WO2016119690A1 - 一种2-氧代-1,2-二氢苯并[cd]吲哚类化合物及其应用 - Google Patents

一种2-氧代-1,2-二氢苯并[cd]吲哚类化合物及其应用 Download PDF

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WO2016119690A1
WO2016119690A1 PCT/CN2016/072266 CN2016072266W WO2016119690A1 WO 2016119690 A1 WO2016119690 A1 WO 2016119690A1 CN 2016072266 W CN2016072266 W CN 2016072266W WO 2016119690 A1 WO2016119690 A1 WO 2016119690A1
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indole
ethyl
dihydrobenzo
oxo
sulfonamide
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PCT/CN2016/072266
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French (fr)
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许�永
薛晓纤
张岩
宋明
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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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Priority to US15/546,251 priority Critical patent/US10183010B2/en
Publication of WO2016119690A1 publication Critical patent/WO2016119690A1/zh

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Definitions

  • the invention relates to the technical field of chemical medicine, in particular to a 2-oxo-1,2-dihydrobenzo[cd]indole compound and application thereof.
  • the Bromodomain family is a class of epigenetic readers that recognize acetylated lysine. These epigenetic readers bind to the acetylated lysine of the tails of histidine H3 and H4 to form a starting complex, thereby altering the binding of chromatin to transcription factors and activating RNA polymerase leading to gene transcription or chromatin recombination.
  • Inhibitors of Bromodomain proteins have important biological significance. For example, a large number of compounds have been reported to be effective in the treatment of neurological diseases, antiviral, anticancer and diseases such as inflammation and autoimmune diseases.
  • the Bromodomain protein was identified in the early 1990s from the Brassica chinensis gene.
  • the human proteome encodes 61 bromo domains, which are present in 46 different nuclear and cytoplasmic proteins. This family of proteins is divided into nine groups depending on the sequence, of which BET bromodomain is one of them.
  • the BET bromodomain protein has four subtypes: BRD2, BRD3, BRD4, and BRD-t.
  • BRD2 and BRD3 are linked to histidine and are located on active transcriptional genes, and thus may be involved in the process of promoting transcriptional elongation.
  • BRD4 can recruit PTEF- ⁇ to bind to inducible genes, resulting in phosphorylation of RNA polymerase and enhanced transcriptional output. .
  • BRD4 and BRD3 can be fused to nuclear proteins (NUT) to form new fusion oncogenes, BRD4-NUT and BRD3-NUT.
  • NUT nuclear proteins
  • BRD-NUT is a major carcinogenic factor.
  • BRD-t is mainly expressed in the testis and ovary.
  • the technical problem to be solved by the present invention is to provide a 2-oxo-1,2-dihydrobenzo[cd]indole compound which can effectively inhibit the BET bromodomain receptor and can be used for treating cancer and cells.
  • R 1 is selected from: H or a C 1 -C 4 linear or branched alkyl group; and R 2 is selected from the group consisting of: C 1 -C 7 alkyl, C 1 -C 4 alkylene-R 6 Or a C 0 -C 4 alkylene-R 7 -cyclic group; said R 6 is selected from the group consisting of -OR 8 , -COR 8 , -CONHR 8 , -COOR 8 , -S(O) m R 8 , S(O) m R 8 , —NHCOOR 8 , —NHCOR 8 or —NH 2 , wherein m is 0 or 2, R 8 is selected from hydrogen or C 1 -C 3 alkyl; and R 7 is selected from - COR 9 , —COOR 9 , —OR 9 or not, wherein R 9 is selected from C 1 -C 3 alkylene; the ring group is selected from C 3 -C 10 cycloalky
  • R 1 is selected from: H or a C 1 -C 4 linear or branched alkyl group; and R 3 is selected from the group consisting of C 1 -C 7 alkyl, C 1 -C 4 alkylene-R 6 Or a C 0 -C 4 alkylene-R 7 -cyclic group; said R 6 is selected from -OR 8 , -COR 8 , -CONHR 8 , -COOR 8 , -S(O) m R 8 or - S(O) m R 8 , wherein m is 0 or 2, R 8 is selected from hydrogen, C 1 -C 3 alkyl; the R 7 is optionally -COR 9 , -COOR 9 , -OR 9 or unselected Wherein R 9 is selected from a C 1 -C 3 alkylene group; said ring group is optionally selected from a C 3 -C 10 cycloalkyl group, a phenyl group or a heterocyclic group; in
  • R 1 is selected from: H or a C 1 -C 4 linear or branched alkyl group; and R 5 is selected from the group consisting of C 1 -C 7 alkyl, C 1 -C 4 alkylene-R 6 Or a C 0 -C 4 alkylene-R 7 -cyclic group; R 6 as described above is selected from the group consisting of -OR 8 , -COR 8 , -CONHR 8 , -COOR 8 , -S(O) m R 8 , -S(O) m R 8 , -NHCOOR 8 or -NHCOR 8 , wherein m is 0 or 2, R 8 is selected from hydrogen, C 1 -C 3 alkyl; and R 7 is selected from -COR 9 , -COOR 9 , -OR 9 or not, wherein R 9 is selected from C 1 -C 3 alkylene.
  • the cyclo group is optionally selected from a C 3 -C 10 cyclo
  • R 1 in formulae I, II, III and IV is selected from the group consisting of: H, methyl, ethyl, propyl, isopropyl or tert-butyl.
  • the cyclic group in the C0-C4 alkylene-R7-cyclic group is selected from the group consisting of: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, phenyl.
