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolysis, and thrombocytopenia , pulmonary hemorrhagic nephritis syndrome, atherosclerosis, Addison's disease,
  • the medicine prepared by the ROR ⁇ receptor inhibitor, and the viral infections that can be treated by the pharmaceutical composition include human papilloma virus, herpes virus, Barr virus, human immunodeficiency virus, hepatitis B virus or hepatitis C virus infection, etc. .
  • the medicine prepared by the ROR ⁇ receptor inhibitor, and the neurodegenerative diseases treatable by the pharmaceutical composition include Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine sponge encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, multiple sclerosis, Parkinson's disease, primary lateral sclerosis or spinal muscular atrophy, etc.
  • the medicine prepared by the ROR ⁇ receptor inhibitor and the pharmaceutical composition can be suitable for various administration routes, and typical but non-limiting examples of the administration routes are: oral, buccal, inhalation, sublingual, rectal, Vaginal, intracisternal or intrathecal, via lumbar puncture, transurethral, transdermal or parenteral (including intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathecal, surgical implantation), etc.
  • compositions described herein may be in liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration used.
  • the compositions described herein can be administered in the following modes of administration: oral, parenteral, intraperitoneal, intravenous, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposome, and the like.
  • Oral pharmaceutical compositions can be solid, gel or liquid.
  • solid formulations include, but are not limited to, tablets, capsules, granules, and bulk powders. These formulations may optionally contain binders, diluents, disintegrants, lubricants, glidants, sweetening and flavoring agents, and the like.
  • binders include, but are not limited to, microcrystalline cellulose, dextrose solution, acacia mucilage, gelatin solution, sucrose, and starch paste;
  • examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate , stearic acid;
  • examples of diluents include but are not limited to lactose, sucrose, starch, mannitol, dicalcium phosphate;
  • examples of glidants include but are not limited to silicon dioxide;
  • disintegrants include but are not limited to Sodium dicarboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar and carboxymethylcellulose.
  • compositions described herein are administered parenterally, generally by injection, including subcutaneous, intramuscular or intravenous injection.
  • injectables can be prepared in any conventional form, such as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or emulsions.
  • pharmaceutically acceptable carriers that can be used in the injectable formulations of the present application include, but are not limited to, aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifying agents, chelating agents and other pharmaceutically acceptable substances.
  • aqueous vehicles include Sodium Chloride Injection, Ringer's Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringer's Injection;
  • non-aqueous vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil;
  • antimicrobial agents include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, etc.;
  • isotonic agents include sodium chloride and dextrose; buffers include phosphates and citrate.
  • compositions described in the present application can also be prepared as sterile lyophilized powder injections by dissolving the compound in a sodium phosphate buffer solution containing glucose or other suitable excipients, followed by standard conditions known to those skilled in the art. Sterile filtration of the solution, followed by lyophilization, yielded the desired formulation.
  • the cancer comprises prostate cancer.
  • the application provides a class of compounds with novel structures that can be used as ROR ⁇ receptor inhibitors, which can effectively inhibit the ROR ⁇ protein and have good selectivity for other nuclear receptor family proteins;
  • the elemental nitrogen-containing heterocyclic compounds or their pharmaceutical compositions can be used to prepare drugs for treating, preventing or improving inflammation, autoimmune diseases, cell proliferative disorders, sepsis, cancer, neurodegenerative diseases or viral infections.
  • the drug has a good inhibitory effect on the treatment of tumors, especially for prostate cancer.
  • the tumor growth inhibition rate (TGI) can reach 109%, and it can also improve the treatment of other diseases, and has a broad application prospect.
  • the compound has stable structure and simple synthesis method, and is suitable for large-scale industrial production.
  • FIG. 1 shows the tumor-inhibitory effect of Example 68 in Test Example 5 on the 22Rv1 mouse xenograft model.
  • FIG. 2 is a graph of changes in the body weight of mice in Example 68 during the administration period in Test Example 5.
  • FIG. 2 is a graph of changes in the body weight of mice in Example 68 during the administration period in Test Example 5.
  • PPA Polyphosphoric acid
  • HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • DCM N,N-diisopropyl dichloromethane
  • HOBT 1-hydroxybenzotriazole
  • EDCI 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • DMSO dimethyl sulfoxide
  • the present application provides a representative synthesis route of the compounds of formula II and formula III.
  • the benzothiazole compound has the structure shown in formula II, and the preparation method includes route 1 and route 2; the benzimidazole compound has the structure shown in formula III. , the preparation method includes route three and route four.
  • the reagents and reaction conditions added in each step are as follows: (a) KOH, H 2 O, reflux, overnight; (b): PPA, 4-aminobenzoic acid or 4-amino-2-chlorobenzoic acid, 220°C, 4h ; (c): R 1 SO 2 Cl, pyridine, 80 deg.] C, overnight; (d): R 1 COOH , HATU, DIPEA, DCM, rt, overnight; (e): NaOH, CH 3 OH, room temperature, overnight.
  • the second route is as follows:
  • the reagents and reaction conditions added in each step are as follows: (a) pyridine, 40°C, 1 hour; (b) Lawesson reagent 1,4-dioxane, 110°C, 3 hours; (c) NaOH, EtOH, ferricyanide potassium, 90 °C, 30 minutes; (d) Pd / C, H 2, 5 h, rt; e) HATU, DIPEA, DCM , rt, overnight.
  • the reagents and reaction conditions added in each step are as follows: (a) R 4 NH 2 , DIPEA, DMSO, 95°C, overnight; or R 4 NH 2 , K 2 CO 3 , DMF, 95° C., 1 hour; (b) Fe, AcOH, NH 4 Cl, H 2 O, 80°C, 1 hour; (c) 4-nitrobenzaldehyde, oxone, DMF, room temperature, 1 hour; (d) 2-(4-(ethylsulfonyl) )phenyl)acetic acid, HATU, DIPEA, DCM, room temperature, overnight; or 2-(4-(ethylsulfonyl)phenyl)acetic acid, HOBT, EDCI, DIPEA, DCM, room temperature, overnight. (e) NaOH, CH 3 OH , room temperature, overnight.
  • the reagents and reaction conditions added in each step are as follows: (a) 5-nitro-2-pyridinecarboxylic acid or 2-((tert-butoxycarbonyl)amino)-2-(4-(ethylsulfonyl)benzene yl) acetic acid, HATU, DIPEA, DCM, rt, overnight; (b) acetic acid, 120 °C, 4.5h; (c ) Fe, AcOH, ammonium chloride, H 2 O, 80 °C, 1 hours; (d) three trifluoroacetic acid (TFA), DCM, rt, 3 hours; (e) Ac 2 O, DCM, Et 3 N, room temperature, for 3 hours.
  • 6-Methylbenzo[d]thiazol-2-amine (5 g, 30.5 mmol) was suspended in a solution of KOH (25 g, 44.6 mmol) in water (50 mL) and heated at reflux overnight, the reaction was monitored by TLC. After the reaction was completed, it was cooled to ambient temperature and the pH of the solution was adjusted to 6 with acetic acid. The thick precipitate was collected by filtration and rinsed with water. The residue was partitioned and extracted between dichloromethane and water, the organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give the title compound as a yellow solid (3.4 g, yield: 80%) .
  • Polyphosphoric acid (20 g) was added to a mixture of 2-amino-5-methylbenzenethiol (2.03 g, 14.58 mmol) and 4-aminobenzoic acid (1.99 g, 14.51 mmol) and heated at 220 °C for 4 Hour.
  • the reaction was monitored by TLC. After the reaction was completed, it was cooled to ambient temperature, and the reaction mixture was slowly poured into ice-cold aqueous sodium carbonate solution (10% w/v) and stirred until gas evolution ceased.
  • the precipitated product was collected by filtration, washed with water, and the residue was partitioned and extracted between ethyl acetate and water.
  • Example 18 (40 mg, 0.09 mmol) was dissolved in 5 mL of methanol, 10 mL of 2M NaOH was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, methanol was removed under reduced pressure, the pH was adjusted to 5-6 with 1M dilute hydrochloric acid, and the precipitated solid was suction filtered to obtain the target compound as a white solid (28.8 mg, yield: 73%).
  • N-(4-Fluorophenyl)-4-nitrobenzamide (3.58 g, 13.76 mmol)
  • Lawson's reagent (2.78 g, 6.88 mmol) was added to 1,4-dioxane (20 mL) solvent , the mixture was heated to 110 °C and stirring was continued for 3 h. After completion, the reaction system was cooled to room temperature, concentrated under reduced pressure, water was added, and the precipitated solid was suction-filtered. The filter cake was washed with water and dried, and recrystallized from methanol to give the target compound as an orange solid (2.74 g, yield: 72%).
  • N-(4-Fluorophenyl)-4-nitrobenzylsulfamide (2.0 g, 7.24 mmol) was dissolved in aqueous sodium hydroxide (2.9 g, 72.4 mmol) containing 3 ml of ethanol and 30 ml of water, then To this solution was added an aqueous solution of potassium ferricyanide (9.54 g, 28.98 mmol) (20 ml) dropwise. The mixture was stirred at 90°C for 30 minutes. After the completion, the reaction system was cooled to room temperature, and a precipitate was deposited. The precipitated solid was suction filtered.
  • Iron powder (3.46 g, 61.8 mmol), ammonium chloride (551.1 mg, 10.3 mmol) and acetic acid (1.24 g, 20.6 mmol) were added to 20 mL of water and heated to 50 °C and stirred for 10 min.
  • the compound 5-methyl-N-(4-methylphenethyl)-2-nitroaniline (2.8 g, 10.3 mmol) was dissolved in 15 mL of DMF, and quickly added to the above mixed solution. Stirring was continued for 1 hour and the reaction was monitored by TLC.
  • Example 60 Using Example 60 as the raw material, the synthesis method refers to Example 19, white solid, yield: 69%.
  • Step 1 tert-Butyl(1-(4-(ethylsulfonyl)phenyl)-2-((4-(6-methyl-1-((S)-1-(p-tolyl)ethyl) )-1H benzo[d]imidazol-2-yl)phenyl)amino)-2-oxoethyl)carbamate synthesis
  • Step 5 tert-Butyl(1-(4-(ethylsulfonyl)phenyl)-2-((6-(6-methyl-1-((S)-1-(p-tolyl)ethyl) )-1H benzo[d]imidazol-2-yl)pyridin-3-yl)amino)-2-oxoethyl)carbamate synthesis
  • the protein thermal stability assay (Thermal stability shift assay, TSA) technology was used to detect the strength of the ability of the compound of the application to bind and stabilize the ROR ⁇ protein.
  • Experimental method add each component to the HSP-96-well reaction plate according to the above volume, centrifuge at 1000r/min for 1 min at room temperature, and incubate on ice for 30 min. Put the incubated 96-well reaction plate into the Real-time PCR instrument, the starting temperature is 30 °C, and the ending temperature is 80 °C, read every 5 seconds, and the temperature increases by 0.3 °C for each reading. Save the file and analyze the data using GraphPad Prism 7 software.
  • the luciferase detection technology (Luciferase) detection technology and the TSA detection technology were respectively used to verify the results.
  • the results of Luciferase are shown in Table 1, and the results of TSA are shown in Table 2.
  • A means IC 50 ⁇ 0.1 ⁇ M
  • B means 0.1 ⁇ M ⁇ IC 50 ⁇ 1 ⁇ M
  • C means 1 ⁇ M ⁇ IC 50 ⁇ 10 ⁇ M
  • D means is between 10 ⁇ M ⁇ IC 50 ⁇ 100 ⁇ M.
  • A refers to ⁇ T m ⁇ 5°C
  • B refers to the range between 5°C ⁇ T m ⁇ 10°C
  • C refers to ⁇ T m ⁇ 10°C
  • Example 35 evaluates the selectivity of Example 35, Example 54, Example 57, Example 67, Example 68 and Example 74 for ROR ⁇ and its homologous proteins in Luciferase assay.
  • Table 3 shows the activity data of Example 35, Example 54, Example 57, Example 67, Example 68 and Example 74 of the present application on ROR ⁇ and its homologous proteins in the Luciferase experiment.
  • This test example evaluated the proliferation-inhibitory effect of Example 35, Example 54, Example 67, Example 68, and Example 74 on AR-positive prostate cancer cell lines.
  • Experimental method Spread 500-1000 cells/well of 20 ⁇ L medium in a 384-well bottom permeable microplate (the actual number of cells is related to cell cycle and cell volume). After 12 hours, 10 [mu]L of culture medium containing compounds (compound concentrations ranging from 5 nM to 100 nM) were added to each well. After incubation with the compound for 72-96 h, Cell-Titer GLO reagent was added to each well, and the plate was shaken for 20 min to lyse the cells. After 10 min of incubation, centrifugation was performed for 1 min, and the luminescence 384 signal value was determined. Inhibition using GraphPad Prism software fitting curve, IC 50.
  • Table 4 shows the anti-proliferative activities of Example 35, Example 54, Example 67, Example 68 and Example 74 of the present application on AR-positive prostate cancer cell lines.
  • compound IC 50 values provided herein may be much less than the IC 50 values of the current marketed drugs Enzalutamide having more excellent effect of inhibiting prostate cancer cell proliferation.
  • Example 67 the pharmacokinetic evaluation of Example 67 and Example 68 was carried out.