  • the cyclic group in the C0-C4 alkylene-R7-cyclic group is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, phenyl, aza.
  • the cyclic group in the C0-C4 alkylene-R7-cyclic group is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, phenyl, aza.
  • the cyclic group in the C0-C4 alkylene-R7-cyclic group is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, phenyl, aza.
  • the heterocyclic group may be selected from 0, 1, 2 or 3, selected from halogen, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, nitro, amino, amide, -COOR.
  • R 9 is selected from C 1 to C 4 alkyl, phenyl, and R 10 is selected from hydrogen, C 1 -C 4 alkyl, halogen, acetyl, methoxy or ethoxy.
  • the C 1 -C 7 alkyl group described in formula I is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl or n- Heptyl; said C 1 -C 4 alkylene-R 6 , wherein R 6 is selected from -OR 8 , -COR 8 , -CONHR 8 , -COOR 8 , -S(O) m R 8 ,- S(O) m R 8 , -NHCOOR 8 , -NHCOR 8 , wherein m is 0 or 2, and R 8 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, t-butyl; said C 0 -C a 4 -alkylene-R 7 -cyclo group, wherein R 7 is selected from -COR 9 , -CO
  • the C 1 -C 7 alkyl group described in the formula II is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl or Heptyl; said C 1 -C 4 alkylene-R 6 , wherein R 6 is selected from -OR 8 , -COR 8 , -CONHR 8 , -COOR 8 , -S(O) m R 8 ,- S(O) m R 8 , -NHCOOR 8 or -NHCOR 8 , wherein m is 0 or 2, and R 8 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, t-butyl; said C 0 -C a 4 -alkylene-R 7 -cyclo group, wherein R 7 is selected from -COR 9 , -COOR 9
  • the C1-C7 alkyl group described in Formula III is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl.
  • the C 1 -C 4 alkylene-R 6 wherein R 6 is selected from the group consisting of -OR 8 , -COR 8 , -CONHR 8 , -COOR 8 , -S(O) m R 8 , -NHCOOR 8 Or -NHCOR 8 , wherein m is 0 or 2, and R 8 is selected from hydrogen, methyl, ethyl, propyl or t-butyl; said C 0 -C 4 alkylene-R 7 -cyclyl, Wherein R 7 is selected from -COR 9 , -COOR 9 , -OR 9 or not, wherein R 9 is selected from C 1 -C 3 alkylene, wherein the ring group is selected from cyclopropane, cyclobutane, and ring.
  • Base isopropyl, tert-butyl, trifluoromethyl, cyano, nitro, amino, amide, -COOR 10 , -COR 10 , -OR 10 , -NHCOR 10 , -NHCOOR 10 , -C 6 H 5 R 11 , morpholinyl, piperidinyl, tetrahydrofuranyl, pyridyl group substituted, wherein R 10 is selected from hydrogen, C 1 -C 4 alkyl, phenyl, R 11 is selected from methyl, ethyl, a propyl group, a fluorine, a chlorine, a bromine, an acetyl group, a methoxy group or an ethoxy group;
  • the C1-C7 alkyl group described in the formula IV is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl or Heptyl; said C 1 -C 4 alkylene-R 6 wherein said R 6 is selected from -OR 8 , -COR 8 , -CONHR 8 , -COOR 8 , -S(O) m R 8 or -NHCOOR 8 , -NHCOR 8 wherein m is 0 or 2, R 8 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, t-butyl; said C 0 -C 4 alkylene-R a 7 -cyclo group, wherein R 7 is selected from -COR 9 , -COOR 9 , -OR 9 or not, wherein R 9 is selected from C 1 -C 4
  • the compound is selected from any of the following compounds:
  • the present invention provides the above 2-oxo-1,2-dihydrobenzo[cd]indole compound or a pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal complex thereof, Use of a hydrate or solvate for the preparation of a BET bromodomain receptor inhibitor; or for the preparation of a medicament for the treatment of cancer, cell-value-added disorders, inflammatory diseases and autoimmune diseases, sepsis or viral infections.
  • the cancer is: adrenal tumor, acoustic neuroma, acral melanoma, acral adenoma, acute eosinophilic leukemia, acute red leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute mononuclear Cell 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, Ameloblastic fibroma, anaplastic large cell lymphoma, undifferentiated thyroid carcinoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical deformity rod-shaped tumor, B-cell chronic lymphocytic leukemia, B-cell chronic
  • the cell proliferation disorder includes: benign soft tissue tumor, brain and spinal cord tumor, orbital and orbital tumor, granuloma, lipoma, meningioma, multiple endocrine neoplasm, nasal polyp, pituitary tumor, prolactinoma Seborrheic keratin, gastric polyps, thyroid nodules, hepatic hemangioma, vocal cord nodules, polyps, cysts, stagnation, cutaneous fibroids, Pilar cysts or purulent granuloma.
  • the inflammatory disease comprises: inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, Gingivitis, pancreatitis, psoriasis, allergies, Crohn's disease, intestinal syndrome, ulcerative colitis, tissue transplant rejection, organ transplant rejection, asthma, allergic rhinitis, chronic obstructive pulmonary disease, autoimmune disease , autoimmune alopecia, anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenia, pulmonary hemorrhagic nephritis syndrome, atherosclerosis, ar Dixon's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock
  • the viral infection comprises: human papillomavirus, herpes virus, Barr virus, human immunodeficiency virus, hepatitis B virus or hepatitis C virus infection.
  • the compounds of the present invention can be applied to various routes of administration when used, including but not limited to the following routes, oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal, through lumbar puncture, menstrual Urethral, transdermal or parenteral (including intravenous, intramuscular, subcutaneous, intradermal, intra-abdominal, intrathecal, surgical implantation).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above 2-oxo-1,2-dihydrobenzo[cd]indole compound or a pharmaceutically acceptable salt, isomer thereof, racemate thereof a prodrug co-crystal complex, hydrate or solvate.
  • compositions of the present invention may be in liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration employed.
  • the compositions of the present invention can be administered by oral, parenteral, intraperitoneal, intravenous, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposome, and the like.
  • Oral compositions can be solid, gel or liquid.
  • solid preparations include, but are not limited to, tablets, capsules, granules, and bulk powders. These preparations may optionally contain a binder, a diluent, a disintegrant, a lubricant, a glidant, a sweetener, a flavoring agent and the like.
  • binders include, but are not limited to, microcrystalline cellulose, dextrose solution, gum arabic, gelatin solution, sucrose, and starch paste;
  • examples of lubricants include But 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 Not limited to silica;
  • examples of disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, and carboxymethyl cellulose. .
  • aqueous carrier examples include sodium chloride injection, lin format injection, isotonic glucose injection, sterile water injection, glucose and lactated Ringer's injection;
  • examples of the non-aqueous carrier include fixed oil of plant origin, Cottonseed oil, corn oil, sesame oil and peanut oil;
  • examples of the antimicrobial agent include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, etc.;
  • isotonic agents include sodium chloride and glucose; buffers include phosphate And citrate.
  • compositions of the invention may also be prepared as sterile lyophilized powders in which the compound is dissolved in a sodium phosphate buffer solution containing glucose or other suitable excipients, followed by standard solutions under standard conditions known to those skilled in the art. The bacteria are filtered, followed by lyophilization to give the desired preparation.
  • the present invention provides a novel structure of 2-oxo-1,2-dihydrobenzo[cd]indole compounds; the compounds are effective for inhibiting BET bromodomain receptors, and can be used for treating cancer and cells.
  • a therapeutic drug for value-added disorders, inflammatory diseases, autoimmune diseases, sepsis, and viral infections.
  • alkyl and alkylene as used herein are meant to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C1-C4" in the "C1-C4" alkyl group includes a group having 1, 2, 3, 4, carbon atoms arranged in a straight chain or a branched chain.
  • C1-C4" alkyl specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl.
  • alkyl, cycloalkyl and The heterocyclyl substituent may be unsubstituted or substituted.
  • a C1-C4 alkyl group may be selected from one, two or three selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, and tert-butyl.
  • Base trifluoromethyl, cyano, carboxyl, nitro, amino, phenyldiazenyl, -CONH 2 , -COOR 7 , -COR 7 , -OR 7 , -NHCOR 7 , -NHCOOR 7 , -C 6 H 5 R 8 , morpholinyl, piperidinyl, tetrahydrofuranyl, pyridyl group substituted, wherein R 7 is selected from C 1 -C 4 alkyl, phenyl, and R 8 is selected from C 1 -C 4 Substituted with a substituent such as an alkyl group, a halogen, an acetyl group, a methoxy group or an ethoxy group.
  • a substituent such as an alkyl group, a halogen, an acetyl group, a methoxy group or an ethoxy group.
  • the present invention includes free forms of the compounds of Formulas I, II, III, IV, as well as pharmaceutically acceptable salts and stereoisomers thereof.
  • Some specific exemplary compounds herein are protonated salts of amine compounds.
  • the term "free form" refers to an amine compound in a non-salt form.
  • the pharmaceutically acceptable salts included include not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of Formulas I, II, III, IV.
  • the free form of the particular salt of the compound can be isolated using techniques known in the art.
  • the free form can be regenerated by treating the salt with a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • the free form differs somewhat from its respective salt form in solubility in certain physical properties, such as in polar solvents, but for purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods.
  • the salt of the basic compound is prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric or excess amount of the desired salt or mixture of the inorganic or organic acid in a suitable solvent or combination of solvents.
  • a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid.
  • conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard.
  • Fatty 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-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.
  • a suitable "pharmaceutically acceptable salt” refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum salts, ammonium salts. Salt, calcium salt, copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganese salt, potassium salt, sodium salt, zinc salt and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred.
  • a salt derived from a pharmaceutically acceptable organic non-toxic base comprising a salt of a primary, secondary and tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin such as a fine Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, B Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine , piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, t
  • the acidic moiety such as a carboxyl group
  • a cationic moiety such as tetravalent
  • the compounds of the invention are potential internal salts or zwitterions.
  • the compounds of the invention can be prepared using the reactions as shown in the scheme below. Accordingly, the following illustrative schemes are for illustrative purposes and are not limited to the listed compounds or any particular substituents.
  • the number of substituents shown in the scheme does not necessarily have to correspond to the number used in the claims, and for the sake of clarity, it is shown that the mono-substituent is attached to a compound which allows multiple substituents under the definition of formulas I, II, III, IV above. on.
  • the structure type when the structure type is III, it can be synthesized from 1,8-naphthalic anhydride as a starting material through a 6-step reaction:
  • Iron powder (462 mg, 8.26 mmol) and ammonium chloride (131 mg, 2.47 mmol) were dissolved in 20 mL of water and 2 mL of acetic acid and heated to 50 °C.
  • 1-Ethyl-6-nitrobenzo[cd]indole-2(1H)-one 400 mg, 1.65 mmol was dissolved in 10 mL of N,N-dimethylformamide and allowed to react for half an hour. After cooling, water was added, and the mixture was extracted with EtOAc EtOAc.