  • Example 68 was dissolved in 15% polyoxyethylene ether (35) Castor oil (Cremophor EL), Calbiochem, 82.5% PBS and 2.5% dimethyl sulfoxide (DMSO) in a dosing vehicle for three consecutive weeks, five days a week.
  • TGI Tumor growth inhibition
  • Figure 2 shows that Example 68 had no significant changes in body weight and behaved normally in mice at all doses.
  • Example 68 specifically demonstrates its effect in inhibiting prostate tumor growth in vivo. According to the available evidence, it is also indicated that such compounds have the potential for the treatment of cancer, cell proliferative disorders, inflammatory diseases and autoimmune diseases, sepsis and viral infections.
  • the present application illustrates the benzofive-membered nitrogen-containing heterocyclic compounds of the present application and their application through the above-mentioned examples, but the present application is not limited to the above-mentioned examples, that is, it does not mean that the present application must rely on the above-mentioned implementation. example can be implemented.
  • Those skilled in the art should understand that any improvement to the application, the equivalent replacement of each raw material of the product of the application, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the application.

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Abstract

本申请涉及一种苯并五元氮杂环化合物及其应用，所述苯并五元氮杂环化合物具有式I所示的结构，所述化合物可作为RORγ受体抑制剂的化合物，该类化合物可有效抑制RORγ蛋白，并对其他核受体家族蛋白具有很好的选择性；本申请提供的苯并五元含氮杂环类化合物或其药物组合物可用于制备治疗、预防或改善炎症、自身免疫性疾病、细胞增殖性紊乱疾病、败血病、癌症、神经性衰退性疾病或病毒感染等疾病的药物，对肿瘤的治疗具有良好的抑制作用，特别是对于前列腺癌的疗效尤为突出，对其他疾病的治疗也具有改善作用。

Description

一种苯并五元氮杂环化合物及其应用 技术领域
本申请涉及化学医药技术领域，尤其涉及一种苯并五元氮杂环化合物及其应用。
背景技术
维甲酸受体相关孤儿受体(Retinoic acid receptor-related orphan receptor，ROR)是核受体家族中一类重要的孤儿受体。该受体家族包括3个成员，即RORα(NR1F1)，RORβ(NR1F2)和RORγ(NR1F3)，分别分布于机体的不同组织和器官中。RORα在骨骼肌、肝脏、肺、皮肤、脂肪细胞组织、肾、胸腺以及脑中广泛表达。RORβ表达部位非常有限，只在中枢神经系统中表达。RORγ存在RORγ1和RORγ2两种亚型，后一种也称为RORγt。其中RORγ1在骨骼肌，肝脏，肾脏和脂肪组织中高度表达。而RORγt仅在包括胸腺在内的免疫组织中高度表达。
TH17细胞是一种能够分泌白细胞介素17(interleukin 17，IL-17)的TH细胞亚群，IL-17作为促炎症因子在炎症发展和自身免疫性疾病中发挥着重要作用，因此调节TH17细胞分化和IL-17分泌能够调节免疫系统响应。2006年，纽约大学的Littman教授首次发现RORγ可以直接促进TH17细胞分化和发展。RORγ直接调控IL-17细胞因子的生成和分泌水平，是TH17细胞发展的一个关键因子。因此，在治疗自生免疫性疾病方面，抑制RORγ转录有希望成为新的选择策略。
前期研究发现核受体RORγ在转移去势抵抗性前列腺癌(Castration-resistant prostate cancer，CRPC)中高表达，可作用于雄激素受体(Androgen Receptor，AR)基因上游并调控AR和AR调控的相关基因的表达。RORγ抑制剂SR2211和基于结构的药物设计方法获得的XY011、XY018和XY101可显著抑制AR和AR-V7的表达，并对二代药物恩杂鲁胺耐药的细胞表现出良好的抑制效果。另外，RORγ抑制剂也在小鼠异种移植CRPC模型上抑制肿瘤生长。综上所述，通过抑制靶标RORγ可以干扰AR基因表达及下游信号通路，可为前列腺癌及其临床耐药提供一种新的治疗方法
发明内容
一方面，本申请提供了一种苯并五元氮杂环化合物。所述苯并五元氮杂环化合物作为RORγ受体抑制剂的化合物，该类化合物可有效抑制RORγ蛋白，并对其他核受体家族蛋白具有很好的选择性。
本申请提供一种苯并五元氮杂环化合物，所述苯并五元氮杂环化合物具有式I所示的结构；
Figure PCTCN2020113949-appb-000001
式I中，所述X选自
Figure PCTCN2020113949-appb-000002
波浪线代表基团的连接键；
式I中，所述Y选自CR 5或N原子；
式I中，所述Z选自S原子或NR 10；
式I中，所述R 1和R 10各自独立地选自0～3个R 11取代的C1～C10烷基、0～3个R 11取代的C6～C10芳基、0～3个R 11取代的C6-C10芳基C1-C3烷基、0～3个R 11取代的C2～C10杂芳 基、0～3个R 11取代的C2～C20杂环基、0～3个R 11取代的C2～C10杂芳基C1-C3烷基、0～3个R 11取代的C2～20杂环基C1-C3烷基、0～3个R 11取代的C3～C10环烷基、0～3个R 11取代的C3～C10环烷基C1-C3烷基中的任意一种；
所述R 11选自卤素、氰基、硝基、羧基、羟基、氨基、C1～C10烷基砜基、至少一个卤素取代的C1～C10烷基砜基、C1～C10烷基酯基、至少一个卤素取代的C1～C10烷基酯基、C1～C10烷基、至少一个卤素取代的C1～C10烷基、C1～C10烷氧基、至少一个卤素取代的C1～C10烷氧基、C3～C10环烷基、至少一个卤素取代的C3～C10环烷基中的任意一种；
式I中，所述R 2-R 9各自独立地选自氢、卤素、C1～C10烷基、至少一个卤素取代的C1～C10烷基、C1～C10烷氧基、至少一个卤素取代的C1～C10烷氧基、C1～C10烷基酰胺基、至少一个卤素取代的C1～C10烷基酰胺基、C1～C10环烷基酰胺基、至少一个卤素取代的C1～C10环烷基酰胺基、C1～C10烷基胺基、至少一个卤素取代的C1～C10烷基胺基、C3～C10环烷基氨基、至少一个卤素取代的C3～C10环烷基氨基中的任意一种。
术语“取代的”是指一个或多个指定原子上的一个或多个氢被指示基团的选择所取代，条件是不超出现有环境下指定原子的正常化合价，以及所述取代导致稳定化合物。
本申请中，卤素包括氟、氯、溴、碘。
本申请中，C2～C20杂环基指的是含有指含有2-10个C的单杂环基和10-20个C的稠杂环基。2-10个C的单杂环基是指含有1-4个杂原子(N、O或S)的饱和或部分饱和的且不具有芳香性的单环环状基团。10-20个C的稠杂环基是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的含有10-20个C原子和1-4个杂原子(N、O或S)的饱和或部分饱和的、非芳香性环状基团，所述的稠环中可以有芳香性环，但稠环整体不具备芳香性。任选地，环状结构中的环原子(例如C、N或S)可以被氧代。2-10个C单杂环基包括但不限于2H-氮杂环丙烷基、二氮杂环丙烷基、氮杂环丁烷基、1,4-二氧杂环己烷基、、1,3-二氧杂环戊烷基、二氢吡咯基、吡咯烷基、咪唑烷基、4,5-二氢咪唑基、吡唑烷基、4,5-二氢吡唑基、2,5-二氢噻吩基、4,5-二氢噻唑基、噻唑烷基、哌啶基、四氢噻吩基、四氢呋喃基、四氢吡啶基、哌啶酮基、四氢吡啶酮基、二氢哌啶酮基、哌嗪基、吗啉基。10-20个C的稠杂环基包括但不限于苯并吡咯烷基、苯并环戊基、苯并环己基、苯并四氢呋喃基、苯并吡咯烷基、苯并咪唑烷基、苯并噁唑烷基、苯并噻唑烷基、苯并异噁唑烷基、苯并异噻唑烷基、苯并哌啶基、苯并吗啉基、苯并哌嗪基、苯并四氢吡喃基、吡咯烷基并环丙基、环戊基并氮杂环丙基、吡咯烷基并环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、吡咯烷基并吗啉基、哌啶基并吗啉基、吡啶并环戊基、吡啶并环己基、吡啶并四氢呋喃基、吡啶并吡咯烷基、吡啶并咪唑烷基、吡啶并噁唑烷基、吡啶并噻唑烷基、吡啶并异噁唑烷基、吡啶并异噻唑烷基、吡啶并哌啶基、吡啶并吗啉基、吡啶并哌嗪基、吡啶并四氢吡喃基、嘧啶并环戊基、嘧啶并环己基、嘧啶并四氢呋喃基、嘧啶并吡咯烷基、嘧啶并咪唑烷基、嘧啶并噁唑烷基、嘧啶并噻唑烷基、嘧啶并异噁唑烷基、嘧啶并异噻唑烷基、嘧啶并哌啶基、嘧啶并吗啉基、嘧啶并哌嗪基、嘧啶并四氢吡喃基。
本申请中，C1～C10烷基是指具有1-10个碳原子的支化或非支化的链状烷基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、正己基等；所有碳原子可任选地被一个或多个卤素取代。
本申请中，C1～C10烷氧基是指-O-C1～C10烷基，所述的C 1～C 10烷基如前文所定义。
本申请中，C1～C10烷基酰胺基是指-CO-NH-C1～C10烷基或C1～C10烷基-CO-NH-，C1～C10烷基如前文所定义。
本申请中，C3～C10环烷基是指具有3-10个碳原子的饱和环烃；包括但不限于环丁基、环戊基、环己基等。其中烷基的所有碳原子任选地被一个或多个卤素取代。
本申请中，C3～C10环烷基C1-C3烷基是指连接至C3～C10烷基的C1-C3环烷基，两者均具有前文所定义的相同含义，C6-C10芳基C1-C3烷基、C2～C10杂芳基C1-C3烷基、C2～20杂环基C1-C3烷基均具有相同的意义，代表两种或三种基团连接而成的基团。
本申请中，C3～C10环烷基酰胺基是指-CO-NH-C3～C10环烷基或C3～C10环烷基-CO-NH-，C3～C10环烷基如前文所定义。
本申请中，C2～C10杂芳基是指含有2-10个碳原子及1-4个选自N、O及S的杂原子且包含芳族5-6元单环杂芳基及芳族7-11元杂芳基双环或稠合环(其中所述环中的至少一者为芳族环)的杂芳基环系统。5至6元单环杂芳基包括但不限于吡啶基、咪唑基、三唑基、呋喃基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基、嘧啶基、吡咯基、噻吩基。7-11元杂芳基双环或稠合环包括但不限于苯并咪唑基、喹啉基、异喹啉基、喹唑啉基、吲唑基、噻吩并嘧啶基、吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并呋喃基、苯并吡喃基、苯并噁唑基、苯并噻唑基、吡咯并吡啶基及咪唑并吡啶基。
本申请中，C1～C10烷基砜基是指-SO 2-C1～C10烷基，C1～C10烷基如前文所定义。
本申请中，C1～C10烷基酯基是指-COO-C1～C10烷基，C1～C10烷基如前文所定义。
本申请中，C1～C10烷基胺基是指-NH-C1～C10烷基，C1～C10烷基如前文所定义。
优选地，所述0～3个R 11取代的C2～C20杂环基为
Figure PCTCN2020113949-appb-000003
波浪线代表基团的连接键。
优选地，R 1中的R 11选自C1～C10烷基、卤素、三氟甲氧基、硝基、氰基、羧基、甲基酯基、乙基酯基、氨基、甲基砜基、乙基砜基中的任意一种或至少两种组合，优选氰基、乙基酯基、乙基砜基中的任意一种或至少两种组合。
优选地，所述R 2-R 5均为氢。
优选地，所述R 6、R 7、R 8和R 9不同时为氢。
优选地，所述R 6和R 9为氢。
优选地，所述R 7和R 8不同时为氢。
优选地，所述R 7和R 8中有且仅有一项为氢。
优选地，所述R 7和R 8各自独立地选自氢、甲基、甲氧基、卤素、三氟甲基、C2～C10烷基酰胺基中的任意一种或至少两种组合。
优选地，所述C2～C10烷基酰胺基为异丙基酰胺基或环戊基酰胺基。
优选地，所述R 10选自C1～C10烷基、环丁基、环丁基甲基、环己基甲基、吡啶甲基、0～3个R 11取代的苯基乙基、0～3个R 11取代的苄基中的任意一种。
优选地，R 10中的R 11选自甲基、羧基、三氟甲基、甲基酯基、卤素、氰基、甲基砜基中的任意一种或至少两种组合。
优选地，所述苯并五元氮杂环化合物具有式II所示的结构；
Figure PCTCN2020113949-appb-000004
式II中，X选自
Figure PCTCN2020113949-appb-000005
式II中，所述R 1选自0～3个R 11取代的C1～C10烷基、0～3个R 11取代的C6～C10芳基、0～3个R 11取代的C6-C10芳基C1-C3烷基、0～3个R 11取代的C2～C20杂环基(例如
Figure PCTCN2020113949-appb-000006
)中的任意一种；R 11选自卤素、氰基、硝基、羧基、羟基、氨基、C1～C10烷基砜基、至少一个卤素取代的C1～C10烷基砜基、C1～C10烷基酯基、至少一个卤素取代的C1～C10烷基酯基、C1～C10烷基、至少一个卤素取代的C1～C10烷基、C1～C10烷氧基、至少一个卤素取代的C1～C10烷氧基中的任意一种；
式II中，所述R 2～R 9各自独立地选自氢、卤素、C1～C10烷基、至少一个卤素取代的C1～C10烷基、C1～C10烷氧基、至少一个卤素取代的C1～C10烷氧基中的任意一种。
优选地，式II中，所述R 2选自氢或氯。
优选地，式II中，所述R 8选自甲基、甲氧基或氟中的任意一种。
优选地，式II中，所述R 7为氢。
优选地，所述苯并五元氮杂环化合物具有式II-2所示的结构；
Figure PCTCN2020113949-appb-000007
式II-2中，所述R 1、R 7和R 8均具有与式II中相同的选择范围。
优选地，所述苯并五元氮杂环化合物具有式III所示的结构；
Figure PCTCN2020113949-appb-000008
式III中，Y选自CR 5或N原子；
式III中，R 2～R 9各自独立地选自氢、卤素、C1～C10烷基、至少一个卤素取代的C1～C10烷基、C1～C10烷氧基、至少一个卤素取代的C1～C10烷氧基、C1～C10烷基酰胺基、至少一个卤素取代的C1～C10烷基酰胺基、C1～C10环烷基酰胺基、至少一个卤素取代的C1～C10环烷基酰胺基中的任意一种；
式III中，所述R 10选自0～3个R 11取代的C1～C10烷基、0～3个R 11取代的C6-C10芳基C1-C3烷基、0～3个R 11取代的C2～C10杂芳基C1-C3烷基(例如吡啶基亚甲基)、0～3个R 11取代的C3～C10环烷基、0～3个R 11取代的C3～C10环烷基C1-C3烷基中的任意一种；所述R 11选自氢、卤素、氰基、羧基、C1～C10烷基、至少一个卤素取代的C1～C10烷基、C1～C10烷基砜基、至少一个卤素取代的C1～C10烷基砜基、C1～C10烷基酯基、至少一个卤素取代的C1～C10烷基酯基；
式III中，所述R 12及R 13各自独立地选自氢、氨基、0～3个R 14取代的C1-10烷基、0～3个R 14取代的C1～C10烷基酰胺基，或R 12及R 13与其所连接的碳一起形成C3-C6碳环；所述R 14选自卤素、羧基、羟基、氨基、C1～C10烷基酰胺基、C1～C10烷基胺基、C1～C10烷基酯基中的任意一种。
优选地，所述R 7选自甲基、甲氧基、异丙基酰胺基或环戊基酰胺基中的任意一种。
优选地，所述R 8选自甲基、甲氧基、三氟甲基、异丙基酰胺基或环戊基酰胺基中的任意一种。
优选地，所述R 12和R 13各自独立地选自氢、氨基或甲基酰胺基(CH 3-CO-NH-)中的任意一种。
优选地，所述苯并五元氮杂环化合物具有式III-2所示的结构；
Figure PCTCN2020113949-appb-000009
式III中，所述Y、R 7、R 8、R 10和R 12均具有与式III中相同的选择范围。
第二方面，本申请提供了第一方面所述的苯并五元氮杂环化合物的药学上可接受的盐、异构体、外消旋体、前体药物、共结晶复合物或溶剂合物。
本申请可通过常规化学方法自含有碱性部分或酸性部分的本申请化合物合成本申请的药学上可接受的盐。通常，通过和适当的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的，通过和适当的无机或有机碱反应形成酸性化合物的盐。因此，本申请化合物的药学上可接受的盐包括通过碱性本申请化合物和无机酸(例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸)或有机酸(例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基-苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸)反应形成的本申请化合物的常规无毒盐。
如果本申请化合物为酸性的，则包括通过药学上可接受的无毒碱包括无机碱(包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐)及有机碱(伯胺、仲胺和叔胺的盐)制备的盐。
术语“异构体”指的是具有相同的化学构成，但是原子或基团的空间排布不同的化合物。主要有非对映异构体(diastereomers)和对映异构体(enantiomers)。
术语“非对映异构体(diastereomers)”指的是具有两个或更多个不对称中心并且其分子不是彼此镜像的立体异构体。
术语“对映异构体(enantiomers)”是指一种化合物的两种互为不能重叠的镜像立体异构体。两种对映异构体的等摩尔混合物被称为“消旋混合物”或“消旋体”。
术语“前体药物(prodrug)”包括具有可在体内代谢的部分的化合物。通常，药物前体在体内通过酯酶或者其他机制代谢为活性药物。可以在化合物最终分离和纯化时原位制备这些药物前体，或将纯化的化合物以酸形式或羟基分别地与适合的酯化剂进行反应。
第三方面，本申请提供了第一方面所述的苯并五元氮杂环化合物或者第二方面所述的药学上可接受的盐、异构体、外消旋体、前体药物、共结晶复合物或溶剂合物在制备RORγ受体抑制剂的应用。
优选地，所述RORγ受体抑制剂用于制备治疗癌症、细胞增殖性紊乱疾病、炎症疾病及自身免疫疾病、败血症、病毒感染或神经性衰退性疾病的药物。
优选地，所述RORγ受体抑制剂用于制备治疗癌症的药物。
优选地，所述RORγ受体抑制剂用于制备治疗前列腺癌的药物。
第四方面，本申请提供了一种药物组合物，所述药物组合物的活性成分包括第一方面所 述的苯并五元氮杂环化合物或者第二方面所述的药学上可接受的盐、异构体、外消旋体、前体药物、共结晶复合物或溶剂合物。
第五方面，本申请提供了第四方面所述的药物组合物在制备治疗、预防或改善炎症、自身免疫性疾病、细胞增殖性紊乱疾病、败血病、癌症、病毒感染或神经性衰退性疾病的药物中的应用。
所述RORγ受体抑制剂制备的药物，以及所述药物组合物可治疗的癌症包括肾上腺肿瘤、听神经瘤、肢端黑色素瘤、肢端汗腺瘤、急性嗜酸性白血病、急性红色的白血病、急性淋巴母细胞性白血病、急性巨核细胞白血病、急性单核细胞的白血病、急性早幼粒细胞性白血病、腺癌、腺样囊性癌、脂肪组织肿瘤、肾上腺皮质癌、成人T细胞白血病/淋巴瘤、艾滋病相关淋巴瘤、肺泡横纹肌肉瘤、肺泡软肉瘤、成釉细胞的纤维瘤、间变性大细胞淋巴瘤、未分化甲状腺癌、血管肌脂肪瘤、血管肉瘤、星形细胞瘤、非典型畸形杆状的肿瘤、B细胞慢性淋巴细胞白血病、B细胞前淋巴细胞白血病、B细胞淋巴瘤、基底细胞癌、胆道癌、膀胱癌、胚细胞瘤、骨肿瘤、棕色肿瘤、伯基特淋巴瘤、乳腺癌、脑癌、原位癌、软骨瘤、牙骨质瘤、髓系肉瘤、软骨瘤、脊索瘤、绒毛膜癌、脉络丛乳头状瘤、肾透明细胞肉瘤、颅咽管瘤、皮肤t细胞淋巴瘤、宫颈癌、结肠癌、小圆细胞肿瘤、细胞弥漫型B细胞淋巴瘤、神经上皮的肿瘤、无性细胞瘤、胚胎性癌内分泌腺肿瘤、内胚层窦肿瘤、食道癌、纤维瘤、纤维肉瘤、滤泡淋巴瘤、滤泡星形胶质细胞瘤、甲状腺癌胃肠道癌症、生殖细胞肿瘤、妊娠期绒毛膜癌、巨细胞成纤维细胞瘤、骨巨细胞瘤、神经胶质细胞瘤、多形性胶质母细胞瘤、神经胶质瘤、颗粒细胞瘤、男性细胞瘤、胆囊癌症、胃癌、成血管细胞瘤、头部和颈部癌症、血管外皮细胞瘤恶性肿瘤、肝母细胞癌、细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、浸润性小叶癌、肠道癌症、肾癌、喉癌、致命的中线癌、白血病、睾丸间质细胞瘤、脂肪肉瘤、肺癌、淋巴管瘤、淋巴上皮瘤、淋巴瘤、急性淋巴管肉瘤，淋巴细胞性白血病、慢性淋巴细胞白血病、肝癌，小细胞肺癌、非小细胞肺癌、麦芽淋巴瘤、恶性纤维组织细胞瘤、恶性周围神经鞘瘤、边缘区b细胞淋巴瘤、肥大细胞白血病、纵隔生殖细胞肿瘤、乳腺髓样癌、髓样甲状腺癌、成神经管细胞瘤、黑色素瘤、脑膜瘤、默克尔细胞癌症、间皮瘤、转移性细胞癌、混合缪氏肿瘤、粘液性肿瘤、多发性骨髓瘤、肌肉组织肿瘤、蕈样黏液样脂肪肉瘤、粘液瘤、粘液肉瘤、鼻咽癌、神经母细胞瘤、神经纤维瘤、神经瘤、眼部癌症、嗜酸性、视神经鞘脑膜瘤、肿瘤、口腔癌、骨肉瘤、卵巢癌、乳头状甲状腺癌、肿瘤副神经节瘤、成松果体细胞瘤、垂体细胞瘤、前体T-淋巴母细胞性淋巴瘤、原发性中枢神经系统淋巴瘤，腹膜癌、前列腺癌、胰腺癌、咽癌、肾细胞癌、肾髓样癌、成视网膜细胞瘤、横纹肌瘤、横纹肌肉瘤、直肠癌、肉瘤、精原细胞瘤、滋养细胞肿瘤、皮肤癌、小圆细胞肿瘤、小细胞癌、软组织肉瘤、生长抑素瘤、脊髓肿瘤、脾边缘带淋巴瘤、鳞状细胞癌、滑膜肉瘤、小肠癌症、鳞状细胞癌、胃癌、T细胞淋巴瘤、睾丸癌、甲状腺癌症、移行细胞癌、喉癌、脐尿管癌、泌尿生殖癌症、子宫癌症、疣状癌、视觉途径神经胶质瘤、外阴癌或阴道癌等。
所述RORγ受体抑制剂制备的药物，以及所述药物组合物可治疗的炎症疾病包括炎症盆腔疾病、尿道炎、皮肤晒伤、鼻窦炎、肺炎、脑炎、脑膜炎、心肌炎、肾炎、骨髓炎、肌炎、肝炎、胃炎、肠炎、皮炎、牙龈炎、胰腺炎、牛皮癣、过敏、克罗恩氏病、肠道综合症、溃疡性结肠炎、组织移植排斥、器官移植排斥、哮喘、过敏性鼻炎、慢性阻塞性肺疾病、自身免疫性疾病、自身免疫性脱发、贫血、肾小球肾炎、皮肌炎、多发性硬化症、硬皮病、血管炎、自身免疫性溶血性和血小板减少、肺出血肾炎综合征、动脉粥样硬化、阿狄森氏病、帕金森氏症、阿尔茨海默氏症、糖尿病、感染性休克、系统性红斑狼疮、类风湿性关节炎、银 屑病关节炎、骨关节炎、慢性特发性血小板减少性紫癜、重症肌无力、桥本甲状腺炎、过敏性皮肤炎、退化性关节疾病、格林-巴利综合征、蕈样真菌病或急性炎症反应等。
所述RORγ受体抑制剂制备的药物，以及所述药物组合物可治疗的病毒感染包括人类乳头瘤病毒、疱疹病毒、巴尔病毒、人类免疫缺陷病毒、乙型肝炎病毒或丙型肝炎病毒感染等。
所述RORγ受体抑制剂制备的药物，以及所述药物组合物可治疗的神经性衰退性疾病包括阿兹海默病、肌肉萎缩性侧索硬化症、共济失调毛细血管扩张症、牛海绵状脑病、克雅二氏病、亨廷顿氏病、小脑萎缩症、多发性硬化症、帕金森氏病、原发性侧索硬化或脊髓性肌萎缩症等。
所述RORγ受体抑制剂制备的药物，以及所述药物组合物可适用于各种给药途径，所述给药途径典型但非限制性实例有：口服、颊、吸入、舌下、直肠、阴道、脑池内的或鞘内、通过腰椎穿刺、经尿道、经皮肤或肠外(包括静脉注射、肌肉注射、皮下、行皮内注射、腹腔内、鞘内、手术植入)等。
本申请所述的药物组合物可以是液体、半液体或固体形式，按照适合于所用的给药途径的方式配制。本申请所述的组合物可以按照下列给药方式给药：口服、肠胃外、腹膜内、静脉内、透皮、舌下、肌内、直肠、口腔、鼻内、脂质体等方式。
口服的药物组合物可以是固体、凝胶或液体。固体制剂的实例包括但不限于片剂、胶囊剂、颗粒剂和散装粉剂。这些制剂可以选择地含有粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂和矫味剂等。粘合剂的实例包括但不限于微晶纤维素、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；润滑剂的实例包括但不限于滑石、淀粉、硬脂酸镁、硬脂酸钙、硬脂酸；稀释剂的实例包括但不限于乳糖、蔗糖、淀粉、甘露糖醇、磷酸二钙；助流剂的实例包括但不限于二氧化硅；崩解剂的实例包括但不限于交联羧甲基纤维素钠、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂和羧甲基纤维素。
以肠胃外给予本申请所述药物组合物，一般以注射为主，包括皮下、肌内或静脉内注射。注射剂可以被制成任何常规形式，如液体溶液或悬液、适合于在注射之前溶解或悬浮在液体中的固体形式或者乳剂。可用于本申请注射剂的药学上可接收的载体的实例包括但不限于水性载体、非水性载体、抗微生物剂、等渗剂、缓冲剂、抗氧剂、悬浮与分散剂、乳化剂、螯合剂和其它药学上可接受的物质。水性载体的实例包括氯化钠注射液、林格式注射液、等渗葡萄糖注射液、无菌水注射液、葡萄糖与乳酸化林格氏注射液；非水性载体的实例包括植物来源的固定油、棉籽油、玉米油、芝麻油和花生油；抗微生物剂的实例包括间甲酚、苄醇、氯丁醇、苯扎氯铵等；等渗剂的实例包括氯化钠和葡萄糖；缓冲剂包括磷酸盐和柠檬酸盐。
本申请所述药物组合物还可以制备成无菌的冻干粉针剂，将化合物溶于磷酸钠缓冲溶液，其中含有葡萄糖或其他适合的赋形剂，随后在本领域技术人员已知的标准条件下将溶液无菌过滤，继之以冷冻干燥，得到所需的制剂。
优选地，所述癌症包括前列腺癌。
相较于现有技术，本申请具有如下有益效果：
本申请提供了一类结构新颖的可作为RORγ受体抑制剂的化合物，该类化合物可有效抑制RORγ蛋白，并对其他核受体家族蛋白具有很好的选择性；本申请提供的苯并五元含氮杂环类化合物或其药物组合物可用于制备治疗、预防或改善炎症、自身免疫性疾病、细胞增殖性紊乱疾病、败血病、癌症、神经性衰退性疾病或病毒感染等疾病的药物，对肿瘤的治疗具有良好的抑制作用，特别是对于前列腺癌的疗效尤为突出，肿瘤生长抑制率(TGI)可达109％，对其他疾病的治疗也具有改善作用，具有广阔的应用前景。该类化合物结构稳定，合成方法 简单，适合大规模工业化生产。
附图说明
图1是测试例5中实施例68在22Rv1小鼠移植瘤模型上对肿瘤的抑制效果。
图2是测试例5中实施例68在用药期间小鼠体重变化图。
具体实施方式
为便于理解本申请，本申请列举实施例如下。本领域技术人员应该明了，所述实施例仅仅是帮助理解本申请，不应视为对本申请的具体限制。
以下具体实施方式中涉及到的英文或英文缩写所代表的意义如下：
多聚磷酸(PPA)；2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)；N,N-二异丙基乙胺(DIPEA)；二氯甲烷(DCM)；1-羟基苯并三氮唑(HOBT)；1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)；二甲基亚砜(DMSO)。
本申请提供式II和式III化合物的代表合成路径，苯并噻唑类化合物具有如式II所示的结构，制备方法包括路线一、路线二；苯并咪唑类化合物具有如式III所示的结构，制备方法包括路线三、路线四。
路线一具体如下所示：
Figure PCTCN2020113949-appb-000010
各步骤中添加的试剂和反应条件如下：(a)KOH，H 2O，回流，过夜；(b)：PPA，4-氨基苯甲酸或4-氨基-2-氯苯甲酸，220℃，4h；(c)：R 1SO 2Cl，吡啶，80℃，过夜；(d)：R 1COOH，HATU，DIPEA，DCM，室温，过夜；(e)：NaOH，CH 3OH，室温，过夜。
路线二具体如下所示：
Figure PCTCN2020113949-appb-000011
各步骤中添加的试剂和反应条件如下：(a)吡啶，40℃，1小时；(b)Lawesson试剂1,4-二恶烷，110℃，3小时；(c)NaOH，EtOH，铁氰化钾，90℃，30分钟；(d)Pd/C，H 2，5小时，室温；e)HATU，DIPEA，DCM，室温，过夜。
路线三具体如下所示：
Figure PCTCN2020113949-appb-000012
各步骤中添加的试剂和反应条件如下：(a)R 4NH 2，DIPEA，DMSO，95℃，过夜；或R 4NH 2，K 2CO 3，DMF，95℃，1小时；(b)Fe，AcOH，NH 4Cl，H 2O，80℃，1小时；(c)4-硝基苯甲醛，oxone，DMF，室温，1小时；(d)2-(4-(乙基磺酰基)苯基)乙酸，HATU，DIPEA，DCM，室温，过夜；或2-(4-(乙基磺酰基)苯基)乙酸，HOBT，EDCI，DIPEA，DCM，室温，过夜。(e)NaOH，CH 3OH，室温，过夜。
路线四具体如下所示：
：
Figure PCTCN2020113949-appb-000013
各步骤中添加的试剂和反应条件如下：(a)5-硝基-2-吡啶羧酸或2-((叔丁氧基羰基)氨基)-2-(4-(乙基磺酰基)苯基)乙酸，HATU，DIPEA，DCM，室温，过夜；(b)乙酸，120℃，4.5h；(c)Fe，AcOH，氯化铵，H 2O，80℃，1小时；(d)三氟乙酸(TFA)，DCM，室温，3小时；(e)Ac 2O，DCM，Et 3N，室温，3小时。
上述制备方法是以说明为的目，而非用来局限于所列化合物或任何特定的取代基。方案中显示的取代基数目并不必需符合权利要求中所用的数目，且为清楚起见，显示单取代基连接到在上文中式II和式III的定义下允许有多取代基的化合物上，通过变换取代基的数量和取代位置可以获得通式I所包含的所有化合物。
实施例1 4-甲基-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)苯磺酰胺
步骤1、2-氨基-5-甲基苯硫醇的合成
Figure PCTCN2020113949-appb-000014
将6-甲基苯并[d]噻唑-2-胺(5g，30.5mmol)悬浮在KOH(25g，44.6mmol)的水(50mL)溶液中，加热回流过夜，反应通过TLC监测。反应结束后冷却至环境温度，用乙酸将溶液调节pH至6。过滤收集浓稠的沉淀物并用水冲洗。将将残余物在二氯甲烷和水之间分配萃取，将有机层用盐水洗涤，无水Na 2SO 4干燥，真空中浓缩，得到目标化合物为黄色固体(3.4g，产率：80％)。 1H NMR(400MHz,DMSO-d 6)δ6.91(dd,J＝8.2,1.7Hz,1H),6.81(d,J＝1.4Hz,1H),6.64(d,J＝8.2Hz,1H),5.21(s,2H),2.05(s,3H).