  • EtOAc (EtOAc) 1H)-ketone 316 mg (90%).
  • 6-Amino-1-ethylbenzo[cd]indole-2(1H)-one (80 mg, 0.38 mmol) and butane-1-sulfonyl chloride (89 mg, 0.57 mmol) were placed in a round bottom flask. Pyridine (5 mL) was added as a solvent, and the mixture was heated to 80 ° C for 2 hours. The mixture was cooled, washed with water and EtOAc EtOAc.
  • 6-Amino-1-ethylbenzo[cd]indole-2(1H)-one 100 mg, 0.47 mmol
  • p-fluorobenzoic acid 98 mg, 0.7 mmol
  • dichloromethane 20 mL
  • a mixture of HATU (269 mg, 0.71 mmol) and DIPEA 183 mg, 1.41 mmol was added and allowed to react at room temperature overnight.
  • the present invention uses the AlphaScreen detection technique to verify the ability of the compounds of the invention to inhibit BRD4(1) protein.
  • the inhibitory activity of the compounds of the invention against the BRD4(1) protein was determined.
  • the protein and short peptide were added to the reaction solution, incubated at 20 ° C for 1.5 hours, and donor and acceptor beads were added and incubated for 1 hour in the dark. Transfer to a 384-well plate, transfer 40 ⁇ L of liquid per well, and pass the PE Envison 2104 multi-function detection microplate reader, excitation wavelength: 680 nM, emission wavelength 520-620 nM detection reading.
  • the present invention uses TSA detection techniques to verify the ability of the compounds of the invention to inhibit BRD4(1) protein.
  • the inhibitory activity of the compounds of the invention against the BRD4(1) protein was determined.
  • the components were added to a BIO-RAD 96-well black PCR plate in the above volume, incubated on ice for 30 minutes in the dark, and detected by a CFX-96 real-time PCR instrument.
  • the procedure is a dissolution curve, 30-80 ° C, 0.5 ° C every 5 seconds, and finally the temperature change value is measured.
  • Example 46 >20 3
  • Example 47 >20 0
  • Example 48 >20 3.6
  • Example 49 >20 0
  • Example 50 >20 1
  • Example 51 >20 2.4
  • Example 52 14.51 4
  • Example 53 >20 0
  • Example 54 >20 0
  • Example 55 >20 0
  • Example 56 >20 0
  • Example 58 2.7 2
  • Example 59 >20 1
  • Example 60 1.77 2
  • Example 61 >20 2
  • Example 62 2.49 2

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Abstract

本发明涉及化学医药技术领域，具体公开了一种2-氧代-1,2-二氢苯并[cd]吲哚类化合物及其应用。本发明所述的化合物及其药学上可接受的盐、异构体、外消旋体、前体药物、共结晶复合物、水合物、溶剂合物可有效抑制BET bromodomain受体，可用于制备治疗癌症、细胞增值性紊乱、炎症疾病及自身免疫疾病、败血症、病毒感染的药物。

Description

一种2-氧代-1,2-二氢苯并[cd]吲哚类化合物及其应用 技术领域
本发明涉及化学医药技术领域，具体涉及一种2-氧代-1,2-二氢苯并[cd]吲哚类化合物及其应用。
背景技术
Bromodomain家族是一类识别乙酰化赖氨酸的表观遗传学读者。这些表观遗传学读者与组氨酸H3和H4的尾部的乙酰化赖氨酸结合形成起始复合物，从而改变染色质与转录因子的结合进而激活RNA聚合酶导致基因转录或染色质重组。Bromodomain蛋白的抑制剂具有重要的生物学意义，例如已有大量化合物被报道其在治疗神经性疾病，抗病毒，抗癌和治疗炎症和自身免疫疾病等疾病具有疗效。
Bromodomain蛋白于20世纪90年代初从黑腹果蝇梵天基因中被鉴定出来。人类蛋白质组编码61种bromodomain，其存在于46个不同的核和胞质蛋白中。这种蛋白质家族根据序列的不同被分为九组，其中BET bromodomain是其中的一类。BET bromodomain蛋白具有四种亚型分别是：BRD2、BRD3、BRD4以及BRD-t。BRD2、BRD3与组氨酸连接后位于活性转录基因上，因此可能参与促进转录延伸的过程，BRD4可以将PTEF-β招募从而结合到诱导性基因上，导致RNA聚合酶的磷酸化和增强转录输出。BRD4和BRD3可以与和核蛋白(NUT)融合形成新的融合致癌基因，即BRD4-NUT和BRD3-NUT，有数据表明BRD-NUT是主要的致癌因素。BRD-t主要在睾丸和卵巢中表达。
大量关于BET bromodomain受体的小分子抑制剂被发现，针对这一受体的第一个小分子工具化合物是周明明等人通过核磁共振技术发现的，随后，通过表观遗传学筛选和靶向生物化学等手段的应用，已有更多的小分子化合物被发现，并研究了这些小分子抑制剂与疾病进程的关系。目前已有针对这一受体的小分子抑制剂进入临床阶段，其主要用于癌症及自身免疫疾病的治疗。
发明内容
本发明所要解决的技术问题是，提供一种2-氧代-1,2-二氢苯并[cd]吲哚类化合物，该类化合物可有效抑制BET bromodomain受体，可作为治疗癌症、细胞增值性紊乱、炎症疾病及自身免疫疾病、败血症、病毒感染的治疗药物。
本发明所要解决的上述问题通过以下技术方案予以实现：
一种2-氧代-1,2-二氢苯并[cd]吲哚类化合物或其药学上可接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物或溶剂合物，具有式Ⅰ、Ⅱ、Ⅲ或Ⅳ所示的结构：
Figure PCTCN2016072266-appb-000001
式Ⅰ中，R1任选自：H或C1～C4直链或支链烷基；R2任选自：C1～C7烷基、C1～C4亚烷基-R6或C0～C4亚烷基-R7-环基；所述的R6任选自-OR8、-COR8、-CONHR8、-COOR8、-S(O)mR8、-S(O)mR8、-NHCOOR8、-NHCOR8或-NH2，其中m为0或2，R8任选自氢或C1～C3烷基；所述R7任选自-COR9、-COOR9、-OR9或不选，其中R9任选自C1～C3亚烷基；所述的环基任选自C3～C10环烷基、苯基或杂环基；
式Ⅱ中，R1任选自：H或C1～C4直链或支链烷基；R3任选自：C1～C7烷基、C1～C4亚烷基-R6或C0～C4亚烷基-R7-环基；所述的R6任选自-OR8、-COR8、-CONHR8、-COOR8、-S(O)mR8或-S(O)mR8，其中m为0或2，R8任选自氢、C1～C3烷基；所述R7任选-COR9、-COOR9、-OR9或不选，其中R9任选自C1～C3亚烷基；所述的环基任选自C3～C10环烷基、苯基或杂环基；式Ⅲ中，R1任选自：H或C1～C4直链或支链烷基；R4任选自：C1～C7烷基、C1～C4亚烷基-R6或C0～C4亚烷基-R7-环基；所述的R6任选自-OR8、-COR8、-CONHR8、-COOR8、-S(O)mR8、-S(O)mR8、-NHCOOR8或-NHCOR8，其中m为0或2，R8任选自氢或C1～C3烷基；所述R7任选自-COR9、-COOR9、-OR9或不选，其中R9任选自C1～C3亚烷基；所述的环基任选自C3～C10环烷基、苯基或杂环基；
式Ⅳ中，R1任选自：H或C1～C4直链或支链烷基；R5任选自：C1～C7烷基、C1～C4亚烷基-R6或C0～C4亚烷基-R7-环基；以上所述的R6任选自-OR8、-COR8、-CONHR8、-COOR8、-S(O)mR8、-S(O)mR8、-NHCOOR8或-NHCOR8，其中m为0或2，R8任选自氢、C1～C3烷基；所述R7任选自-COR9、-COOR9、-OR9或不选，其中R9任选自C1～C3亚烷基。所述的环基任选自C3～C10环烷基、苯基或杂环基；
优选地，式Ⅰ、Ⅱ、Ⅲ和Ⅳ中所述R1选自：H、甲基、乙基、丙基、异丙基或叔丁基。
优选地，在式Ⅰ中，所述C0～C4亚烷基-R7-环基中的环基任选自：环丙烷、环丁烷、环戊烷、环己烷、环庚烷、苯基、萘基，氮杂环丁烷、氧杂环丁烷、氮杂环戊烷、氧杂环戊烷、氮杂环己烷、氧杂环己烷、氮杂环己基、咪唑-2-酮基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、嘧啶基、吡咯基、哌嗪基、四氢吡咯基、哌啶基、吗啉基、1,3-二氧戊环基或苯并[d]噻唑基，且所述环烷基被0、1、2或3个任选自卤素、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、氰基、硝基、氨基、酰胺、-COOR10、-COR10、-OR10、-NHCOR10、-NHCOOR10、-C6H5R11、吗啉基、哌啶基、四氢呋喃基或吡啶基基团取代，其中R10任选自氢、C1～C4烷基、苯基，R11任选自C1～C4烷基、卤素、乙酰基、甲氧基或乙氧基；
在式Ⅱ中，所述C0～C4亚烷基-R7-环基中的环基任选自：环丙烷、环丁烷、环戊烷、环己烷、环庚烷、苯基、氮杂环丁烷、氧杂环丁烷、氮杂环戊烷、氧杂环戊烷、氮杂环己烷、氧杂环己烷、氮杂环己基、吠喃基、噻吩基、噁唑基、异噁唑基、嘧啶基、吡咯基、四氢吡咯基、哌啶基、吗啉基、1,3-二氧戊环基或苯并[d]噻唑基，且所述环烷基被0、1、2或3个任选自卤素、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、氰基、羧基、硝基、氨基、-CONH2、-COOR10、-COR10、-OR10、-NHCOR10、-NHCOOR10、-C6H5R11、吗啉基、哌啶基、四氢呋喃基或吡啶基基团取代，其中R10任选自氢、C1～C4烷基或苯基，R11任选自C1～C4烷基、卤素、乙酰基、甲氧基或乙氧基；
在式Ⅲ中，所述C0～C4亚烷基-R7-环基中的环基任选自：环丙烷、环丁烷、环戊烷、环己烷、环庚烷、苯基、氮杂环丁烷、氧杂环丁烷、氮杂环戊烷、氧杂环戊烷、氮杂环己烷、氧杂环己烷、氮杂环己基、咪唑-2-酮基、咪唑基、吠喃基、噻吩基、噁唑基、异噁唑基、嘧啶基、吡咯基、哌嗪基、四氢吡咯基、哌啶基、吗啉基、1,3-二氧戊环基或苯并[d]噻唑基，且所述环烷基被0、1、2或3个任选自卤素、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、氰基、硝基、氨基、-CONH2、-COOR10、-COR10、-OR10、-NHCOR10、-NHCOOR10、-C6H5R11、吗啉基、哌啶基、四氢呋喃基或吡啶基基团取代，其中R10任选自氢、C1～C4烷基、苯基，R11任选自C1～C4烷基、卤素、乙酰基、甲氧基或乙氧基；
在式Ⅳ中，所述C0～C4亚烷基-R7-环基中的环基任选自：环丙烷、环丁烷、环戊烷、环己烷、环庚烷、苯基、氮杂环丁烷、氧杂环丁烷、氮杂环戊烷、氧杂环戊烷、氮杂环己烷、氧杂环己烷、氮杂环己基、咪唑-2-酮基、吠喃基、噻吩基、噁唑基、异噁唑基、吡咯基、哌嗪基、四氢吡咯基、哌啶基、吗啉基、1,3-二氧戊环基或1H-吲哚基，且所述杂环基可被0、1、2或3个任选自卤素、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、硝基、氨基、酰胺、-COOR9、-COR9、-OR9、-NHCOR9、-NHCOOR9、-C6H5R10、吗啉基、哌啶基、四氢呋喃基、吡啶基基团取代，其中R9任选自C1～C4烷基、苯基，R10任选自氢、C1～C4烷基、卤素、乙酰基、甲氧基或乙氧基。
更优选地，式Ⅰ中所述的C1～C7烷基任选自：甲基、乙基、丙基、异丙基、正丁基、叔丁基、正戊基、正己基或正庚基；所述的C1～C4亚烷基-R6，其中R6任选自-OR8、-COR8、-CONHR8、-COOR8、-S(O)mR8、-S(O)mR8、-NHCOOR8、-NHCOR8，其中m为0或2，R8任选自氢、甲基、乙基、丙基、叔丁基；所述的C0～C4亚烷基-R7-环基，其中R7任选自-COR9、-COOR9、-OR9或不选，其中R9任选自C1～C3亚烷基，其中环基任选自环丙烷、环丁烷、环戊烷、环己烷、环庚烷、苯基、氮杂环丁烷、氧杂环丁烷、氮杂环戊烷、氧杂环戊烷、氮杂环己烷、氧杂环己烷、氮杂环己基、咪唑-2-酮基或1,3-二氧戊环基，且所述环烷基被0、1、2或3个任选自卤素、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、氰基、硝基、氨基、酰胺、-COOR10、-COR10、-OR10、-NHCOR10、-NHCOOR10、-C6H5R11、吗啉基、哌啶基、四氢呋喃基或吡啶基基团取代，其中R10任选自氢、C1～C4烷基、苯基，R11任选自甲基、乙基、丙基、氟、氯、溴、乙酰基、甲氧基，乙氧基；
更优选地，Ⅱ式中所述的C1～C7烷基任选自：甲基、乙基、丙基、异丙基、正丁基、叔丁基、正戊基、正己基或正庚基；所述的C1～C4亚烷基-R6，其中R6任选自-OR8、-COR8、-CONHR8、-COOR8、-S(O)mR8、-S(O)mR8、-NHCOOR8或-NHCOR8，其中m为0或2，R8任选自氢、甲基、乙基、丙基、叔丁基；所述的C0～C4亚烷基-R7-环基，其中R7任选自-COR9、-COOR9、-OR9或不选，其中R9任选自C1～C3亚烷基，其中环基任选自环丙烷、环丁烷、环戊烷、环己烷、环庚烷、苯基、氮杂环丁烷、氧杂环丁烷、氮杂环戊烷、氧杂环戊烷、氮杂环己烷、氧杂环己烷、氮杂环己基、吠喃基、噻吩基、噁唑基、异噁唑基、嘧啶基、吡咯基、四氢吡咯基、哌啶基、吗啉基、1,3-二氧戊环基或苯并[d]噻唑基，且所述环烷基被0、1、2或3个任选自卤素、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、氰基、硝基、氨基、酰胺、-COOR10、-COR10、-OR10、-NHCOR10、-NHCOOR10、-C6H5R11、吗啉基、哌啶基、四氢呋喃基、吡啶基基团取代，其中R10任选自氢、C1～C4烷基、苯基，R11任选自甲基、乙基、丙基、氟、氯、溴、乙酰基、甲氧基或乙氧基；