步骤2、4-(6-甲基苯并[d]噻唑-2-基)苯胺的合成
Figure PCTCN2020113949-appb-000015
将多聚磷酸(20g)加入到2-氨基-5-甲基苯硫醇(2.03g，14.58mmol)和4-氨基苯甲酸(1.99g，14.51mmol)的混合物中，在220℃下加热4小时。反应通过TLC监测。反应结束后冷却至环境温度，将反应混合物缓慢倒入冰冷的碳酸钠水溶液(10％w/v)中，搅拌直至气体逸出停止。过滤收集沉淀产物，用水洗涤，将残余物在乙酸乙酯和水之间分配萃取。将有机层用盐水洗涤，无水硫酸钠干燥，真空中浓缩，并将粗产物通过硅胶柱色谱(PE:EA＝4:1,v/v)纯化，得到目标化合物为棕色固体(3.14g，产率：90％)。 1H NMR(400MHz,DMSO-d 6)δ7.80(s,1H),7.77(d,J＝8.3Hz,1H),7.72(d,J＝8.6Hz,2H),7.26(dd,J＝8.3,1.1Hz,1H),6.65(d,J＝8.6Hz,2H),5.85(s,2H),2.42(s,3H).
步骤3、4-甲基-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)苯磺酰胺(4a)的合成
Figure PCTCN2020113949-appb-000016
将化合物4-(6-甲基苯并[d]噻唑-2-基)苯胺(73mg，0.3mmol)和4-甲基苯磺酰氯(85.8mg，0.45mmol)溶于10mL吡啶中，80℃反应4h。TLC监测反应，反应结束后冷却至室温，向反应混合物中加入30mL稀盐酸，乙酸乙酯萃取三次(50mL×3)，合并有机相，再用饱和食盐水洗涤一遍，无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(PE:EA＝4:1v/v)，得到目标化合物为白色固体(37mg，产率：31％)。 1H NMR(500MHz,DMSO-d 6)δ10.71(s,1H),7.93(d,J＝8.7Hz,2H),7.90–7.85(m,2H),7.72(d,J＝8.3Hz,2H),7.37(d,J＝8.2Hz,2H),7.32(dd,J＝8.4,1.1Hz,1H),7.27(d,J＝8.7Hz,2H),2.43(s,3H),2.32(s,3H).MS(ESI),m/z for C 21H 18N 2O 2S 2([M+H] +):Calcd 394.51,found 395.0.
实施例2 4-(叔丁基)-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)苯磺酰胺
Figure PCTCN2020113949-appb-000017
合成方法如实施例1，白色固体，产率：79％。 1H NMR(400MHz,DMSO-d 6)δ10.75(s,1H),7.94(d,J＝8.7Hz,2H),7.90–7.84(m,2H),7.78(d,J＝8.5Hz,2H),7.60(d,J＝8.6Hz,2H),7.35–7.26(m,3H),2.44(s,3H),1.25(s,9H).MS(ESI),m/z for C 24H 24N 2O 2S 2([M+H] +):Calcd436.59,found 437.2.
实施例3 4-氟-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)苯磺酰胺
Figure PCTCN2020113949-appb-000018
合成方法如实施例1，白色固体，产率：61％。 1H NMR(400MHz,DMSO-d 6)δ10.76(s,1H),7.95(d,J＝8.7Hz,2H),7.92–7.86(m,4H),7.42(t,J＝8.8Hz,2H),7.33(dd,8.4,0.8Hz,1H),7.28(d,J＝8.7Hz,2H),2.44(s,3H).MS(ESI),m/z for C 20H 15FN 2O 2S 2([M+H] +):Calcd 398.47,found 398.9.
实施例4 N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-4-(三氟甲氧基)苯磺酰胺
Figure PCTCN2020113949-appb-000019
合成方法如实施例1，白色固体，产率：74％。 1H NMR(400MHz,DMSO-d 6)δ10.87(s,1H),8.00–7.92(m,4H),7.91–7.85(m,2H),7.58(d,J＝8.3Hz,2H),7.33(d,J＝8.5Hz,1H),7.29(d,J＝8.7Hz,2H),2.44(s,3H).MS(ESI),m/z for C 21H 15F 3N 2O 3S 2([M+H] +):Calcd 464.48,found465.0.
实施例5 N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-4-硝基苯磺酰胺
Figure PCTCN2020113949-appb-000020
合成方法如实施例1，白色固体，产率：50％。 1H NMR(400MHz,DMSO-d 6)δ11.04(s,1H),8.39(d,J＝8.9Hz,2H),8.07(d,J＝8.9Hz,2H),7.97(d,J＝8.7Hz,2H),7.91–7.85(m,2H),7.36–7.27(m,3H),2.44(s,3H).MS(ESI),m/z for C 20H 15N 3O 4S 2([M+H] +):Calcd 425.48,found 426.0.
实施例6 N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-3-硝基苯磺酰胺
Figure PCTCN2020113949-appb-000021
合成方法如实施例1，白色固体，产率：38％。 1H NMR(400MHz,DMSO-d 6)δ11.01(s,1H),8.58–8.54(m,1H),8.46(dd,J＝8.2,1.6Hz,1H),8.21(d,J＝7.9Hz,1H),7.96(d,J＝8.6Hz,2H),7.91–7.85(m,3H),7.36–7.27(m,3H),2.44(s,3H).MS(ESI),m/z for C 20H 15N 3O 4S 2([M+H] +):Calcd 425.48,found 426.0.
实施例7 N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-2-硝基苯磺酰胺
Figure PCTCN2020113949-appb-000022
合成方法如实施例1，白色固体，产率：54％。 1H NMR(400MHz,DMSO-d 6)δ11.16(s,1H),8.07–8.03(m,1H),8.03–7.95(m,3H),7.91–7.81(m,4H),7.36–7.32(m,1H),7.30(d,J＝8.7 Hz,2H),2.44(s,3H).MS(ESI),m/z for C 20H 15N 3O 4S 2([M+H] +):Calcd 425.48,found 426.0.
实施例8 N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-3-(甲磺酰基)苯磺酰胺
Figure PCTCN2020113949-appb-000023
合成方法如实施例1，白色固体，产率：34％。 1H NMR(400MHz,DMSO-d 6)δ10.93(s,1H),8.32(s,1H),8.20(d,J＝7.7Hz,1H),8.12(d,J＝8.0Hz,1H),7.96(d,J＝8.6Hz,2H),7.92–7.84(m,3H),7.33(d,J＝8.8Hz,1H),7.29(d,J＝8.6Hz,2H),3.28(s,3H),2.44(s,3H).MS(ESI),m/z for C 21H 18N 2O 4S 3([M+H] +):Calcd 458.57,found 459.2.
实施例9 2，4-二氟-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)苯磺酰胺
Figure PCTCN2020113949-appb-000024
合成方法如实施例1，白色固体，产率：73％。 1H NMR(400MHz,DMSO-d 6)δ11.13(s,1H),8.03–7.92(m,3H),7.90–7.85(m,2H),7.58–7.50(m,1H),7.36–7.24(m,4H),2.44(s,3H).MS(ESI),m/z for C 20H 14F 2N 2O 2S 2([M+H] +):Calcd 416.46,found 417.1.
实施例10 2，4，6-三甲基-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)苯磺酰胺
Figure PCTCN2020113949-appb-000025
合成方法如实施例1，白色固体，产率：72％。 1H NMR(400MHz,DMSO-d 6)δ10.69(s,1H),7.92(d,J＝8.7Hz,2H),7.89–7.83(m,2H),7.32(dd,J＝8.4,0.8Hz,1H),7.13(d,J＝8.7Hz,2H),7.03(s,2H),2.61(s,6H),2.43(s,3H),2.21(s,3H).MS(ESI),m/z for C 23H 22N 2O 2S 2([M-H] -):Calcd 422.56,found 421.2.
实施例11 1-乙基N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺
Figure PCTCN2020113949-appb-000026
合成方法如实施例1，白色固体，产率：19％。 1H NMR(500MHz,DMSO-d 6)δ11.06(s,1H),8.74(d,J＝8.4Hz,1H),8.26(d,J＝7.7Hz,1H),8.13(d,J＝7.0Hz,1H),8.00–7.93(m,1H),7.90–7.81(m,4H),7.32–7.28(m,2H),7.24(d,J＝8.8Hz,2H),3.88(q,J＝7.1Hz,2H),2.42(s,3H),1.22(t,J＝7.2Hz,3H).MS(ESI),m/z for C 27H 21N 3O 3S 2([M+H] +):Calcd 499.60,found500.02.
实施例12 N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-1-(对甲苯基)甲磺酰胺
Figure PCTCN2020113949-appb-000027
合成方法如实施例1，白色固体，产率：31％。 1H NMR(400MHz,DMSO)δ10.22(s,1H),8.01(d,J＝8.7Hz,2H),7.94–7.87(m,2H),7.38–7.30(m,3H),7.20–7.09(m,4H),4.51(s,2H),2.46(s,3H),2.28(s,3H).MS(ESI),m/z for C 22H 20N 2O 2S 2([M+H] +):Calcd 408.53,found 409.0.
实施例13 1-(4-氟苯基)-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)甲磺酰胺
Figure PCTCN2020113949-appb-000028
合成方法如实施例1，白色固体，产率：26％。 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),8.01(d,J＝8.7Hz,2H),7.94–7.87(m,2H),7.38–7.27(m,5H),7.19(t,J＝8.9Hz,2H),4.60(s,2H),2.46(s,3H).MS(ESI),m/z for C 21H 17FN 2O 2S 2([M–1] –):Calcd 412.50,found 411.1.
实施例14 N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-1-(4-(三氟甲基)苯基)甲磺酰胺
Figure PCTCN2020113949-appb-000029
合成方法如实施例1，白色固体，产率：47％。 1H NMR(500MHz,DMSO-d 6)δ10.34(s,1H),8.01(d,J＝8.7Hz,2H),7.94–7.88(m,2H),7.74(d,J＝8.2Hz,2H),7.51(d,J＝8.1Hz,2H),7.38–7.30(m,3H),4.75(s,2H),2.46(s,3H).MS(ESI),m/z for C 22H 17F 3N 2O 2S 2([M+H] +):Calcd 462.51,found 463.0.
实施例15 N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-1-(4-硝基苯基)甲磺酰胺
Figure PCTCN2020113949-appb-000030
合成方法如实施例1，白色固体，产率：40％。 1H NMR(400MHz,DMSO-d 6)δ10.36(s,1H),8.22(d,J＝8.7Hz,2H),8.02(d,J＝8.6Hz,2H),7.94–7.88(m,2H),7.57(d,J＝8.7Hz,2H),7.38–7.31(m,3H),4.81(s,2H),2.46(s,3H).MS(ESI),m/z for C 21H 17N 3O 4S 2([M+H] +):Calcd439.50,found 440.0.
实施例16 1-(4-氰基苯基)-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)甲磺酰胺
Figure PCTCN2020113949-appb-000031
合成方法如实施例1，白色固体，产率：22％。 1H NMR(500MHz,DMSO-d 6)δ10.36(s,1H),8.02(d,J＝8.7Hz,2H),7.94–7.88(m,2H),7.85(d,J＝8.2Hz,2H),7.48(d,J＝8.2Hz,2H),7.38–7.30(m,3H),4.75(s,2H),2.46(s,3H).MS(ESI),m/z for C 22H 17N 3O 2S 2([M+H] +):Calcd419.52,found 420.0.
实施例17 N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-1-(4-(甲基磺酰基)苯基)甲磺酰胺
Figure PCTCN2020113949-appb-000032
合成方法如实施例1，白色固体，产率：60％。 1H NMR(400MHz,DMSO-d 6)δ10.37(s,1H),8.02(d,J＝8.7Hz,2H),7.94–7.88(m,4H),7.56(d,J＝8.3Hz,2H),7.39–7.30(m,3H),4.76(s,2H),3.20(s,3H),2.46(s,3H).MS(ESI),m/z for C 22H 20N 2O 4S 3([M+H] +):Calcd 472.59,found472.9.
实施例18 4-((N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)氨磺酰基)甲基)苯甲酸甲酯
Figure PCTCN2020113949-appb-000033
合成方法如实施例1，白色固体，产率：30％。 1H NMR(500MHz,DMSO-d 6)δ10.33(s,1H),8.01(d,J＝8.6Hz,2H),7.95–7.89(m,4H),7.43(d,J＝8.2Hz,2H),7.37–7.30(m,3H),4.71(s,2H),3.83(s,3H),2.46(s,3H).MS(ESI),m/z for C 23H 20N 2O 4S 2([M+H] +):Calcd 452.54,found453.0.
实施例19 4-((N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)氨磺酰基)甲基)苯甲酸
Figure PCTCN2020113949-appb-000034
将实施例18(40mg，0.09mmol)溶于5mL甲醇，加入10mL 2M的NaOH，室温搅拌2h。反应结束，减压旋去甲醇，用1M的稀盐酸调节pH至5～6，将析出的固体抽滤，得到目标化合物为白色固体(28.8mg，产率：73％) 1H NMR(500MHz,DMSO-d 6)δ10.38(s,1H),8.23(d,J＝8.7Hz,2H),8.02(d,J＝8.7Hz,2H),7.94–7.88(m,2H),7.57(d,J＝8.6Hz,2H),7.38–7.31(m,3H),4.82(s,2H),2.46(s,3H).MS(ESI),m/z for C 22H 18N 2O 4S 2([M+H] +):Calcd438.52,found 440.0.MS(ESI),m/z for C 23H 20N 2O 4S 2([M+H] +):Calcd 452.54,found 453.0.
实施例20 4-((N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)氨磺酰基)甲基)苯基丙酸酯
Figure PCTCN2020113949-appb-000035
合成方法如实施例1，白色固体，产率：55％。 1H NMR(400MHz,DMSO-d 6)δ10.30(s,1H),8.01(d,J＝8.7Hz,2H),7.95–7.87(m,4H),7.42(d,J＝8.2Hz,2H),7.38–7.29(m,3H),4.70(s,2H),4.29(q,J＝7.1Hz,2H),2.46(s,3H),1.28(t,J＝7.1Hz,3H).MS(ESI),m/z for C 24H 22N 2O 4S 2([M+H] +):Calcd 466.57,found 467.1.
实施例21 N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-1-(3-硝基苯基)甲磺酰胺
Figure PCTCN2020113949-appb-000036
合成方法如实施例1，白色固体，产率：55％。 1H NMR(400MHz,DMSO-d 6)δ10.33(s,1H),8.21(d,J＝8.2Hz,1H),8.16(s,1H),8.00(d,J＝8.7Hz,2H),7.94–7.88(m,2H),7.74(d,J＝7.7Hz,1H),7.67(t,J＝7.8Hz,1H),7.38–7.29(m,3H),4.83(s,2H),2.46(s,3H).MS(ESI),m/z for C 21H 17N 3O 4S 2([M-H] -):Calcd 439.50,found 438.0.