更优选地，式Ⅲ中所述的C1～C7烷基任选自：甲基、乙基、丙基、异丙基、正丁基、叔丁基、正戊基、正己基，正庚基；所述的C1～C4亚烷基-R6；其中R6任选自-OR8、-COR8、-CONHR8、-COOR8、-S(O)mR8、-NHCOOR8或-NHCOR8，其中m为0或2，R8任选自氢、甲基、乙基、丙基或叔丁基；所述的C0～C4亚烷基-R7-环基，其中R7任选自-COR9、-COOR9、-OR9或不选，其中R9任选自C1～C3亚烷基，其中环基任选自环丙烷、环丁烷、环戊烷、环己烷、环庚烷、苯基、氮杂环丁烷、氧杂环丁烷、氮杂环戊烷、氧杂环戊烷、氮杂环己烷、氧杂环己烷、氮杂环己基、咪唑-2-酮基、咪唑基、吠喃基、噻吩基、噁唑基、异噁唑基、嘧啶基、吡咯基、哌嗪基、四氢吡咯基、哌啶基、吗啉基、1,3-二氧戊环基或苯并[d]噻唑基，且所述环烷基被0、1、2或3个任选自卤素、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、氰基、硝基、氨基、酰胺、-COOR10、-COR10、-OR10、-NHCOR10、-NHCOOR10、-C6H5R11、吗啉基、哌啶基、四氢呋喃基、吡啶基基团取代，其中R10任选自氢、C1～C4烷基、苯基，R11任选自甲基、乙基、丙基、氟、氯、溴、乙酰基、甲氧基或乙氧基；
更优选地，Ⅳ式中所述所述的C1～C7烷基任选自：甲基、乙基、丙基、异丙基、正丁基、叔丁基、正戊基、正己基或正庚基；所述的C1～C4亚烷基-R6，其中所述的R6任选自-OR8、-COR8、-CONHR8、-COOR8、-S(O)mR8或-NHCOOR8、-NHCOR8，其中m为0或2，R8任选自氢、甲基、乙基、丙基、叔丁基；所述的C0～C4亚烷基-R7-环基，其中R7任选自-COR9、-COOR9、-OR9或不选，其中R9任选自C1～C3亚烷基，其中环基任选自环丙烷、环丁烷、环戊烷、环己烷、环庚烷、苯基、氮杂环丁烷、氧杂环丁烷、氮杂环戊烷、氧杂环戊烷、氮杂环己烷、氧杂环己烷、氮杂环己基、咪唑-2-酮基、吠喃基、噻吩基、噁唑基、异噁唑基、吡咯基、哌嗪基、四氢吡咯基、哌啶基、吗啉基、1,3-二氧戊环基或1H-吲哚基，且所述环烷基被0、1、2或3个任选自卤素、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、氰基、硝基、氨基、酰胺、-COOR10、-COR10、-OR10、-NHCOR10、-NHCOOR10、-C6H5R11、吗啉基、哌啶基、四氢呋喃基或吡啶基基团取代，其中R10任选自氢、C1～C4烷基、苯基，R11任选自甲基、乙基、丙基、氟、氯、溴、乙酰基、甲氧基或乙氧基。
最优选地，所述的化合物选自下述化合物中的任一一种：
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)丁烷-1-磺酰胺；
2-氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-氟苯磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)噻吩-2-磺酰胺；
5-氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2-甲氧基苯磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)环己烷磺酰胺；
2-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸甲酯；
2-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-氟苯磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-3-氟苯磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)乙磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-甲氧基苯磺酰胺；
4-氰基-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-硝基苯磺酰胺；
4-(叔丁基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-(三氟甲氧基)苯磺酰胺；
3-氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2-氟苯磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-甲基苯磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2,4-二氟苯磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)丙烷-1-磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)环戊烷磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-(三氟甲基)苯磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-3-(甲基磺酰基)苯磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)萘-2-磺酰胺；
甲基-4-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸甲酯；
4-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸；
3-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸甲酯；
3-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd〕吲哚-6-基)-2,3-二氢苯并[b][1,4]二氧杂环己烯-6-磺酰胺；
2-溴-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺；
5-溴-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2-甲氧基苯磺酰胺；
2,6-二氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2,3-二甲氧基苯磺酰胺；
3,5-二氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺；
2,3-二氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺；
甲基4-((N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)甲基)苯甲酸甲酯；
4-((N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)甲基)苯甲酸；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-1-(3-氟苯基)甲磺酰胺；
甲基3-((N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)甲基)苯甲酸甲酯；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-1-(4-(三氟甲基)苯基)甲磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-1-(对甲苯基)甲磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-1-(2-氟苯基)甲2磺酰胺；
1-(4-氯苯基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)甲磺酰胺；
1-(4-氰基苯基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)甲磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-1-(4-氟苯基)甲磺酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-氟苯甲酰胺；
2-(4-氯苯基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)乙酰胺；
2-(3,4-二甲氧基苯基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)乙酰胺；