实施例22 N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-1-(2-硝基苯基)甲磺酰胺
Figure PCTCN2020113949-appb-000037
合成方法如实施例1，白色固体，产率：20％。 1H NMR(400MHz,DMSO-d 6)δ10.47(s,1H),8.04(d,J＝8.1Hz,1H),8.00(d,J＝8.6Hz,2H),7.94–7.89(m,2H),7.73(td,J＝7.6,0.7Hz,1H),7.64(t,J＝7.5,Hz,1H),7.50(d,J＝7.0Hz,1H),7.35(dd,J＝8.5,0.8Hz,1H),7.28(d,J＝8.7Hz,2H),5.05(s,2H),2.46(s,3H).MS(ESI),m/z for C 21H 17N 3O 4S 2([M+H] +):Calcd 439.50,found440.0.
实施例23 3-((N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)氨磺酰基)甲基)苯甲酸甲酯
Figure PCTCN2020113949-appb-000038
合成方法如实施例1，白色固体，产率：25％。 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),8.00(d,J＝8.6Hz,2H),7.95–7.86(m,4H),7.58–7.48(m,2H),7.37–7.28(m,3H),4.71(s,2H),3.83(s,3H),2.46(s,3H).MS(ESI),m/z for C 23H 20N 2O 4S 2([M+H] +):Calcd 452.54,found 453.0.
实施例24 1-(3-氨基苯基)-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)甲磺酰胺
Figure PCTCN2020113949-appb-000039
将实施例21(50mg，0.11mmol)，10％钯碳(约含水55％)(100mg)，加入到MeOH(10mL)溶剂中，并在氢气环境中于室温搅拌过夜。结束后，使用硅藻土助滤将混合物抽滤，并将滤液浓缩，得到粗产物，硅胶柱层析分离(PE:EA＝4:1,v/v)，得到目标化合物为白色固体(13mg，产率：29％)。 1H NMR(400MHz,DMSO-d 6)δ10.24(s,1H),8.15–7.78(m,4H),7.47–7.21(m,3H),7.09–6.85(m,1H),6.62–6.45(m,2H),6.44–6.25(m,1H),5.11(s,2H),4.35(s,2H),2.45(s,3H).MS(ESI),m/z for C 21H 19N 3O 2S 2([M+H] +):Calcd 409.52,found 410.0.
实施例25 2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000040
将化合物4-(6-甲基苯并[d]噻唑-2-基)苯胺(80mg，0.33mmol)，二异丙基乙胺(127.7mg，0.99mmol)和HATU(188.1mg，0.495mmol)溶于10mL DCM。将反应混合物搅拌15分钟，然后加入化合物2-(4-(乙基磺酰基)苯基)乙酸(112.86mg，0.495mmol)，并将所得混合物在室温下搅拌过夜。反应完成后，加水稀释并用二氯甲烷(20mL×3)萃取。将合并的有机层用无水Na 2SO 4干燥并减压浓缩。粗产物通过硅胶柱层析分离(PE:EA＝3:1v/v)，得到目标化合物为白色固体(70mg，产率：47％)。 1H NMR(400MHz,DMSO-d 6)δ10.56(s,1H),8.02(d,J＝8.7Hz,2H),7.92–7.83(m,4H),7.79(d,J＝8.7Hz,2H),7.63(d,J＝8.2Hz,2H),7.34(d,J＝8.4Hz,1H),3.86(s,2H),3.32–3.23(m,2H),2.45(s,3H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 24H 22N 2O 3S 2([M+H] +):Calcd 450.57,found 451.1.
实施例26 N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)庚酰胺
Figure PCTCN2020113949-appb-000041
合成方法如实施例25，白色固体，产率：39％。 1H NMR(400MHz,DMSO-d 6)δ10.16(s,1H),8.00(d,J＝8.7Hz,2H),7.92–7.86(m,2H),7.78(d,J＝8.7Hz,2H),7.34(d,J＝8.4Hz,1H),2.45(s,3H),2.35(t,J＝7.4Hz,2H),1.67–1.55(m,2H),1.35–1.25(m,6H),0.87(t,J＝6.7Hz,3H).MS(ESI),m/z for C 21H 24N 2OS([M+H] +):Calcd 352.50,found 353.1.
实施例27 N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-2-(对甲苯基)乙酰胺
Figure PCTCN2020113949-appb-000042
合成方法如实施例25，白色固体，产率：23％。 1H NMR(400MHz,DMSO-d 6)δ10.44(s,1H),8.01(d,J＝8.7Hz,2H),7.93–7.85(m,2H),7.78(d,J＝8.7Hz,2H),7.34(d,J＝8.8Hz,1H),7.23(d,J＝7.9Hz,2H),7.14(d,J＝7.8Hz,2H),3.63(s,2H),2.45(s,3H),2.28(s,3H).MS(ESI),m/z for C 23H 20N 2OS([M+H] +):Calcd 372.49,found 373.0.
实施例28 N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-2-(2-硝基苯基)乙酰胺
Figure PCTCN2020113949-appb-000043
合成方法如实施例25，白色固体，产率：35％。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),8.08(d,J＝7.9Hz,1H),8.02(d,J＝8.7Hz,2H),7.93–7.86(m,2H),7.78–7.70(m,3H),7.62–7.55(m,2H),7.34(d,J＝8.8Hz,1H),4.19(s,2H),2.45(s,3H).MS(ESI),m/z for C 22H 17N 3O 3S([M+H] +):Calcd 403.46,found 404.3.
实施例29 N-(3-氯-4-(6-甲基苯并[d]噻唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000044
合成方法如实施例25，白色固体。产率：42％。 1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.24(d,J＝8.7Hz,1H),8.05(d,J＝1.8Hz,1H),7.99–7.93(m,2H),7.86(d,J＝8.2Hz,2H),7.66(dd,J＝8.9,1.9Hz,1H),7.62(d,J＝8.2Hz,2H),7.39(dd,J＝8.4,0.8Hz,1H),3.88(s,2H),3.28(q,J＝7.6Hz,2H),2.47(s,3H),1.10(t,J＝7.4Hz,3H).MS(ESI),m/z for C 24H 21ClN 2O 3S 2([M+H] +):Calcd 485.01,found 485.0.
实施例30 2-(4-(乙基磺酰基)苯基)-N-(4-(6-氟苯并[d]噻唑-2-基)苯基)乙酰胺
步骤1、N-(4-氟苯基)-4-硝基苯甲酰胺的合成
Figure PCTCN2020113949-appb-000045
将化合物4-氟苯胺(2g,18.0mmol)溶于吡啶(10mL)中，后缓慢加入4-硝基苯甲酰氯(4.0g,21.6mmol)，40℃反应1小时。TLC监测反应，反应结束后冷却至室温，向反应混合物中加入50mL稀盐酸，乙酸乙酯萃取三次(50mL×3)，合并有机相，再用饱和食盐水洗涤一遍，无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(PE:EA＝4:1v/v)，得到目标化合物为白色固体(3.58g，产率：76％)。 1H NMR(400MHz,DMSO-d 6)δ10.60(s,1H),8.37(d,J＝8.8Hz,2H),8.18(d,J＝8.8Hz,2H),7.88–7.70(m,2H),7.22(t,J＝8.9Hz,2H).
步骤2.、N-(4-氟苯基)-4-硝基苯甲硫酰胺的合成
Figure PCTCN2020113949-appb-000046
将N-(4-氟苯基)-4-硝基苯甲酰胺(3.58g,13.76mmol)，劳森试剂(2.78g,6.88mmol)加入1,4-二氧六环(20mL)溶剂中，将混合物加热至110℃并继续搅拌3h。结束后，将反应体系冷却至室温，并减压浓缩，然后加入水，将析出的固体抽滤。滤饼用水洗涤并干燥，甲醇重结晶得到目标化合物为橙色固体(2.74g，产率：72％)。 1H NMR(400MHz,DMSO-d 6)δ12.16(s,1H),8.29(d,J＝8.7Hz,2H),8.01(d,J＝8.6Hz,2H),7.94–7.80(m,2H),7.29(t,J＝8.8Hz,2H).
步骤3、6-氟-2-(4-硝基苯基)苯并[d]噻唑的合成
Figure PCTCN2020113949-appb-000047
将N-(4-氟苯基)-4-硝基苯甲硫酰胺(2.0g，7.24mmol)溶于氢氧化钠水溶液(2.9g，72.4mmol)(包含3ml乙醇和30ml水)中，然后向该溶液中逐滴添加铁氰化钾(9.54g，28.98mmol)水溶液(20ml)。将混合物在90℃下搅拌30分钟。结束后，将反应体系冷却至室温，有沉淀析出。将析出的固体抽滤。滤饼用水洗涤并干燥，重结晶(EA:PE＝1:2,v/v)，得到目标化合物为黄色固体(1.6g，产率：81％)。 1H NMR(400MHz,DMSO-d 6)δ8.38(d,J＝8.8Hz,2H),8.32(d,J＝8.8Hz,2H),8.20–8.11(m,2H),7.47(td,J＝9.1,2.5Hz,1H).
步骤4.、4-(6-氟苯并[d]噻唑-2-基)苯胺的合成
Figure PCTCN2020113949-appb-000048
将化合物6-氟-2-(4-硝基苯基)苯并[d]噻唑(0.8g,2.92mmol)，10％钯碳(约含水55％)(160mg)，加入到MeOH(10mL)溶剂中，并在氢气环境中于室温搅拌过夜。结束后，使用硅藻土助滤将混合物抽滤，并将滤液浓缩，得到粗产物，硅胶柱层析分离(PE:EA＝4:1,v/v)，得到目标化合物为白色固体(0.5g，产率：70％)。 1H NMR(400MHz,DMSO-d 6)δ8.00–7.85(m,2H),7.73(d,J＝8.5Hz,2H),7.30(td,J＝9.0,2.5Hz,1H),6.67(d,J＝8.5Hz,2H),5.88(s,2H).
步骤5、2-(4-(乙基磺酰基)苯基)-N-(4-(6-氟苯并[d]噻唑-2-基)苯基)乙酰胺的合成
Figure PCTCN2020113949-appb-000049
合成方法如实施例25，白色固体，产率：56％。 1H NMR(400MHz,DMSO-d 6)δ10.59(s,1H),8.07–7.98(m,4H),7.85(d,J＝8.2Hz,2H),7.80(d,J＝8.7Hz,2H),7.63(d,J＝8.2Hz,2H),7.39(td,J＝9.1,2.6Hz,1H),3.86(s,2H),3.27(q,J＝7.2Hz,2H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 23H 19FN 2O 3S 2([M+H] +):Calcd 454.53,found 455.0.
实施例31 2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲氧基苯并[d]噻唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000050
合成方法如实施例30，白色固体，产率：56％。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),7.99(d,J＝8.7Hz,2H),7.89(d,J＝8.9Hz,1H),7.85(d,J＝8.2Hz,2H),7.77(d,J＝8.7Hz,2H),7.69(d,J＝2.5Hz,1H),7.62(d,J＝8.3Hz,2H),7.11(dd,J＝8.9,2.6Hz,1H),3.85(s,2H),3.84(s,3H),3.27(q,J＝7.6Hz,2H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 24H 22N 2O 4S 2([M+Na] +):Calcd 466.57,found 489.7.
实施例32 2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(4-甲基苯乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
步骤1、5-甲基-N-(4-甲基苯乙基)-2-硝基苯胺的合成
Figure PCTCN2020113949-appb-000051
将化合物3-氟-4-硝基甲苯(2.0g，12.9mmol)溶于DMSO(5mL)，后加入对甲基苯乙胺(5.23g，38.7mmol)和DIPEA(2.51g，19.4mmol)。将反应混合物在95℃下搅拌过夜。TLC监测反应，结束后加入水并用乙酸乙酯(50mL×3)萃取。将合并的有机层用无水Na 2SO 4干燥并减压浓缩。粗产物通过硅胶柱层析分离(PE:EA＝50:1v/v)，得到目标化合物为黄色固体(2.8g，产率：80％) 1H NMR(400MHz,DMSO-d 6)δ8.09(s,1H),7.94(d,J＝8.4Hz,1H),7.19(d,J＝6.6Hz,1H),7.12(d,J＝5.7Hz,1H),6.88(s,1H),6.51(d,J＝7.9Hz,1H),3.62–3.50(m,2H),2.90(t,J＝6.8Hz,2H),2.31(s,3H),2.27(s,3H).
步骤2. 5-甲基-N 1-(4-甲基苯乙基)苯-1,2-二胺的合成
Figure PCTCN2020113949-appb-000052
将铁粉(3.46g，61.8mmol)，氯化铵(551.1mg，10.3mmol)和乙酸(1.24g，20.6mmol)加入20mL水中，并加热至50℃搅拌10min。将化合物5-甲基-N-(4-甲基苯乙基)-2-硝基苯胺(2.8g，10.3mmol)溶于15mL DMF中，并迅速加入上述混合溶液中。继续搅拌1小时，TLC监测反应。结束后冷却至室温，将混合物抽滤，水层用碳酸钠溶液调节pH至8～9，再用乙酸乙酯(50mL×3)萃取，合并有机层并用饱和氯化钠溶液洗涤，无水Na 2SO 4干燥，减压浓缩，将粗产物通过硅胶柱层析分离(PE:EA＝10:1v/v)，得到目标化合物为黄色油状液体(2.1g，产率：81％)。 1H NMR(400MHz,DMSO-d 6)δ7.17(d,J＝8.0Hz,2H),7.11(d,J＝7.9Hz,2H),6.43(d,J＝7.6Hz,1H),6.28(s,1H),6.22(d,J＝7.6Hz,1H),4.36(t,J＝5.5Hz,1H),4.21(s,2H),3.23–3.15(m,2H),2.83(t,J＝7.4Hz,2H),2.27(s,3H),2.12(s,3H).
步骤3、6-甲基-1-(4-甲基苯乙基)-2-(4-硝基苯基)-1H-苯并[d]咪唑的合成
Figure PCTCN2020113949-appb-000053
将5-甲基-N 1-(4-甲基苯乙基)苯-1,2-二胺(1.3g，5.4mmol)，对硝基苯甲醛(816.0mg，5.4mmol)和OXONE(1.84g，3.0mmol)加入20mL DMF中，室温下搅拌1小时，TLC监测反应。结束后加入水并用乙酸乙酯(50mL×3)萃取，合并有机层并用饱和氯化钠溶液洗涤，无水Na 2SO 4干燥，减压浓缩，将粗产物通过硅胶柱色谱纯化(PE:EA＝2:1v/v)，得到目标化合物为黄色固体(1.78g，产率：86％)。 1H NMR(400MHz,CDCl 3)δ8.21(d,J＝8.8Hz,2H),7.72(d,J＝8.2Hz,1H),7.48(d,J＝8.8Hz,2H),7.27(s,1H),7.19(d,J＝8.3Hz,1H),6.94(d,J＝7.8Hz,2H),6.64(d,J＝7.9Hz,2H),4.45(t,J＝6.8Hz,2H),3.03(t,J＝6.8Hz,2H),2.57(s,3H),2.29(s,3H).
步骤4、4-(6-甲基-1-(4-甲基苯乙基)-1H-苯并[d]咪唑-2-基)苯胺的合成
Figure PCTCN2020113949-appb-000054
以中间体6-甲基-1-(4-甲基苯乙基)-2-(4-硝基苯基)-1H-苯并[d]咪唑为原料。合成方法参照步骤2。黄色固体，产率：85％。 1H NMR(400MHz,DMSO)δ7.46(d,J＝8.1Hz,1H),7.36(s,1H),7.28(d,J＝8.5Hz,2H),7.04(d,J＝7.8Hz,2H),7.00(dd,J＝8.3,1.0Hz,1H),6.97(d,J＝8.0Hz,2H),6.65(d,J＝8.5Hz,2H),5.51(s,2H),4.34(t,J＝8.0Hz,2H),2.97(t,J＝7.6Hz,2H),2.45(s,3H),2.25(s,3H).
步骤5、2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(4-甲基苯乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺的合成
Figure PCTCN2020113949-appb-000055
将化合物4-(6-甲基-1-(4-甲基苯乙基)-1H-苯并[d]咪唑-2-基)苯胺(150mg，0.44mmol)，二异丙基乙胺(170.3mg，1.32mmol)和HATU(250.8mg，0.66mmol)溶于10mL DCM。将反应混合物搅拌15分钟，然后加入化合物2-(4-(乙基磺酰基)苯基)乙酸(121.0mg，0.53mmol)，并将所得混合物在室温下搅拌过夜。反应完成后，加水稀释并用二氯甲烷(50mL×3)萃取。合并有机层并用无水Na 2SO 4干燥，减压浓缩。粗产物通过硅胶柱层析分离(DCM:CH 3OH＝70:1v/v)，得到目标化合物为白色固体(70mg，产率：29％)。 1H NMR(400MHz,DMSO-d 6)δ10.47(s,1H),7.87(d,J＝8.3Hz,2H),7.71(d,J＝8.6Hz,2H),7.64(d,J＝8.3Hz,2H),7.51(d,J＝8.2Hz,1H),7.48(d,J＝8.7Hz,2H),7.43(s,1H),7.05(dd,J＝8.2,0.8Hz,1H),6.98(d,J＝7.7Hz,2H),6.86(d,J＝7.9Hz,2H),4.39(t,J＝7.3Hz,2H),3.86(s,2H),3.28(q,J＝7.5Hz,2H),2.95(t,J＝7.3Hz,2H),2.47(s,3H),2.23(s,3H),1.11(t,J＝7.4Hz,3H).MS(ESI),m/z for C 33H 33N 3O 3S([M-H] -):Calcd 551.71,found 550.4.
实施例33 2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-丙基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000056
合成方法如实施例32，白色固体，产率：45％。 1H NMR(500MHz,DMSO-d 6)δ10.51(s,1H),7.86(d,J＝8.2Hz,2H),7.79(d,J＝8.6Hz,2H),7.70(d,J＝8.8Hz,2H),7.64(d,J＝8.2Hz,2H),7.52(d,J＝8.2Hz,1H),7.42(s,1H),7.05(d,J＝8.1Hz,1H),4.21(t,J＝7.4Hz,2H),3.86(s,2H),3.28(q,J＝7.5Hz,2H),2.46(s,3H),1.71–1.64(m,2H),1.10(t,J＝7.4Hz,3H),0.73(t,J＝7.3Hz,3H).MS(ESI),m/z for C 27H 29N 3O 3S([M+H] +):Calcd 475.61,found 476.3.
实施例34 N-(4-(1-丁基-6-甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000057
合成方法如实施例32，白色固体，产率：26％。 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),7.87(d,J＝8.2Hz,2H),7.80(d,J＝8.6Hz,2H),7.71(d,J＝8.6Hz,2H),7.64(d,J＝8.2Hz,2H),7.53(d,J＝8.2Hz,1H),7.45(s,1H),7.08(d,J＝8.1Hz,1H),4.26(t,J＝7.3Hz,2H),3.86(s,2H),3.33–3.23(m,2H),2.47(s,3H),1.71–1.59(m,2H),1.19–1.07(m,5H),0.76(t,J＝7.3Hz,3H).MS(ESI),m/z for C 28H 31N 3O 3S([M+H] +):Calcd 489.63,found 490.5.
实施例35 2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-戊基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000058
合成方法如实施例32，白色固体，产率：31％。 1H NMR(400MHz,DMSO-d 6)δ10.50(s,1H),7.86(d,J＝8.2Hz,2H),7.79(d,J＝8.6Hz,2H),7.70(d,J＝8.6Hz,2H),7.64(d,J＝8.2Hz,2H),7.52(d,J＝8.2Hz,1H),7.41(s,1H),7.06(d,J＝8.1Hz,1H),4.24(t,J＝7.3Hz,2H),3.86(s,2H),3.28(q,J＝7.2Hz,2H),2.46(s,3H),1.70–1.61(m,2H),1.20–1.06(m,7H),0.75(t,J＝7.0Hz,3H).MS(ESI),m/z for C 29H 33N 3O 3S([M+H] +):Calcd 503.66,found 504.7.
实施例36 2-(4-(乙基磺酰基)苯基)-N-(4-(1-异丙基-6-甲基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000059
合成方法如实施例32，白色固体，产率：28％。 1H NMR(400MHz,DMSO)δ10.52(s,1H),7.86(d,J＝8.2Hz,2H),7.78(d,J＝8.5Hz,2H),7.64(d,J＝8.2Hz,2H),7.61–7.56(m,3H),7.51(d,J＝8.2Hz,1H),7.03(d,J＝8.1Hz,1H),4.75–4.63(m,1H),3.86(s,2H),3.28(q,J＝7.3Hz,2H),2.46(s,3H),1.57(d,J＝6.9Hz,6H),1.11(t,J＝7.3Hz,3H).MS(ESI),m/z for C 27H 29N 3O 3S([M+H] +):Calcd 475.61,found 476.3.
实施例37 2-(4-(乙基磺酰基)苯基)-N-(4-(1-异丁基-6-甲基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000060
合成方法如实施例32，白色固体，产率：27％。 1H NMR(400MHz,DMSO-d 6)δ10.54(s,1H),7.87(d,J＝8.2Hz,2H),7.80(d,J＝8.6Hz,2H),7.73(d,J＝8.6Hz,2H),7.64(d,J＝8.2Hz,2H),7.55(d,J＝8.2Hz,1H),7.50(s,1H),7.10(d,J＝8.2Hz,1H),4.16(d,J＝7.5Hz,2H),3.87(s,2H),3.28(q,J＝7.2Hz,2H),2.47(s,3H),2.01–1.87(m,1H),1.11(t,J＝7.3Hz,3H),0.64(d,J＝6.6Hz,6H).MS(ESI),m/z for C 28H 31N 3O 3S([M+H] +):Calcd 489.63,found 490.5.
实施例38 2-(4-(乙基磺酰基)苯基)-N-(4-(1-异戊基-6-甲基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000061
合成方法如实施例32，白色固体，产率：41％。 1H NMR(400MHz,DMSO-d 6)δ10.50(s,1H),7.87(d,J＝6.9Hz,2H),7.80(d,J＝7.4Hz,2H),7.70(d,J＝7.3Hz,2H),7.64(d,J＝7.0Hz,2H),7.52(d,J＝7.4Hz,1H),7.39(s,1H),7.05(d,J＝7.2Hz,1H),4.33–4.16(m,2H),3.87(s,2H),3.32–3.22(m,2H),2.47(s,3H),1.63–1.52(m,2H),1.51–1.41(m,1H),1.11(t,J＝7.4Hz,3H),0.79(d,J＝5.0Hz,6H).MS(ESI),m/z for C 29H 33N 3O 3S([M+H] +):Calcd 503.66,found 504.7.
实施例39 N-(4-(1-环丁基-6-甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000062
合成方法如实施例32，白色固体，产率：30％。 1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),7.87(d,J＝8.2Hz,2H),7.79(d,J＝8.5Hz,2H),7.67–7.58(m,5H),7.54(d,J＝8.2Hz,1H),7.09(d,J＝8.2Hz,1H),5.13–5.01(m,1H),3.87(s,2H),3.28(q,J＝7.2Hz,2H),2.76–2.61(m,2H),2.49(s,3H),2.43–2.32(m,2H),1.95–1.70(m,2H),1.11(t,J＝7.3Hz,3H).MS(ESI),m/z for C 28H 29N 3O 3S([M+H] +):Calcd 487.62,found 488.5.
实施例40 N-(4-(1-(环丁基甲基)-6-甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000063
合成方法如实施例32，白色固体，产率：22％。 1H NMR(400MHz,DMSO-d 6)δ10.50(s,1H),7.87(d,J＝8.1Hz,2H),7.79(d,J＝8.5Hz,2H),7.70(d,J＝8.5Hz,2H),7.64(d,J＝8.1Hz,2H),7.50(d,J＝8.2Hz,1H),7.44(s,1H),7.04(d,J＝8.2Hz,1H),4.35(d,J＝7.2Hz,2H),3.86(s,2H),3.32–3.24(m,2H),2.60–2.51(m,1H),2.46(s,3H),1.78–1.57(m,4H),1.54–1.44(m,2H),1.11(t,J＝7.3Hz,3H).MS(ESI),m/z for C 29H 31N 3O 3S([M+H] +):Calcd 501.65,found502.5.
实施例41 N-(4-(1-(环己基甲基)-6-甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000064
合成方法如实施例32，白色固体，产率：40％。 1H NMR(400MHz,DMSO-d 6)δ10.50(s,1H),7.87(d,J＝8.2Hz,2H),7.78(d,J＝8.6Hz,2H),7.70(d,J＝8.5Hz,2H),7.64(d,J＝8.1Hz,2H),7.51(d,J＝8.1Hz,1H),7.42(s,1H),7.04(d,J＝8.2Hz,1H),4.17(d,J＝7.2Hz,2H),3.86(s,2H),3.28(q,J＝7.2Hz,2H),2.46(s,3H),1.69–1.56(m,1H),1.53–1.42(m,4H),1.34–1.19(m,6H),1.11(t,J＝7.6Hz,3H).MS(ESI),m/z for C 31H 35N 3O 3S([M+H] +):Calcd 529.70,found530.7.
实施例42 N-(4-(1-苄基-6-甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000065
合成方法如实施例32，白色固体，产率：20％。 1H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),7.85(d,J＝8.2Hz,2H),7.72(d,J＝8.7Hz,2H),7.66(d,J＝8.7Hz,2H),7.64–7.55(m,3H),7.32–7.20(m,4H),7.08(d,J＝8.1Hz,1H),6.99(d,J＝7.2Hz,2H),5.55(s,2H),3.84(s,2H),3.32–3.22(m,2H),2.39(s,3H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 31H 29N 3O 3S([M+H] +):Calcd 523.65,found 524.3.
实施例43 2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(4-甲基苄基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000066
合成方法如实施例32，白色固体，产率：25％。 1H NMR(400MHz,DMSO-d 6)δ10.49(s,1H),7.85(d,J＝8.2Hz,2H),7.73(d,J＝8.7Hz,2H),7.66(d,J＝8.7Hz,2H),7.62(d,J＝8.2Hz,2H),7.57(d,J＝8.2Hz,1H),7.25(s,1H),7.12–7.03(m,3H),6.88(d,J＝7.9Hz,2H),5.49(s,2H),3.84(s,2H),3.27(q,J＝7.2Hz,2H),2.39(s,3H),2.22(s,3H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 32H 31N 3O 3S([[M+H] +):Calcd 537.68,found 538.6.
实施例44 2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-苯乙基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000067
合成方法如实施例32，白色固体，产率：45％。 1H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),7.87(d,J＝8.2Hz,2H),7.72(d,J＝8.5Hz,2H),7.64(d,J＝8.2Hz,2H),7.55–7.47(m,3H),7.45(s,1H),7.22–7.13(m,3H),7.06(d,J＝8.2Hz,1H),7.02–6.95(m,2H),4.43(t,J＝7.3Hz,2H),3.86(s,2H),3.28(q,J＝7.6Hz,2H),3.01(t,J＝7.3Hz,2H),2.47(s,3H),1.11(t,J＝7.3Hz,3H).MS(ESI),m/z for C 32H 31N 3O 3S([M+H] +):Calcd 537.68,found 538.6.
实施例45 2-(4-(乙基磺酰基)苯基)-N-(4-(1-(4-氟苄基)-6-甲基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000068
合成方法如实施例32，白色固体，产率：26％。 1H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),7.85(d,J＝8.3Hz,2H),7.73(d,J＝8.7Hz,2H),7.65(d,J＝8.7Hz,2H),7.62(d,J＝8.2Hz,2H),7.57(d,J＝8.2Hz,1H),7.28(s,1H),7.11(t,J＝8.8Hz,2H),7.07(d,J＝8.4Hz,1H),7.04–6.98(m,2H),5.53(s,2H),3.84(s,2H),3.27(q,J＝7.2Hz,2H),2.40(s,3H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 31H 28FN 3O 3S([M+H] +):Calcd 541.64,found 542.3.
实施例46 2-(4-(乙基磺酰基)苯基)-N-(4-(1-(3-氟苄基)-6-甲基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000069
合成方法如实施例32，白色固体，产率：29％。 1H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),7.85(d,J＝8.3Hz,2H),7.73(d,J＝8.7Hz,2H),7.69–7.56(m,5H),7.36–7.29(m,1H),7.28(s,1H),7.08(d,J＝8.3Hz,2H),6.82(d,J＝9.9Hz,1H),6.76(d,J＝7.8Hz,1H),5.56(s,2H),3.84(s,2H),3.31–3.23(m,2H),2.40(s,3H),1.10(t,J＝7.4Hz,3H).MS(ESI),m/z for C 31H 28FN 3O 3S([M+H] +):Calcd 541.64,found 542.3.
实施例47 2-(4-(乙基磺酰基)苯基)-N-(4-(1-(2-氟苄基)-6-甲基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000070
合成方法如实施例32，白色固体，产率：25％。 1H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),7.85(d,J＝8.2Hz,2H),7.72(d,J＝8.6Hz,2H),7.67–7.55(m,5H),7.34–7.25(m,2H),7.20(t,J＝8.7Hz,1H),7.11–7.02(m,2H),6.69(t,J＝7.6Hz,1H),5.57(s,2H),3.84(s,2H),3.27(q,J＝7.2Hz,2H),2.39(s,3H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 31H 28FN 3O 3S([M+H] +):Calcd 541.64,found 542.3.
实施例48 N-(4-(1-(2，6-二氟苄基)-6-甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000071
合成方法如实施例32，白色固体，产率：35％。 1H NMR(400MHz,DMSO-d 6)δ10.49(s,1H),7.86(d,J＝8.2Hz,2H),7.76(d,J＝8.6Hz,2H),7.69(d,J＝8.6Hz,2H),7.64(d,J＝8.1Hz,2H),7.52(d,J＝8.1Hz,1H),7.39–7.28(m,1H),7.18(s,1H),7.07–6.94(m,3H),5.60(s,2H),3.86(s,2H),3.28(q,J＝7.6Hz,2H),2.38(s,3H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 31H 27F 2N 3O 3S([M+H] +):Calcd 559.63,found 560.3.
实施例49 N-(4-(1-(4-氰基苄基)-6-甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙 基磺酰基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000072
合成方法如实施例32，白色固体，产率：31％。 1H NMR(400MHz,DMSO-d 6)δ10.47(s,1H),7.85(d,J＝8.3Hz,2H),7.76(d,J＝8.3Hz,2H),7.71(d,J＝8.7Hz,2H),7.66–7.55(m,5H),7.26(s,1H),7.14(d,J＝8.3Hz,2H),7.08(d,J＝8.3Hz,1H),5.65(s,2H),3.83(s,2H),3.31–3.23(m,2H),2.39(s,3H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 32H 28N 4O 3S([M+H] +):Calcd 548.66,found 549.2.
实施例50 2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(4-(甲基磺酰基)苄基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000073
合成方法如实施例32，白色固体，产率：49％。 1H NMR(400MHz,DMSO-d 6)δ10.49(s,1H),7.90–7.81(m,4H),7.72(d,J＝8.6Hz,2H),7.68–7.56(m,5H),7.29–7.18(m,3H),7.08(d,J＝8.1Hz,1H),5.67(s,2H),3.83(s,2H),3.33–3.23(m,2H),3.17(s,3H),2.39(s,3H),1.09(t,J＝7.2Hz,3H).MS(ESI),m/z for C 32H 31N 3O 5S 2([M-H] -):Calcd 601.74,found 600.8.
实施例51 2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(吡啶-2-基甲基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000074
合成方法如实施例32，白色固体，产率：41％。 1H NMR(400MHz,DMSO-d 6)δ10.46(s,1H),8.49(d,J＝4.4Hz,1H),7.85(d,J＝8.1Hz,2H),7.79–7.66(m,5H),7.61(d,J＝8.1Hz,2H),7.56(d,J＝8.2Hz,1H),7.31–7.24(m,1H),7.20(s,1H),7.09(d,J＝7.8Hz,1H),7.05(d,J＝8.2Hz,1H),5.57(s,2H),3.83(s,2H),3.27(q,J＝7.2Hz,2H),2.37(s,3H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 30H 28N 4O 3S([M+H] +):Calcd 524.64,found 525.4.
实施例52 N-(4-(1-苄基-6-氯-1H-苯并[d]咪唑-2-基)苯基)-2-(4-乙基磺酰)苯基)乙酰胺
Figure PCTCN2020113949-appb-000075
合成方法如实施例32，白色固体，产率：37％。 1H NMR(400MHz,DMSO-d 6)δ10.51(s,1H),7.85(d,J＝8.3Hz,2H),7.77–7.67(m,5H),7.65–7.59(m,3H),7.32–7.19(m,4H),6.97(d,J＝7.1Hz,2H),5.61(s,2H),3.84(s,2H),3.27(q,J＝7.3Hz,2H),1.10(t,J＝7.4Hz,3H).MS(ESI),m/z for C 30H 26ClN 3O 3S([M+H] +):Calcd 544.07,found 544.4.
实施例53 N-(4-(1-苄基-5-氯-1H-苯并[d]咪唑-2-基)苯基)-2-(4-乙基磺酰)苯基)乙酰胺
Figure PCTCN2020113949-appb-000076
合成方法如实施例32，白色固体，产率：35％。 1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),7.85(d,J＝8.1Hz,2H),7.78–7.67(m,5H),7.62(d,J＝8.1Hz,2H),7.51(d,J＝8.6Hz,1H),7.31–7.20(m,4H),6.97(d,J＝7.0Hz,2H),5.60(s,2H),3.84(s,2H),3.27(q,J＝7.2Hz,2H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 30H 26ClN 3O 3S([M+H] +):Calcd 544.07,found 544.3.HPLC analysis:MeOH(1‰NH 3·H 2O)-H 2O(75:25),t R＝17.64min,96.13％purity.
实施例54(S)-2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
步骤1.(S)-4-(6-甲基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯胺的合成
Figure PCTCN2020113949-appb-000077
以3-氟-4-硝基甲苯和(S)-1-(4-甲基苯基)乙胺为原料，合成方法参照实施例31的步骤1～4。淡黄色固体，产率：93％。 1H NMR(400MHz,DMSO-d 6)δ7.47(d,J＝8.1Hz,1H),7.31(d,J＝8.4Hz,2H),7.14(d,J＝8.0Hz,2H),7.05(d,J＝8.0Hz,2H),6.94(d,J＝8.1Hz,1H),6.88(s,1H),6.66(d,J＝8.4Hz,2H),5.80(q,J＝6.8Hz,1H),5.54(s,2H),2.27(s,3H),2.26(s,3H),1.90(d,J＝7.1Hz,3H).
步骤2.(S)-2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺的合成
Figure PCTCN2020113949-appb-000078
将2-(4-(乙基磺酰基)苯基)乙酸(121.0mg，0.53mmol)，HOBT(89.2mg，0.66mmol)， EDCI(126.5mg，0.66mol)和二异丙基乙胺(170.6mg，1.32mmol)溶于10mL DCM。将反应混合物搅拌15分钟，然后加入化合物(S)-4-(6-甲基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯胺(150.2mg，0.44mmol)，并将所得混合物在室温下搅拌过夜。反应完成后，加水稀释并用二氯甲烷(50mL×3)萃取。合并有机层并用无水Na 2SO 4干燥，减压浓缩。粗产物通过硅胶柱层析分离(PE:EA＝1:1v/v)，得到目标化合物为白色固体(53.4mg，产率：22％)。 1H NMR(400MHz,DMSO-d 6)δ10.51(s,1H),7.85(d,J＝8.1Hz,2H),7.77(d,J＝8.5Hz,2H),7.66–7.58(m,4H),7.53(d,J＝8.1Hz,1H),7.14(d,J＝7.8Hz,2H),7.05(d,J＝7.9Hz,2H),6.99(d,J＝8.3Hz,1H),6.95(s,1H),5.82–5.72(m,1H),3.85(s,2H),3.31–3.22(m,2H),2.29(s,3H),2.26(s,3H),1.92(d,J＝7.0Hz,3H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 33H 33N 3O 3S([M+H] +):Calcd 551.71,found 552.8.
实施例55 2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(吡啶-4-基甲基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺的合成
步骤1. 5-甲基-2-硝基-N-(吡啶-4-基甲基)苯胺的合成
Figure PCTCN2020113949-appb-000079
将3-氟-4-硝基甲苯(2g，12.9mmol)、4-吡啶甲胺(1.68g，15.5mmol)和碳酸钾(2.68g，19.4mmol)溶于20mL DMF，80℃反应1h。TLC监测反应，反应结束后冷却至室温，加水稀释，乙酸乙酯萃取三次(50mL×3)，合并有机相，再用饱和食盐水洗涤一遍，无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(PE:EA＝4:1v/v)，得到目标化合物为黄色固体(2.2g，产率：70％)。 1H NMR(400MHz,DMSO-d 6)δ8.72(t,J＝6.2Hz,1H),8.51(d,J＝5.9Hz,2H),7.99(d,J＝8.7Hz,1H),7.34(d,J＝5.5Hz,2H),6.65(s,1H),6.52(dd,J＝8.8,0.8Hz,1H),4.68(d,J＝6.4Hz,2H),2.19(s,3H).
步骤2. 4-(6-甲基-1-(吡啶-4-基甲基)-1H-苯并[d]咪唑-2-基)苯胺的合成
Figure PCTCN2020113949-appb-000080
以中间体5-甲基-2-硝基-N-(吡啶-4-基甲基)苯胺为原料。合成方法参照实施例31的步骤2～4。黄色固体，产率：69％。 1H NMR(400MHz,DMSO-d 6)δ8.49(d,J＝6.0Hz,2H),7.53(d,J＝8.2Hz,1H),7.32(d,J＝8.6Hz,2H),7.15(s,1H),7.04(dd,J＝8.2,0.8Hz,1H),6.98(d,J＝5.9Hz,2H),6.60(d,J＝8.6Hz,2H),5.60–5.47(m,4H),2.37(s,3H).
步骤3. 2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(吡啶-4-基甲基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺的合成
Figure PCTCN2020113949-appb-000081
以中间体4-(6-甲基-1-(吡啶-4-基甲基)-1H-苯并[d]咪唑-2-基)苯胺为原料，合成方法参照实施例54的步骤2。白色固体，产率：26％。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),8.43(m,2H),7.84(d,J＝8.3Hz,2H),7.72(d,J＝8.7Hz,2H),7.66–7.57(m,5H),7.24(s,1H),7.09(dd,J＝8.2,0.8Hz,1H),6.97–6.93(m,2H),5.58(s,2H),3.84(s,2H),3.26(q,J＝7.6Hz, 2H),2.39(s,3H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 30H 28N 4O 3S([M+H] +):Calcd524.64,found 525.4.
实施例56 2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000082
合成方法如实施例54，白色固体，产率：25％。 1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),7.85(d,J＝8.2Hz,2H),7.77(d,J＝8.6Hz,2H),7.66–7.58(m,4H),7.53(d,J＝8.2Hz,1H),7.14(d,J＝8.0Hz,2H),7.05(d,J＝8.0Hz,2H),6.99(d,J＝8.4Hz,1H),6.95(s,1H),5.76(q,J＝6.8Hz,2H),3.85(s,2H),3.27(q,J＝7.2Hz,2H),2.29(s,3H),2.26(s,3H),1.92(d,J＝7.1Hz,3H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 33H 33N 3O 3S([M+H] +):Calcd 551.71,found552.6.
实施例57(R)-2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000083
合成方法如实施例54，白色固体，产率：18％。 1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),7.85(d,J＝8.2Hz,2H),7.77(d,J＝8.5Hz,2H),7.66–7.58(m,4H),7.53(d,J＝8.2Hz,1H),7.14(d,J＝8.0Hz,2H),7.05(d,J＝8.0Hz,2H),6.99(d,J＝8.2Hz,1H),6.95(s,1H),5.76(q,J＝6.8Hz,1H),3.85(s,2H),3.27(q,J＝7.2Hz,2H),2.29(s,3H),2.26(s,3H),1.92(d,J＝7.1Hz,3H),1.10(t,J＝7.4Hz,3H).MS(ESI),m/z for C 33H 33N 3O 3S([M+H] +):Calcd 551.71,found552.7.
实施例58 2-(4-(乙基磺酰基)苯基)-N-(4-(1-(4-氟苯乙基)-6-甲基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000084
合成方法如实施例54，白色固体，产率：29％。 1H NMR(400MHz,DMSO-d 6)δ10.47(s,1H),7.87(d,J＝8.4Hz,2H),7.72(d,J＝8.7Hz,2H),7.64(d,J＝8.4Hz,2H),7.53–7.47(m,3H),7.43(s,1H),7.05(dd,J＝8.2,0.8Hz,1H),6.99–6.94(m,4H),4.44(t,J＝7.3Hz,2H),3.86(s,2H),3.31–3.23(m,2H),2.98(t,J＝7.4Hz,2H),2.46(s,3H),1.11(t,J＝7.4Hz,3H).MS(ESI),m/z for C 32H 30FN 3O 3S([M-H] -):Calcd 555.67,found 554.7.