2-(2,4-二氯苯基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)乙酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-3-苯基丙酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4,4,4-三氟丁酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)丙酰胺；
4-氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯甲酰胺；
N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2-(对甲苯基)乙酰胺；
(E)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-3-(呋喃-2-基)丙烯酰胺；
1-乙基-6-((3-苯丙基)氨基)苯并[cd]吲哚-2(1H)-酮；
1-乙基-6-((3-吗啉代丙基)氨基)苯并[cd]吲哚-2(1H)-酮；
1-乙基-6-((4-甲氧基苄基)氨基)苯并[cd]吲哚-2(1H)-酮；
1-乙基-6-((4-甲基苄基)氨基)苯并[cd]吲哚-2(1H)-酮；
1-乙基-6-((4-(三氟甲基)苄基)氨基)苯并[cd]吲哚-2(1H)-酮；
6-((4-氯苄基)氨基)-1-乙基苯并[cd]吲哚-2(1H)-酮；
1-乙基-6-((4-氟苄基)氨基)苯并[cd〕吲哚-2(1H)-酮；
N-((1-乙酰基哌啶-4-取代)甲基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)环己烷甲酰胺；
1-乙基-N-((3-异丙基-4,5-二氢异恶唑-5–取代)甲基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-E-7磺酰胺；
N-((3,5-二甲基-4,5-二氢异恶唑-5-基)甲基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-(4-乙酰基苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-(2-氯苄基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-乙基-N-(2-氟苄基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-(1-乙酰基-4–取代)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
叔丁基4-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)哌啶-1-甲酸叔丁酯；
N-环戊基-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-((1-乙基-2-氧代-1-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)甲基)环戊烷羧酸甲酯；
1-((1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)甲基)环戊烷羧酸；
N-(4-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)苯基)乙酰胺；
2-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)苯甲酸；
1-乙基-N-(4-氟苯基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-丁基-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-(2-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)乙基)乙酰胺；
1-乙基-N-(2-(甲基磺酰基)乙基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-乙基-2-氧代-N-(2-(2-氧代咪唑烷-1-基)乙基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
叔丁基(4-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)丁基)氨基甲酸叔丁酯；
N-(5-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)吡啶-2-基)乙酰胺；
叔丁基-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)吡咯烷-1-甲酸叔丁酯；
叔丁基-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)氮杂环丁烷-1-甲酸叔丁酯；
N-(2-环己基乙基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-乙基-2-氧代-N-(吡咯烷-3-基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-(氮杂环丁烷-3-基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-N-乙基-N-己基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-乙基-2-氧代-N-(2-(吡咯烷-1-基)乙基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-乙基-2-氧代-N-(2-(四氢-2H-吡喃-4-基)乙基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-乙基-2-氧代-N-(四氢呋喃-3-基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-(2-(4-氯苯氧基)乙基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N，1-二乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-乙基-2-氧代-正戊基-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-N-乙基-N-甲基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-环己基-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
叔丁基-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)哌啶-1-羧酸叔丁酯；
1-N-乙基-N-异丁基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-乙基-2-氧代基-N-丙基-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-乙基-N-(3-(4-甲基哌嗪-1-基)丙基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-乙基-2-氧代-N-(2-(哌啶-1-基)乙基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-(4,4-二乙氧基丁基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
乙基-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)丙酸甲酯；