实施例59 2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(4-(三氟甲基)苄基)-1H- 苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000085
合成方法如实施例54，白色固体，产率：23％。 1H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),7.85(d,J＝8.1Hz,2H),7.75–7.54(m,9H),7.26(s,1H),7.18(d,J＝8.1Hz,2H),7.08(d,J＝8.1Hz,1H),5.65(s,2H),3.83(s,2H),3.32–3.22(m,2H),2.39(s,3H),1.09(t,J＝7.3Hz,3H).MS(ESI),m/z for C 32H 28F 3N 3O 3S([M-H] -):Calcd 591.65,found 590.3.
实施例60 4-((2-(4-(2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-6-甲基-1H-苯并[d]咪唑-1-基)甲基)苯甲酸甲酯
Figure PCTCN2020113949-appb-000086
合成方法如实施例54，白色固体，产率：29％。 1H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),7.88(d,J＝8.2Hz,2H),7.84(d,J＝8.3Hz,2H),7.70(d,J＝8.7Hz,2H),7.66–7.56(m,5H),7.24(s,1H),7.12(d,J＝8.2Hz,2H),7.08(dd,J＝8.2,0.4Hz,1H),5.63(s,2H),3.83(s,2H),3.81(s,3H),3.27(q,J＝7.2Hz,2H),2.38(s,3H),1.09(t,J＝7.3Hz,3H).MS(ESI),m/z for C 33H 31N 3O 5S([M+H] +):Calcd 581.69,found 582.4.
实施例61 4-((2-(4-(2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-6-甲基-1H-苯并[d]咪唑-1-基)甲基)苯甲酸
Figure PCTCN2020113949-appb-000087
以实施例60为原料，合成方法参照实施例19，白色固体，产率：69％。 1H NMR(500MHz,DMSO)δ10.78(s,1H),7.87(d,J＝8.2Hz,2H),7.84(d,J＝8.2Hz,2H),7.81(d,J＝8.3Hz,2H),7.74–7.66(m,3H),7.62(d,J＝7.9Hz,2H),7.43(s,1H),7.26(d,J＝7.9Hz,1H),7.18(d,J＝8.0Hz,2H),5.71(s,2H),3.87(s,2H),3.27(q,J＝7.5Hz,2H),2.42(s,3H),1.09(t,J＝7.3Hz,3H).MS(ESI),m/z for C 32H 29N 3O 5S([M+H] +):Calcd 567.66,found 568.7.
实施例62 2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(吡啶-3-基甲基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000088
合成方法如实施例54，白色固体，产率：44％。 1H NMR(400MHz,DMSO-d 6)δ10.51(s,1H),8.46–8.40(t,J＝2.8Hz,1H),8.26(s,1H),7.85(d,J＝8.1Hz,2H),7.74(d,J＝8.5Hz,2H),7.67(d,J＝8.6Hz,2H),7.62(d,J＝8.1Hz,2H),7.58(d,J＝8.3Hz,1H),7.35(s,1H),7.31–7.25(m,2H),7.08(d,J＝8.1Hz,1H),5.61(s,2H),3.85(s,2H),3.28(q,J＝7.6Hz,2H),2.40(s,3H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 30H 28N 4O 3S([M+H] +):Calcd 524.64,found 525.4.
实施例63 (R)-2-(4-(乙基磺酰基)苯基)-N-(4-(1-(1-(对甲苯基)乙基)-6-(三氟甲基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000089
合成方法如实施例54，白色固体，产率：44％。 1H NMR(400MHz,DMSO-d 6)δ10.57(s,1H),7.89–7.84(m,3H),7.82(d,J＝8.5Hz,2H),7.69(d,J＝8.3Hz,2H),7.63(d,J＝7.9Hz,2H),7.50(d,J＝8.5Hz,1H),7.37(s,1H),7.16(d,J＝7.8Hz,2H),7.10(d,J＝7.8Hz,2H),5.95–5.83(m,1H),3.86(s,2H),3.31–3.22(m,2H),2.26(s,3H),1.94(d,J＝6.9Hz,3H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 33H 30F 3N 3O 3S([M-H] -):Calcd 605.68,found 604.4.
实施例64 (R)-2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲氧基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000090
合成方法如实施例54，白色固体，产率：27％。 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),7.86(d,J＝8.2Hz,2H),7.78(d,J＝8.6Hz,2H),7.66–7.59(m,4H),7.54(d,J＝8.8Hz,1H),7.15(d,J＝8.0Hz,2H),7.09(d,J＝8.0Hz,2H),6.81(dd,J＝8.8,2.2Hz,1H),6.53(d,J＝1.9Hz,1H),5.76(q,J＝6.8Hz,1H),3.85(s,2H),3.62(s,3H),3.28(q,J＝7.4Hz,2H),2.26(s,3H),1.91(d,J＝7.1Hz,3H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 33H 33N 3O 4S([M-H] -):Calcd567.70,found 566.4.
实施例65 (R)-2-(4-(乙基磺酰基)苯基)-N-(4-(5-甲基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000091
合成方法如实施例54，白色固体，产率：31％。 1H NMR(400MHz,DMSO-d 6)δ10.54(s,1H),7.85(d,J＝8.3Hz,2H),7.78(d,J＝8.6Hz,2H),7.67–7.60(m,4H),7.44(s,1H),7.12(d,J＝8.0Hz,2H),7.04(d,J＝8.0Hz,2H),6.98(d,J＝8.3Hz,1H),6.88(d,J＝8.2Hz,1H),5.76(q,J＝7.1Hz,1H),3.85(s,2H),3.28(q,J＝7.4Hz,2H),2.35(s,3H),2.24(s,3H),1.92(d,J＝7.0Hz,3H),1.09(t,J＝7.3Hz,3H).MS(ESI),m/z for C 33H 33N 3O 3S([M-H] -):Calcd 551.71,found 550.4.
实施例66 (R)-2-(4-(乙基磺酰基)苯基)-N-(4-(5-甲氧基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺(27f)
Figure PCTCN2020113949-appb-000092
合成方法如实施例54，白色固体，产率：25％。 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),7.85(d,J＝7.8Hz,2H),7.78(d,J＝8.2Hz,2H),7.69–7.58(m,4H),7.17(s,1H),7.12(d,J＝7.5Hz,2H),7.05(d,J＝7.5Hz,2H),6.98(d,J＝8.9Hz,1H),6.70(d,J＝8.8Hz,1H),5.82–5.69(m,1H),3.85(s,2H),3.75(s,3H),3.33–3.22(m,2H),2.25(s,3H),1.91(d,J＝6.7Hz,3H),1.10(t,J＝7.2Hz,3H).MS(ESI),m/z for C 33H 33N 3O 4S([M+H] +):Calcd 567.70,found 568.8.
实施例67 (R)-2-(4-(乙基磺基)苯基)-N-(4-(1-(1-(4-氟苯基)乙基)-6-(三氟甲基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000093
合成方法如实施例54，白色固体，产率：39％。 1H NMR(500MHz,DMSO-d 6)δ10.58(s,1H),7.91–7.84(m,3H),7.82(d,J＝7.9Hz,2H),7.69(d,J＝8.1Hz,2H),7.63(d,J＝7.5Hz,2H),7.51(d,J＝8.1Hz,1H),7.35(s,1H),7.30–7.23(m,2H),7.22–7.15(m,2H),5.96–5.96(m,1H),3.86(s,2H),3.32–3.23(m,2H),1.96(d,J＝6.5Hz,3H),1.10(t,J＝7.1Hz,3H).MS(ESI),m/z for C 32H 27F 4N 3O 3S([M-H] -):Calcd 609.64,found 608.2.HPLC analysis:MeOH-H 2O(85:15),t R＝13.02min,98.08％purity.
实施例68 (S)-2-(4-(乙基磺基)苯基)-N-(4-(1-(1-(4-氟苯基)乙基)-6-(三氟甲基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000094
合成方法如实施例54，白色固体，产率：28％。 1H NMR(500MHz,DMSO-d 6)δ10.58(s,1H),7.90–7.83(m,3H),7.82(d,J＝8.6Hz,2H),7.69(d,J＝8.6Hz,2H),7.63(d,J＝8.2Hz,2H),7.51(d,J＝8.1Hz,1H),7.35(s,1H),7.29–7.24(m,2H),7.18(t,J＝8.8Hz,2H),5.92(q,J＝6.8Hz,1H),3.86(s,2H),3.28(q,J＝7.4Hz,2H),1.96(d,J＝7.1Hz,3H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 32H 27F 4N 3O 3S([M-H] -):Calcd 609.64,found 608.3.
实施例69(R)-2-(4-(2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-N-异丙基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-6-甲酰胺
步骤1. 3-氟-N-异丙基-4-硝基苯甲酰胺的合成
Figure PCTCN2020113949-appb-000095
以3-氟-4-硝基苯甲酸和异丙铵为原料，合成方法参照实施例31的步骤5，黄色固体，产率：95％。 1H NMR(400MHz,DMSO-d 6)δ8.59(d,J＝7.2Hz,1H),8.25(t,J＝8.1Hz,1H),7.97(dd,J＝12.1,1.5Hz,1H),7.87(d,J＝8.5Hz,1H),4.14–4.02(m,1H),1.18(d,J＝6.6Hz,6H).
步骤2.(R)-2-(4-(2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-N-异丙基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-6-甲酰胺的合成
Figure PCTCN2020113949-appb-000096
以3-氟-N-异丙基-4-硝基苯甲酰胺和(R)-1-(4-甲基苯基)乙胺为原料，合成方法参照实施例53。白色固体，产率：26％。 1H NMR(400MHz,DMSO-d 6)δ10.57(s,1H),8.14(d,J＝7.8Hz,1H),7.85(d,J＝8.3Hz,2H),7.79(d,J＝8.7Hz,2H),7.76–7.60(m,7H),7.14(d,J＝8.1Hz,2H),7.05(d,J＝8.0Hz,2H),5.88–5.80(m,1H),4.10–4.01(m,1H),3.86(s,2H),3.32–3.22(m,2H),2.25(s,3H),1.97(d,J＝7.1Hz,3H),1.14(d,J＝6.5Hz,6H),1.10(t,J＝7.4Hz,3H).MS(ESI),m/z for C 36H 38N 4O 4S([M-H] -):Calcd 622.78,found 621.0.
实施例70 (R)-N-环戊基-2-(4-(2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-6-甲酰胺
Figure PCTCN2020113949-appb-000097
合成方法如实施例69，白色固体，产率：12％。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),8.19(d,J＝7.0Hz,1H),7.85(d,J＝8.3Hz,2H),7.79(d,J＝8.3Hz,2H),7.76–7.57(m,7H), 7.14(d,J＝7.3Hz,2H),7.05(d,J＝7.7Hz,2H),5.89–5.78(m,1H),4.23–4.12(m,1H),3.85(s,2H),3.33–3.22(m,2H),2.25(s,3H),1.97(d,J＝7.0Hz,3H),1.92–1.79(m,2H),1.75–1.62(m,2H),1.59–1.44(m,4H),1.09(t,J＝7.3Hz,3H).MS(ESI),m/z for C 38H 40N 4O 4S([M+H] +):Calcd 648.82,found 650.0.
实施例71 (R)-2-(4-(2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-N-异丙基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑唑-5-甲酰胺
Figure PCTCN2020113949-appb-000098
合成方法如实施例69，白色固体，产率：29％。 1H NMR(400MHz,DMSO-d 6)δ10.57(s,1H),8.18(s,1H),8.14(d,J＝6.7Hz,1H),7.86(d,J＝7.6Hz,2H),7.81(d,J＝7.7Hz,2H),7.68(d,J＝7.3Hz,2H),7.63(d,J＝7.5Hz,2H),7.57(d,J＝7.9Hz,1H),7.17–7.09(m,3H),7.08–7.00(m,2H),5.88–5.74(m,1H),4.16–4.02(m,1H),3.86(s,2H),3.31–3.22(d,J＝7.1Hz,2H),2.24(s,3H),1.96(d,J＝4.8Hz,3H),1.16(d,J＝5.5Hz,6H),1.13–1.07(m,3H).MS(ESI),m/z for C 36H 38N 4O 4S([M+H] +):Calcd 622.78,found 623.3.
实施例72 (R)-N-环戊基-2-(4-(2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑唑-5-甲酰胺
Figure PCTCN2020113949-appb-000099
合成方法如实施例69，白色固体，产率：11％。 1H NMR(400MHz,DMSO-d 6)δ10.56(s,1H),8.24–8.15(m,2H),7.85(d,J＝8.1Hz,2H),7.80(d,J＝8.6Hz,2H),7.67(d,J＝8.6Hz,2H),7.62(d,J＝8.1Hz,2H),7.56(d,J＝8.5Hz,1H),7.16–7.09(m,3H),7.04(d,J＝7.9Hz,2H),5.86–5.76(m,1H),4.28–4.17(m,1H),3.86(s,2H),3.33–3.23(m,2H),2.24(s,3H),1.96(d,J＝6.9Hz,3H),1.92–1.80(m,2H),1.76–1.64(m,2H),1.58–1.48(m,4H),1.09(t,J＝7.3Hz,3H).MS(ESI),m/z for C 38H 40N 4O 4S([M+H] +):Calcd 648.82,found 649.9.
实施例73 2-乙酰氨基-2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-((S)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
步骤1.叔丁基(1-(4-(乙基磺酰)苯基)-2-((4-(6-甲基-1-((S)-1-(对甲苯基)乙基)-1H苯并[d]咪唑-2-基)苯基)氨基)-2-氧代乙基)氨基甲酸酯的合成
Figure PCTCN2020113949-appb-000100
以(S)-4-(6-甲基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯胺和2-((叔丁 氧基羰基)氨基)-2-(4-(乙基磺酰基)苯基)乙酸原料，合成法参照实施例31的步骤5。白色固体，产率：46％。 1H NMR(400MHz,DMSO-d 6)δ10.62(s,1H),7.89(d,J＝8.2Hz,2H),7.82–7.69(m,5H),7.60(d,J＝8.4Hz,2H),7.52(d,J＝8.2Hz,1H),7.12(d,J＝7.9Hz,2H),7.04(d,J＝7.9Hz,2H),6.98(d,J＝8.3Hz,1H),6.94(s,1H),5.74(q,J＝7.2Hz,1H),5.52(d,J＝7.2Hz,1H),3.31–3.20(m,2H),2.28(s,3H),2.25(s,3H),1.90(d,J＝7.0Hz,3H),1.40(s,9H),1.08(t,J＝7.3Hz,3H).
步骤2. 2-氨基-2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-((S)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑吡啶-2-基)苯基)乙酰胺的合成
Figure PCTCN2020113949-appb-000101
将叔丁基(1-(4-(乙基磺酰)苯基)-2-((4-(6-甲基-1-((S)-1-(对甲苯基)乙基)-1H苯并[d]咪唑-2-基)苯基)氨基)-2-氧代乙基)氨基甲酸酯(190mg，0.28mmol)溶于10mL二氯甲烷中，滴加5mL三氟乙酸，室温反应3h。反应结束后，旋去有机溶剂，乙酸乙酯和石油醚混合溶剂重结晶，目标产物为白色固体(130mg，收率：82％)。MS(ESI),m/z for C 33H 34N 4O 3S([M+H] +):Calcd 566.72,found 567.5.
步骤3. 2-乙酰氨基-2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-((S)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺的合成
Figure PCTCN2020113949-appb-000102
将2-氨基-2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-((S)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑吡啶-2-基)苯基)乙酰胺(130mg，0.23mmol)溶于10mL DCM中，然后加入三乙胺(23.3mg，0.23mmol)和醋酸酐(23.5mg，0.23mmol)，将混合物在室温下搅拌反应3小时。反应完成后，加水稀释并用二氯甲烷(50mL×3)萃取。合并有机层并用无水Na 2SO 4干燥，减压浓缩。粗产物通过硅胶柱层析分离(PE:EA＝1:4v/v)，得到目标化合物为白色固体(86.8mg，产率：62％)。 1H NMR(400MHz,DMSO-d 6)δ10.74(s,1H),8.89(d,J＝7.8Hz,1H),7.91(d,J＝8.3Hz,2H),7.80–7.73(m,4H),7.61(d,J＝8.6Hz,2H),7.53(d,J＝8.2Hz,1H),7.13(d,J＝8.1Hz,2H),7.05(d,J＝8.0Hz,2H),6.99(d,J＝8.5Hz,1H),6.94(s,1H),5.82(d,J＝7.8Hz,1H),5.75(q,J＝6.9Hz,1H),3.31–3.23(m,2H),2.29(s,3H),2.25(s,3H),1.96(s,3H),1.91(d,J＝7.1Hz,3H),1.09(t,J＝7.3Hz,3H).MS(ESI),m/z for C 35H 36N 4O 4S([M+H] +):Calcd 608.76,found 609.8.
实施例73的异构体1(实施例74)和异构体2(实施例75)
将实施例73(2.72g)通过SFC手性分离纯化(Chiralpak IC，0.46cm ID×15cm L，214nm，己烷/乙醇＝30/70(V/V)，1mL/min，35℃)得到相应的两种异构体：异构体1(实施例74)(峰1，1.25g，>98％ee，白色固体)和异构体2(实施例75)(峰2，1.31g，>98％ee，白 色固体)。注：目前还没获得化合物单晶，不能确定化合物绝对构型。
实施例74：异构体1(R or S) 1H NMR(500MHz,DMSO-d 6)δ10.75(s,1H),8.91(d,J＝7.7Hz,1H),7.91(d,J＝7.6Hz,2H),7.79–7.73(m,4H),7.61(d,J＝7.8Hz,2H),7.53(d,J＝8.2Hz,1H),7.13(d,J＝7.6Hz,2H),7.04(d,J＝7.6Hz,2H),6.99(d,J＝8.1Hz,1H),6.94(s,1H),5.82(d,J＝7.7Hz,1H),5.74(q,J＝6.2Hz,1H),3.28(q,J＝7.4Hz,2H),2.29(s,3H),2.25(s,3H),1.95(s,3H),1.91(d,J＝7.0Hz,3H),1.09(t,J＝7.9Hz,3H).MS(ESI),m/z for C 35H 36N 4O 4S([M+H] +):Calcd 608.76,found 609.8.
实施例75：异构体2(S or R) 1H NMR(500MHz,DMSO-d 6)δ10.75(s,1H),8.91(d,J＝7.8Hz,1H),7.91(d,J＝7.7Hz,2H),7.79–7.74(m,4H),7.61(d,J＝8.0Hz,2H),7.53(d,J＝8.1Hz,1H),7.13(d,J＝7.6Hz,2H),7.04(d,J＝7.6Hz,2H),6.99(d,J＝8.2Hz,1H),6.94(s,1H),5.82(d,J＝7.6Hz,1H),5.74(q,J＝6.3Hz,1H),3.28(q,J＝7.5Hz,2H),2.29(s,3H),2.25(s,3H),1.95(s,3H),1.91(d,J＝7.0Hz,3H),1.09(t,J＝7.3Hz,3H).MS(ESI),m/z for C 35H 36N 4O 4S([M+H] +):Calcd 608.76,found 609.8.
实施例76 2-乙酰氨基-2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-戊基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000103
合成方法如实施例73，白色固体，产率：47％。 1H NMR(400MHz,DMSO-d 6)δ10.72(s,1H),8.89(d,J＝7.6Hz,1H),7.93(d,J＝8.1Hz,2H),7.81–7.74(m,4H),7.70(d,J＝8.4Hz,2H),7.51(d,J＝8.1Hz,1H),7.40(s,1H),7.04(d,J＝8.1Hz,1H),5.83(d,J＝7.6Hz,1H),4.23(t,J＝7.1Hz,2H),3.33–3.24(m,2H),2.46(s,3H),1.96(s,3H),1.70–1.58(m,2H),1.20–1.04(m,7H),0.74(t,J＝6.9Hz,3H).MS(ESI),m/z for C 31H 36N 4O 4S([M+H] +):Calcd 560.71,found561.8.
实施例77 2-乙酰氨基-2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-((R)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑吡啶-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000104
合成方法如实施例73，白色固体，产率：45％。 1H NMR(400MHz,DMSO-d 6)δ10.75(s,1H),8.90(d,J＝7.8Hz,1H),7.91(d,J＝8.4Hz,2H),7.80–7.73(m,4H),7.61(d,J＝8.6Hz,2H),7.53(d,J＝8.2Hz,1H),7.13(d,J＝8.1Hz,2H),7.04(d,J＝7.9Hz,2H),6.98(d,J＝8.6Hz,1H),6.94(s,1H),5.82(d,J＝7.8Hz,1H),5.74(q,J＝6.9Hz,1H),3.28(q,J＝7.4Hz,2H),2.29(s,3H),2.25(s,3H),1.95(s,3H),1.91(d,J＝7.1Hz,3H),1.09(t,J＝7.3Hz,3H).MS(ESI),m/z for C 35H 36N 4O 4S([M+H] +):Calcd 608.76,found 609.7.
实施例78 2-(4-(2-乙酰氨基-2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-N-异丙基-1-((R)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-5-甲酰胺
Figure PCTCN2020113949-appb-000105
合成方法如实施例73，白色固体，产率：46％。 1H NMR(400MHz,DMSO-d 6)δ10.78(s,1H),8.91(d,J＝7.7Hz,1H),8.18(s,1H),8.13(d,J＝8.1Hz,1H),7.92(d,J＝8.4Hz,2H),7.80(d,J＝8.6Hz,2H),7.77(d,J＝8.3Hz,2H),7.68(d,J＝8.5Hz,2H),7.57(d,J＝8.8Hz,1H),7.18–7.09(m,3H),7.04(d,J＝7.8Hz,2H),5.85–5.75(m,2H),4.15–4.03(m,1H),3.33–3.24(m,2H),2.24(s,3H),1.98–1.91(m,6H),1.15(d,J＝6.6Hz,6H),1.09(t,J＝7.3Hz,3H).MS(ESI),m/z for C 38H 41N 5O 5S([M+H] +):Calcd 679.84,found 680.8.
实施例79 2-(4-(2-乙酰氨基-2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-N-异丙基-1-((S)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-5-甲酰胺
Figure PCTCN2020113949-appb-000106
合成方法如实施例73，白色固体，产率：40％。 1H NMR(400MHz,DMSO-d 6)δ10.79(s,1H),8.91(d,J＝7.8Hz,1H),8.18(s,1H),8.13(d,J＝7.7Hz,1H),7.92(d,J＝8.4Hz,2H),7.80(d,J＝8.6Hz,2H),7.77(d,J＝8.4Hz,2H),7.68(d,J＝8.6Hz,2H),7.57(dd,J＝8.6,1.3Hz,1H),7.17–7.09(m,3H),7.04(d,J＝7.7Hz,2H),5.86–5.75(m,2H),4.15–4.03(m,1H),3.33–3.23(m,2H),2.24(s,3H),1.99–1.91(m,6H),1.16(d,J＝6.6Hz,6H),1.09(t,J＝7.3Hz,3H).MS(ESI),m/z for C 38H 41N 5O 5S([M+Na] +):Calcd 679.84,found 702.4.
实施例80 2-乙酰氨基-2-(4-(乙基磺酰基)苯基)-N-(6-(6-甲基-1-((S)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)吡啶-3-基)乙酰胺
步骤1.(S)-5-甲基-N 1-(1-(对甲苯基)乙基)苯-1,2-二胺的合成
Figure PCTCN2020113949-appb-000107
以3-氟-4-硝基甲苯和(S)-1-(4-甲基苯基)乙胺为原料，合成方法参照实施例31的步骤1～2。黄紫色液体，产率：90％。 1H NMR(400MHz,DMSO-d 6)δ7.24(d,J＝7.5Hz,2H),7.08(d,J＝7.4Hz,2H),6.40(d,J＝7.6Hz,1H),6.13(d,J＝7.4Hz,1H),6.02(s,1H),4.71(d,J＝6.2Hz,1H),4.52–4.29(m,3H),2.24(s,3H),1.94(s,3H),1.41(d,J＝6.5Hz,3H).
步骤2.(S)-N-(4-甲基-2-((1-(对甲苯基)乙基)氨基)苯基)-5-硝基吡啶的合成
Figure PCTCN2020113949-appb-000108
以(S)-5-甲基-N 1-(1-(对甲苯基)乙基)苯-1,2-二胺和5-硝基-2-吡啶羧酸为原料，合成方法参照实施例31的步骤5。黄色固体，产率：75％。 1H NMR(400MHz,DMSO-d 6)δ10.34(s,1H),9.47(d,J＝2.4Hz,1H),8.81(dd,J＝8.6,2.5Hz,1H),8.38(d,J＝8.6Hz,1H),7.31(d,J＝7.9Hz,2H),7.21(d,J＝7.9Hz,1H),7.09(d,J＝7.8Hz,2H),6.43(d,J＝8.1Hz,1H),6.32(s,1H),5.30(d,J＝6.4Hz,1H),4.52–4.42(m,1H),2.25(s,3H),2.09(s,3H),1.38(d,J＝6.6Hz,3H).
步骤3.(S)-6-甲基-2-(5-硝基吡啶-2-基)-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑的合成
Figure PCTCN2020113949-appb-000109
将(S)-N-(4-甲基-2-((1-(对甲苯基)乙基)氨基)苯基)-5-硝基吡啶(3.25g，8.32mmol)溶于150mL冰醋酸中，然后将溶液在120℃下回流搅拌4.5小时。反应完成后，先用饱和NaHCO 3洗涤溶液，直至醋酸完全消除，然后用乙酸乙酯多次萃取，合并有机相，再用饱和食盐水洗涤一遍，无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(PE:EA＝5:1v/v)，得到目标化合物为亮黄色固体(2.69g，产率：87％)。 1H NMR(400MHz,DMSO-d 6)δ9.46(d,J＝2.2Hz,1H),8.76(dd,J＝8.8,2.6Hz,1H),8.59(d,J＝8.8Hz,1H),7.65(d,J＝8.3Hz,1H),7.32(q,J＝6.4Hz,1H),7.21(d,J＝7.9Hz,2H),7.14(d,J＝7.9Hz,2H),7.07(d,J＝8.3Hz,1H),6.99(s,1H),2.30(s,3H),2.26(s,3H),1.98(d,J＝7.1Hz,3H).
步骤4.(S)-6-(6-甲基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)吡啶-3-胺的合成
Figure PCTCN2020113949-appb-000110
以(S)-6-甲基-2-(5-硝基吡啶-2-基)-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑为原料，合成方法参照实施例31的步骤2。白色固体，产率：71％。 1H NMR(400MHz,DMSO)δ8.01–7.95(m,2H),7.47(d,J＝8.2Hz,1H),7.31(q,J＝7.0Hz,1H),7.18(d,J＝8.1Hz,2H),7.12(d,J＝8.1Hz,2H),7.08(dd,J＝8.6,2.8Hz,1H),6.93(d,J＝8.2Hz,1H),6.85(s,1H),5.80(s,2H),2.25(s,6H),1.90(d,J＝7.1Hz,3H).
步骤5.叔丁基(1-(4-(乙基磺酰)苯基)-2-((6-(6-甲基-1-((S)-1-(对甲苯基)乙基)-1H苯并[d]咪唑-2-基)吡啶-3-基)氨基)-2-氧代乙基)氨基甲酸酯的合成
Figure PCTCN2020113949-appb-000111
以(S)-5-(6-甲基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)吡啶-2-胺和2-((叔丁氧基羰基)氨基)-2-(4-(乙基磺酰基)苯基)乙酸原料，合成法参照实施例31的步骤5。白色固体，产率：39％。 1H NMR(400MHz,DMSO-d 6)δ10.84(s,1H),8.86(d,J＝1.5Hz,1H),8.29–8.20(m,2H),7.94–7.85(m,3H),7.78(d,J＝8.3Hz,2H),7.55(d,J＝8.3Hz,1H),7.26–7.16(m,3H),7.12(d,J＝7.8Hz,2H),6.99(d,J＝8.3Hz,1H),6.92(s,1H),3.33–3.22(m,2H),2.27(s,3H),2.25(s,3H),1.92(dd,J＝6.9,2.7Hz,3H),1.40(s,9H),1.09(t,J＝7.3Hz,3H).
步骤6. 2-氨基-2-(4-(乙基磺酰基)苯基)-N-(6-(6-甲基-1-((S)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)吡啶-3-基)乙酰胺的合成
Figure PCTCN2020113949-appb-000112
以叔丁基(1-(4-(乙基磺酰)苯基)-2-((6-(6-甲基-1-((S)-1-(对甲苯基)乙基)-1H苯并[d]咪唑-2-基)吡啶-3-基)氨基)-2-氧代乙基)氨基甲酸酯为原料，合成法参照实施例72的步骤2。白色固体，产率：80％。MS(ESI),m/z for C 32H 33N 5O 3S([M+H] +):Calcd 567.71,found 568.8.
步骤7. 2-乙酰氨基-2-(4-(乙基磺酰基)苯基)-N-(6-(6-甲基-1-((S)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)吡啶-3-基)乙酰胺的合成
Figure PCTCN2020113949-appb-000113
以2-氨基-2-(4-(乙基磺酰基)苯基)-N-(6-(6-甲基-1-((S)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)吡啶-3-基)乙酰胺为原料，合成法参照实施例72的步骤3。白色固体，产率：70％。 1H NMR(400MHz,DMSO-d 6)δ10.96(s,1H),8.95(d,J＝7.7Hz,1H),8.87(s,1H),8.31–8.19(m,2H),7.92(d,J＝8.3Hz,2H),7.77(d,J＝8.3Hz,2H),7.55(d,J＝8.2Hz,1H),7.26–7.15(m,3H),7.12(d,J＝7.8Hz,2H),6.99(d,J＝8.0Hz,1H),6.92(s,1H),5.83(d,J＝7.6Hz,1H),3.33–3.23(m,2H),2.27(s,3H),2.25(s,3H),1.96(s,3H),1.92(dd,J＝7.0,1.7Hz,3H),1.09(t,J＝7.3Hz,3H).MS(ESI),m/z for C 34H 35N 5O 4S([M+H] +):Calcd 609.75,found 610.7.
实施例81 2-乙酰氨基-2-(4-(乙基磺酰基)苯基)-N-(6-(6-甲基-1-戊基-1H-苯并[d]咪唑-2-基)吡啶-3-基)乙酰胺
Figure PCTCN2020113949-appb-000114
合成方法如实施例80，白色固体，产率：63％。 1H NMR(400MHz,DMSO-d 6)δ10.91(s,1H),8.97–8.88(m,2H),8.27(d,J＝8.5Hz,1H),8.18(d,J＝7.7Hz,1H),7.93(d,J＝7.8Hz,2H),7.78(d,J＝7.9Hz,2H),7.55(d,J＝8.0Hz,1H),7.42(s,1H),7.07(d,J＝7.8Hz,1H),5.82(d,J＝7.3Hz,1H),4.81–4.67(m,2H),3.33–3.23(m,2H),2.47(s,3H),1.97(s,3H),1.79–1.67(m,2H),1.31–1.20(m,4H),1.10(t,J＝7.2Hz,3H),0.81(t,J＝6.4Hz,3H).MS(ESI),m/z for C 30H 35N 5O 4S([M+H] +):Calcd 561.70,found 562.7.
实施例82 2-乙酰氨基-2-(4-(乙基磺酰基)苯基)-N-(6-(6-甲基-1-((R)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)吡啶-3-基)乙酰胺
Figure PCTCN2020113949-appb-000115
合成方法如实施例80，白色固体，产率：65％。 1H NMR(400MHz,DMSO-d 6)δ10.96(s,1H),8.95(d,J＝7.7Hz,1H),8.87(d,J＝1.8Hz,1H),8.30–8.21(m,2H),7.92(d,J＝8.4Hz,2H),7.77(d,J＝8.4Hz,2H),7.55(d,J＝8.2Hz,1H),7.26–7.16(m,3H),7.12(d,J＝8.0Hz,2H),6.99(d,J＝8.3Hz,1H),6.92(s,1H),5.83(d,J＝7.7Hz,1H),3.28(q,J＝7.3Hz,2H),2.27(s,3H),2.25(s,3H),1.96(s,3H),1.92(dd,J＝7.1,1.9Hz,3H),1.09(t,J＝7.3Hz,3H).MS(ESI),m/z for C 34H 35N 5O 4S([M+H] +):Calcd 609.75,found 610.7.
实施例83 2-(5-(2-乙酰氨基-2-(4-(乙基磺酰基)苯基)乙酰氨基)吡啶-2-基)-N-异丙基-1-((R)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-5-甲酰胺
Figure PCTCN2020113949-appb-000116
合成方法如实施例80，白色固体，产率：49％。 1H NMR(400MHz,DMSO-d 6)δ11.00(s,1H),8.95(d,J＝7.7Hz,1H),8.92(d,J＝2.1Hz,1H),8.34–8.23(m,2H),8.20(d,J＝0.8Hz,1H),8.12(d,J＝7.7Hz,1H),7.92(d,J＝8.4Hz,2H),7.77(d,J＝8.4Hz,2H),7.55(dd,J＝8.6,1.4Hz,1H),7.25(q,J＝7.0Hz,1H),7.18(d,J＝8.1Hz,2H),7.15–7.07(m,3H),5.84(d,J＝7.7Hz,1H),4.14–4.03(m,1H),3.33–3.24(m,2H),2.24(s,3H),1.99–1.91(m,6H),1.15(d,J＝6.5Hz,6H),1.09(t,J＝7.3Hz,3H).MS(ESI),m/z for C 37H 40N 6O 5S([M+Na] +):Calcd 680.82,found703.3.
实施例84 2-(5-(2-乙酰氨基-2-(4-(乙基磺酰基)苯基)乙酰氨基)吡啶-2-基)-N-异丙基-1-((S)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-5-甲酰胺
Figure PCTCN2020113949-appb-000117
合成方法如实施例80，白色固体，产率：33％。 1H NMR(400MHz,DMSO-d 6)δ11.00(s,1H),8.95(d,J＝7.7Hz,1H),8.91(d,J＝2.2Hz,1H),8.34–8.24(m,2H),8.20(s,1H),8.12(d,J＝7.9Hz,1H),7.92(d,J＝8.3Hz,2H),7.77(d,J＝8.4Hz,2H),7.55(dd,J＝8.7,1.2Hz,1H),7.25(q,J＝6.8Hz,1H),7.18(d,J＝8.0Hz,2H),7.10(m,3H),5.84(d,J＝8.0Hz,1H),4.13–4.02(m,1H),3.32–3.25(m,2H),2.24(s,3H),1.98–1.90(m,6H),1.15(d,J＝6.5Hz,6H),1.09(t,J＝7.4Hz,3H).MS(ESI),m/z for C 37H 40N 6O 5S([M-H] -):Calcd 680.82,found 679.5.
实施例85 N-(4-(1-苄基-5，6-二甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000118
以1-氯-4,5-二甲基-2-硝基苯和苄胺为原料，合成方法参照实施例32。白色固体，产率：43％。 1H NMR(400MHz,CDCl 3)δ9.21(s,1H),7.83–7.70(m,2H),7.60–7.50(m,3H),7.49–7.38(m,4H),7.35–7.24(m,3H),7.10–6.96(m,3H),5.36(s,2H),3.77(s,2H),3.14–2.99(m,2H),2.36(s,3H),2.33(s,3H),1.28–1.18(m,3H).MS(ESI),m/z for C 32H 31N 3O 3S([M+H] +):Calcd 537.68,found 538.6.
实施例86 N-(4-(1-苄基-5，6-二氯-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000119
以1,2-二氯-4-氟-5-硝基苯和苄胺为原料，合成方法参照实施例32。白色固体，产率：47％。 1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),7.99(s,1H),7.91(s,1H),7.85(d,J＝8.2Hz,2H),7.77–7.68(m,4H),7.61(d,J＝8.2Hz,2H),7.32–7.20(m,3H),6.96(d,J＝7.0Hz,2H),5.63(s,2H),3.84(s,2H),3.27(q,J＝7.3Hz,2H),1.10(t,J＝7.3Hz,3H).MS(ESI),m/z for C 30H 25Cl 2N 3O 3S([M+H] +):Calcd 578.51,found 578.4.
实施例87 2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
Figure PCTCN2020113949-appb-000120
将N-(4-(1-苄基-6-甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺(100mg，0.19mmol)溶解在甲醇(20mL)中，加入Pd-C(100mg)。将反应混合物在氢气保护下在室温下搅拌过夜。反应结束后，用硅胶土过滤反应混合物，溶剂浓缩，之后硅胶柱色谱(PE:EA＝4:1,v/v)纯化，得到目标化合物为白固体(65.9mg，产率：80％)。 1H NMR(400MHz,DMSO-d 6)δ10.49(s,1H),8.08(d,J＝8.8Hz,2H),7.86(d,J＝8.3Hz,2H),7.75(d,J＝8.8Hz,2H),7.63(d,J＝8.3Hz,2H),7.44(d,J＝8.2Hz,1H),7.34(s,1H),7.01(dd,J＝8.2,1.0Hz,1H),3.85(s,2H),3.28(q,J＝7.4Hz,2H),2.42(s,3H),1.10(t,J＝7.4Hz,3H).MS(ESI),m/z for C 24H 23N 3O 3S([M+H] +):Calcd 433.53,found 434.5.
测试例1体外活体实验
本测试例采用蛋白热稳定性实验(Thermal stability shift assay,TSA)技术检测本申请化合物结合并稳定RORγ蛋白能力的强弱。
实验材料：目的蛋白hRORγ2μL(终浓度10μM)、SYPRO Orange荧光染料2μL、化合物10μL(终浓度200μM)、缓冲液2μL、去离子水4μL。HSP-96孔反应板。阳性抑制剂：SR2211。
实验方法：按上述体积将各组分加入到HSP-96孔反应板，1000r/min室温离心1min，冰上孵育30min。将孵育好的96孔反应板放入Real-time PCR仪，起始温度30℃，终止温度80℃，每5秒读一次，每读一次温度升高0.3℃。保存文件，使用GraphPad Prism 7软件分析数据。
分别采用荧光素酶检测技术(Luciferase)检测技术和TSA检测技术验证结果，Luciferase结果如表1所示，TSA结果如表2所示。
表1
Figure PCTCN2020113949-appb-000121
注：“A”指的是IC 50＜0.1μM，“B”指的是0.1μM≤IC 50＜1μM之间，“C”指的是1μM≤IC 50＜10μM之间，“D”指的是10μM≤IC 50＜100μM之间。
表2
Figure PCTCN2020113949-appb-000122
Figure PCTCN2020113949-appb-000123
注：“A”指的是ΔT m≤5℃，“B”指的是5℃＜ΔT m＜10℃之间，“C”指的是ΔT m≥10℃
表1和表2的活性数据表明，本申请提供的化合物可较好的抑制RORγ的转录活性，并可显著增强RORγ蛋白的热稳定性。
测试例2对RORγ以及其同源蛋白的选择性测试
本测试例评价实施例35、实施例54、实施例57、实施例67、实施例68和实施例74在Luciferase实验中对RORγ以及其同源蛋白的选择性。
实验材料：人肾上皮细胞系293T细胞；含有10％胎牛血清的DMEM培养基；96孔板透明板；双报告基因检测试剂盒；Opti-MEM试剂；Lipo-fectamine 2000转染试剂；重组质粒：Gal4-RORγLBD：25ng，RORE_Luc：25ng，pG5-luc、荧光素酶(Renilla)；阳性抑制剂：SR2211。
实验方法：人肾上皮细胞系293T细胞，用含有10％胎牛血清的DMEM培养基培养。转染前一天将细胞制备与96孔板中，细胞密度为1.5x10 4个/孔。贴壁生长24小时后进行瞬时转染，采用双报告基因共转染的方法，转染试剂为Lipo-fectamine2000，用Opti-MEM试剂分别稀释转染试剂和质粒。Gal4-RORγLBD每孔25ng；pG5-luc基因每孔25ng；Renilla每孔5ng，共转染24小时后加入不同浓度的化合物，孵育24小时后，采用Luciferase双报告基因检测试剂盒，检测发光信号，每个样品3个复孔，利用软件计算IC 50值(半抑制浓度)。
实验结果：本申请实施例35、实施例54、实施例57、实施例67、实施例68和实施例74在Luciferase实验中对RORγ以及其同源蛋白的活性数据如表3所示。
表3
Figure PCTCN2020113949-appb-000124
实验结果表明：本申请提供的化合物对RORγ具有特异的选择性，特别是实施例35、实施例54、实施例57、实施例67、实施例68和实施例74对RORγ蛋白相对于其它核受体蛋白表现出更优秀的选择性。
测试例3对AR阳性前列腺癌细胞系的增殖抑制作用测试
本测试例评价实施例35、实施例54、实施例67、实施例68和实施例74对AR阳性前列腺癌细胞系的增殖抑制作用。
实验材料：荧光信号检测仪器EnSpire Alpha 2390多功能酶标仪(Perkin Elmer公司生产)；384孔底透微孔板；Cell-Titer GLO发光试剂；前列腺癌细胞系LNCaP、C4-2B和22Rv1；细胞培养所需的培养基和胎牛血清。阳性药：恩杂鲁胺(Enzalutamide)，SR2211。
实验方法：在384孔底透微孔板中铺入20μL介质的500-1000个/孔的待测细胞(实际细胞数量的选取与细胞周期和细胞自身体积有关)。12小时后，每孔加入10μL含有化合物(化 合物浓度由5nM到100nM)的培养介质。与化合物孵育72-96h小时后，每孔加入Cell-Titer GLO试剂，震板20min，使细胞裂解。孵育10min后，离心1min，测定luminescence 384信号值。使用GraphPad Prism软件拟合抑制曲线，计算IC 50。
实验结果：本申请实施例35、实施例54、实施例67、实施例68和实施例74对AR阳性前列腺癌细胞系的抗增殖活性如表4。
表4
Figure PCTCN2020113949-appb-000125
由表4的结果可知，本申请提供的化合物IC 50值可远小于目前已上市的药物Enzalutamide的IC 50值，具有更良好的抑制前列腺癌细胞增殖的作用。
测试例4药物代谢动力学评价
本测试例对实施例67、实施例68进行药物代谢动力学评价。
实验材料：药代动力学分析由上海的Medicilon Corporation公司分析。Sprague-Dawley(SD)大鼠由上海Super--B&K laboratory animal Corp.Ltd提供。
实验方法：将化合物溶解于5％DMA、10％Solutol和85％的Saline中作为储备溶液。将储备溶液以25mg/kg的剂量口服给予3只SD大鼠，并以5mg/kg的单剂量静脉内给予3只SD大鼠。在口服给药前和口服给药后0.25、0.5、1、2、4、6、8和24小时，从颈静脉采集血液。在静脉注射给药前和在静脉注射给药后0.083、0.25、0.5、1、2、4、6、8和24小时，从颈静脉采集血液。将约200μL血液样品收集到肝素化管中，然后立即以8000转/分钟离心6分钟，获得的血浆储存-80℃直至分析。
实验结果：实施例67、实施例68的各项药物代谢动力学数据如表5所示：
表5
Figure PCTCN2020113949-appb-000126
注：——代表数据未测。
实验结果表明：本申请提供的化合物具有良好的药代动力学性质。
测试例5 22Rv1异种移植模型小鼠体内药效研究
实验目的：异种移植小鼠实验，采用该实验验证本申请化合物在体内对肿瘤的抑制效果。
实验方法：三周龄雄性小鼠(株：NOD/MrkBomTac-Prkdc scid)购自北京维通利华实验动物技术有限公司并用于异种移植肿瘤建立。在每只小鼠小腹一侧的皮下接种22Rv1肿瘤细胞，每只注射3×10 6个细胞，细胞混悬于100μL的PBS和Matrigel(比例为1:1)中。当肿瘤体积达到约100mm 3左右时，小鼠被随机分组(每组n＝6～7)，然后通过口服灌胃的方式对小鼠进行给药，实施例68溶解于15％聚氧乙烯醚(35)蓖麻油(Cremophor EL)，Calbiochem，82.5％PBS和2.5％二甲基亚砜(DMSO)的给药溶媒中，连续给药三周，每周给药五天。通过卡尺监测肿瘤块的长度(L)和宽度(W)，体积以mm 3表示，用下式计算：V＝π/6×(L×W 2)。使用以下公式计算肿瘤生长抑制(TGI)：TGI＝[1-(T-T 0)/(C-C 0)]×100，其中，T是特定实验日的平均肿瘤体积，T 0治疗初期的平均肿瘤体积；同样C和C 0分别是特定实验日和治疗初期空白组的平均肿瘤体积。
测试例5采用小鼠移植瘤模型实验检测，选用22Rv1前列腺癌细胞异种移植的小鼠模型，通过口服给药实施例68(给药剂量：10mg/kg或40mg/kg)，每周给药五次，给药3周，观察小鼠体内肿瘤体积的变化。数据表示为每个治疗组中动物的平均肿瘤体积±标准偏差(每组n＝6～7)。
实施例68在22Rv1小鼠移植瘤模型上对肿瘤的抑制效果的结果见图1和2：图1显示，实施例68在10mg/kg剂量下可以显著抑制小鼠体内肿瘤的生长(TGI＝83％)。在40mg/kg剂量下不仅能显著抑制小鼠体内肿瘤生长，还能长久而持续的完全消退肿瘤(TGI＝109％)。此外，图2显示，实施例68在所有剂量下，小鼠体重都没有明显变化且行为正常。这些结果表明实施例68在22Rv1小鼠移植瘤模型上具有显著的抑制体内肿瘤生长的效果，且没有任何明显的毒性作用。
这些化合物通过有效结合并抑制RORγ受体蛋白的转录，从而抑制下游信号通路，进而达到抑制肿瘤生长，改善炎症等效果。实施例68具体展示了其在体内抑制前列腺肿瘤生长的效果。根据现有已报道的证据也表明这类化合物具有成为治疗癌症、细胞增殖性紊乱、炎症疾病及自身免疫性疾病、败血症和病毒感染等疾病的潜力。
申请人声明，本申请通过上述实施例来说明本申请的苯并五元含氮杂环类化合物及其应用，但本申请并不局限于上述实施例，即不意味着本申请必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本申请的任何改进，对本申请产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本申请的保护范围和公开范围之内。

Claims (14)

  1. 一种苯并五元氮杂环化合物，其具有式I所示的结构；
    Figure PCTCN2020113949-appb-100001
    式I中，所述X选自
    Figure PCTCN2020113949-appb-100002
    波浪线代表基团的连接键；
    式I中，所述Y选自CR 5或N原子；
    式I中，所述Z选自S原子或NR 10；
    式I中，所述R 1和R 10各自独立地选自0～3个R 11取代的C1～C10烷基、0～3个R 11取代的C6～C10芳基、0～3个R 11取代的C6-C10芳基C1-C3烷基、0～3个R 11取代的C2～C10杂芳基、0～3个R 11取代的C2～C20杂环基、0～3个R 11取代的C2～C10杂芳基C1-C3烷基、0～3个R 11取代的C2～20杂环基C1-C3烷基、0～3个R 11取代的C3～C10环烷基、0～3个R 11取代的C3～C10环烷基C1-C3烷基中的任意一种；
    所述R 11选自卤素、氰基、硝基、羧基、羟基、氨基、C1～C10烷基砜基、至少一个卤素取代的C1～C10烷基砜基、C1～C10烷基酯基、至少一个卤素取代的C1～C10烷基酯基、C1～C10烷基、至少一个卤素取代的C1～C10烷基、C1～C10烷氧基、至少一个卤素取代的C1～C10烷氧基、C3～C10环烷基、至少一个卤素取代的C3～C10环烷基中的任意一种；
    式I中，所述R 2-R 9各自独立地选自氢、卤素、C1～C10烷基、至少一个卤素取代的C1～C10烷基、C1～C10烷氧基、至少一个卤素取代的C1～C10烷氧基、C1～C10烷基酰胺基、至少一个卤素取代的C1～C10烷基酰胺基、C1～C10环烷基酰胺基、至少一个卤素取代的C1～C10环烷基酰胺基、C1～C10烷基胺基、至少一个卤素取代的C1～C10烷基胺基、C3～C10环烷基氨基、至少一个卤素取代的C3～C10环烷基氨基中的任意一种。
  2. 根据权利要求1所述的苯并五元氮杂环化合物，其中，所述0～3个R 11取代的C2～C20杂环基为
    Figure PCTCN2020113949-appb-100003
    波浪线代表基团的连接键。
  3. 根据权利要求1所述的苯并五元氮杂环化合物，其中，R 1中的R 11选自C1～C10烷基、卤素、三氟甲氧基、硝基、氰基、羧基、甲基酯基、乙基酯基、氨基、甲基砜基、乙基砜基中的任意一种或至少两种组合，优选氰基、乙基酯基、乙基砜基中的任意一种或至少两种组合；
    任选地，所述R 2-R 5均为氢；
    任选地，所述R 6、R 7、R 8和R 9不同时为氢；
    任选地，所述R 6和R 9为氢；
    任选地，所述R 7和R 8不同时为氢；
    任选地，所述R 7和R 8中有且仅有一项为氢；
    任选地，所述R 7和R 8各自独立地选自氢、甲基、甲氧基、卤素、三氟甲基、C2～C10烷基酰胺基中的任意一种或至少两种组合；
    任选地，所述C2～C10烷基酰胺基为异丙基酰胺基或环戊基酰胺基；
    任选地，所述R 10选自C1～C10烷基、环丁基、环丁基甲基、环己基甲基、吡啶甲基、0～3个R 11取代的苯基乙基、0～3个R 11取代的苄基中的任意一种；
    任选地，R 10中的R 11选自甲基、羧基、三氟甲基、甲基酯基、卤素、氰基、甲基砜基中的任意一种或至少两种组合。
  4. 根据权利要求1所述的苯并五元氮杂环化合物，其中，所述苯并五元氮杂环化合物具有式II所示的结构；
    Figure PCTCN2020113949-appb-100004
    式II中，X选自
    Figure PCTCN2020113949-appb-100005
    式II中，所述R 1选自0～3个R 11取代的C1～C10烷基、0～3个R 11取代的C6～C10芳基、0～3个R 11取代的C6-C10芳基C1-C3烷基、0～3个R 11取代的C2～C20杂环基中的任意一种；R 11选自卤素、氰基、硝基、羧基、羟基、氨基、C1～C10烷基砜基、至少一个卤素取代的C1～C10烷基砜基、C1～C10烷基酯基、至少一个卤素取代的C1～C10烷基酯基、C1～C10烷基、至少一个卤素取代的C1～C10烷基、C1～C10烷氧基、至少一个卤素取代的C1～C10烷氧基中的任意一种；
    式II中，所述R 2～R 9各自独立地选自氢、卤素、C1～C10烷基、至少一个卤素取代的C1～C10烷基、C1～C10烷氧基、至少一个卤素取代的C1～C10烷氧基中的任意一种；
    任选地，式II中，所述R 2选自氢或氯；
    任选地，式II中，所述R 8选自甲基、甲氧基或氟中的任意一种；
    任选地，式II中，所述R 7为氢。
  5. 根据权利要求1所述的苯并五元氮杂环化合物，其中，所述苯并五元氮杂环化合物具有式III所示的结构；
    Figure PCTCN2020113949-appb-100006
    式III中，Y选自CR 5或N原子；
    式III中，R 2～R 9各自独立地选自氢、卤素、C1～C10烷基、至少一个卤素取代的C1～C10烷基、C1～C10烷氧基、至少一个卤素取代的C1～C10烷氧基、C1～C10烷基酰胺基、至少一个卤素取代的C1～C10烷基酰胺基、C1～C10环烷基酰胺基、至少一个卤素取代的C1～C10环烷基酰胺基中的任意一种；
    式III中，所述R 10选自0～3个R 11取代的C1～C10烷基、0～3个R 11取代的C6-C10芳基C1-C3烷基、0～3个R 11取代的C2～C10杂芳基C1-C3烷基、0～3个R 11取代的C3～C10环烷基、0～3个R 11取代的C3～C10环烷基C1-C3烷基中的任意一种；所述R 11选自氢、卤素、氰基、羧基、C1～C10烷基、至少一个卤素取代的C1～C10烷基、C1～C10烷基砜基、至少一个卤素取代的C1～C10烷基砜基、C1～C10烷基酯基、至少一个卤素取代的C1～C10烷基酯基；
    式III中，所述R 12及R 13各自独立地选自氢、氨基、0～3个R 14取代的C1-10烷基、0～3个R 14取代的C1～C10烷基酰胺基，或R 12及R 13与其所连接的碳一起形成C3-C6碳环；所述R 14选自卤素、羧基、羟基、氨基、C1～C10烷基酰胺基、C1～C10烷基胺基、C1～C10烷基酯基中的任意一种；
    任选地，所述R 7选自甲基、甲氧基、异丙基酰胺基或环戊基酰胺基中的任意一种；
    任选地，所述R 8选自甲基、甲氧基、三氟甲基、异丙基酰胺基或环戊基酰胺基中的任意一种；
    任选地，所述R 12和R 13各自独立地选自氢、氨基或甲基酰胺基中的任意一种。
  6. 根据权利要求1所述的苯并五元氮杂环化合物，其中，所述苯并五元氮杂环化合物具有如下结构中的任意一种：
    4-甲基-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)苯磺酰胺
    4-(叔丁基)-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)苯磺酰胺
    4-氟-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)苯磺酰胺
    N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-4-(三氟甲氧基)苯磺酰胺
    N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-4-硝基苯磺酰胺
    N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-3-硝基苯磺酰胺
    N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-2-硝基苯磺酰胺
    N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-3-(甲磺酰基)苯磺酰胺
    2，4-二氟-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)苯磺酰胺
    2，4，6-三甲基-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)苯磺酰胺
    1-乙基N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺
    N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-1-(对甲苯基)甲磺酰胺
    1-(4-氟苯基)-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)甲磺酰胺
    N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-1-(4-(三氟甲基)苯基)甲磺酰胺
    N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-1-(4-硝基苯基)甲磺酰胺
    1-(4-氰基苯基)-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)甲磺酰胺
    N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-1-(4-(甲基磺酰基)苯基)甲磺酰胺
    4-((N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)氨磺酰基)甲基)苯甲酸甲酯
    4-((N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)氨磺酰基)甲基)苯甲酸
    4-((N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)氨磺酰基)甲基)苯基丙酸酯
    N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-1-(3-硝基苯基)甲磺酰胺
    N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-1-(2-硝基苯基)甲磺酰胺
    3-((N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)氨磺酰基)甲基)苯甲酸甲酯
    1-(3-氨基苯基)-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)甲磺酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)乙酰胺
    N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)庚酰胺
    N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-2-(对甲苯基)乙酰胺
    N-(4-(6-甲基苯并[d]噻唑-2-基)苯基)-2-(2-硝基苯基)乙酰胺
    N-(3-氯-4-(6-甲基苯并[d]噻唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(6-氟苯并[d]噻唑-2-基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲氧基苯并[d]噻唑-2-基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(4-甲基苯乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-丙基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    N-(4-(1-丁基-6-甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-戊基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(1-异丙基-6-甲基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(1-异丁基-6-甲基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(1-异戊基-6-甲基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    N-(4-(1-环丁基-6-甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
    N-(4-(1-(环丁基甲基)-6-甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
    N-(4-(1-(环己基甲基)-6-甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
    N-(4-(1-苄基-6-甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(4-甲基苄基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-苯乙基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(1-(4-氟苄基)-6-甲基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(1-(3-氟苄基)-6-甲基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(1-(2-氟苄基)-6-甲基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    N-(4-(1-(2，6-二氟苄基)-6-甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
    N-(4-(1-(4-氰基苄基)-6-甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(4-(甲基磺酰基)苄基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(吡啶-2-基甲基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    N-(4-(1-苄基-6-氯-1H-苯并[d]咪唑-2-基)苯基)-2-(4-乙基磺酰)苯基)乙酰胺
    N-(4-(1-苄基-5-氯-1H-苯并[d]咪唑-2-基)苯基)-2-(4-乙基磺酰)苯基)乙酰胺
    (S)-2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(吡啶-4-基甲基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    (R)-2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(1-(4-氟苯乙基)-6-甲基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(4-(三氟甲基)苄基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    4-((2-(4-(2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-6-甲基-1H-苯并[d]咪唑-1-基)甲基)苯甲酸甲酯
    4-((2-(4-(2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-6-甲基-1H-苯并[d]咪唑-1-基)甲基)苯甲酸
    2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-(吡啶-3-基甲基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    (R)-2-(4-(乙基磺酰基)苯基)-N-(4-(1-(1-(对甲苯基)乙基)-6-(三氟甲基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    (R)-2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲氧基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    (R)-2-(4-(乙基磺酰基)苯基)-N-(4-(5-甲基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    (R)-2-(4-(乙基磺酰基)苯基)-N-(4-(5-甲氧基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    (R)-2-(4-(乙基磺基)苯基)-N-(4-(1-(1-(4-氟苯基)乙基)-6-(三氟甲基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    (S)-2-(4-(乙基磺基)苯基)-N-(4-(1-(1-(4-氟苯基)乙基)-6-(三氟甲基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    (R)-2-(4-(2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-N-异丙基-1-(1-(对甲 苯基)乙基)-1H-苯并[d]咪唑-6-甲酰胺
    (R)-N-环戊基-2-(4-(2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑-6-甲酰胺
    (R)-2-(4-(2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-N-异丙基-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑唑-5-甲酰胺
    (R)-N-环戊基-2-(4-(2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-1-(1-(对甲苯基)乙基)-1H-苯并[d]咪唑唑-5-甲酰胺
    2-乙酰氨基-2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-((S)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    2-乙酰氨基-2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-戊基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺
    2-乙酰氨基-2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1-((R)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑吡啶-2-基)苯基)乙酰胺
    2-(4-(2-乙酰氨基-2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-N-异丙基-1-((R)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-5-甲酰胺
    2-(4-(2-乙酰氨基-2-(4-(乙基磺酰基)苯基)乙酰氨基)苯基)-N-异丙基-1-((S)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-5-甲酰胺
    2-乙酰氨基-2-(4-(乙基磺酰基)苯基)-N-(6-(6-甲基-1-((S)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)吡啶-3-基)乙酰胺
    2-乙酰氨基-2-(4-(乙基磺酰基)苯基)-N-(6-(6-甲基-1-戊基-1H-苯并[d]咪唑-2-基)吡啶-3-基)乙酰胺
    2-乙酰氨基-2-(4-(乙基磺酰基)苯基)-N-(6-(6-甲基-1-((R)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-2-基)吡啶-3-基)乙酰胺
    2-(5-(2-乙酰氨基-2-(4-(乙基磺酰基)苯基)乙酰氨基)吡啶-2-基)-N-异丙基-1-((R)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-5-甲酰胺
    2-(5-(2-乙酰氨基-2-(4-(乙基磺酰基)苯基)乙酰氨基)吡啶-2-基)-N-异丙基-1-((S)-1-(对甲苯基)乙基)-1H-苯并[d]咪唑-5-甲酰胺
    N-(4-(1-苄基-5，6-二甲基-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
    N-(4-(1-苄基-5，6-二氯-1H-苯并[d]咪唑-2-基)苯基)-2-(4-(乙基磺酰基)苯基)乙酰胺
    2-(4-(乙基磺酰基)苯基)-N-(4-(6-甲基-1H-苯并[d]咪唑-2-基)苯基)乙酰胺。
  7. 一种根据权利要求1-6中任一项所述的苯并五元氮杂环化合物的药学上可接受的盐、异构体、外消旋体、前体药物、共结晶复合物或溶剂合物。
  8. 一种根据权利要求1-6中任一项所述的苯并五元氮杂环化合物或者权利要求7所述的药学上可接受的盐、异构体、外消旋体、前体药物、共结晶复合物或溶剂合物在制备RORγ受体抑制剂的应用。
  9. 根据权利要求8所述的应用，其中，所述RORγ受体抑制剂用于制备治疗癌症、细胞增殖性紊乱疾病、炎症疾病及自身免疫疾病、败血症、病毒感染或神经性衰退性疾病的药物。
  10. 根据权利要求7所述的应用，其中，所述RORγ受体抑制剂用于制备治疗癌症的药 物；
  11. 根据权利要求7所述的应用，其中，所述RORγ受体抑制剂用于制备治疗前列腺癌的药物。
  12. 一种药物组合物，其中，所述药物组合物的活性成分包括权利要求1-6中任一项所述的苯并五元氮杂环化合物或者权利要求7所述的药学上可接受的盐、异构体、外消旋体、前体药物、共结晶复合物或溶剂合物。
  13. 一种根据权利要求10所述的药物组合物在制备治疗、预防或改善炎症、自身免疫性疾病、细胞增殖性紊乱疾病、败血病、癌症、病毒感染或神经性衰退性疾病的药物中的应用。
  14. 根据权利要求13所述的应用，其中，所述癌症包括前列腺癌。
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