1-乙基-N-((1-乙基吡咯烷-2-基)甲基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-乙基-N-(1-甲基哌啶-4-基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-环庚基-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-乙基-2-氧代-N-(四氢-2H-吡喃-4-基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
叔丁基4-(2-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)乙基)哌嗪-1-甲酸叔丁酯；
N-环己基-1-甲基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-丁基-1-甲基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-环己基-2-氧代-1-丙基-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
2-氧代-N，1-二丙基-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-丁基-2-氧代-1-丙基-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-丁基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-丁基-1-异丁基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-环己基-1-异丁基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-环己基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-(3-乙酰基苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-(4-氯苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
1-乙基-2-氧代-N-苯基-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-(2-氯苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
N-(3-氯苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺。
本发明提供上述2-氧代-1,2-二氢苯并[cd]吲哚类化合物或其药学上可接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物或溶剂合物在制备BET bromodomain受体抑制剂中的应用；或在制备治疗癌症、细胞增值性紊乱疾病、炎症疾病及自身免疫疾病、败血症或病毒感染的药物中的应用。
优选地，所述的癌症为：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。
优选地，所述的细胞增值性紊乱疾病包括：良性软组织肿瘤、脑和脊髓肿瘤、眼睑和轨道肿瘤、肉芽肿、脂肪瘤、脑膜瘤、多发性内分泌瘤、鼻息肉、垂体肿瘤、泌乳素瘤、脂溢性角质的、胃息肉、甲状腺结节、肝血管瘤、声带结节、息肉、囊肿、藏毛病、皮肤纤维瘤、皮拉尔囊肿或化脓性肉芽肿。
优选地，所述的炎症疾病包括：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。
优选地，所述的病毒感染包括：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。
本发明所述的化合物在使用时可适用于各种给药途径，包括但不限于以下途径，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。
本发明提供一种药物组合物，其含有上述的2-氧代-1,2-二氢苯并[cd]吲哚类化合物或其药学上可接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物或溶剂合物。
本发明所述的组合物可以是液体、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。本发明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。
以肠胃外给予本发明组合物，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。可用于本发明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。
发明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。
有益效果：本发明提供了一类结构新颖的2-氧代-1,2-二氢苯并[cd]吲哚类化合物；该类化合物可有效抑制BET bromodomain受体，可作为治疗癌症、细胞增值性紊乱、炎症疾病及自身免疫疾病、败血症、病毒感染的治疗药物。
具体实施方式
本发明所述化合物中，当任何变量(例如R1、R2等)在任何组分中出现超过一次，则其每次出现的定义独立于其它每次出现的定义。同样，允许取代基及变量的组合，只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环，其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定。本文所用术语“烷基”和“亚烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如，“C1-C4”烷基中“C1-C4”的定义包括以直链或支链排列的具有1、2、3、4、碳原子的基团。例如，“C1-C4”烷基“具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基。除非另有定义，烷基、环烷基和杂环基取代基可为未被取代的或取代的。例如，C1-C4烷基可被一个、两个或三个选自卤素、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、氰基、羧基、硝基、氨基、苯基二氮烯基、-CONH2、-COOR7、-COR7、-OR7、-NHCOR7、-NHCOOR7、-C6H5R8、吗啉基、哌啶基、四氢呋喃基、吡啶基基团取代，其中R7任选自C1～C4烷基、苯基，R8任选自C1～C4烷基、卤素、乙酰基、甲氧基，乙氧基等的取代基取代。
本发明包括式Ⅰ、Ⅱ、Ⅲ、Ⅳ化合物的游离形式，也包括其药学上可接受的盐及立体异构体。本文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐，也包括所有式Ⅰ、Ⅱ、Ⅲ、Ⅳ化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如，可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别，但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常，通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式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，本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如，常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐，也包括自有机酸例如乙酸、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、三氟乙酸等制备的盐。
如果本发明化合物为酸性的，则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐.得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐，所述碱包括伯胺、仲胺和叔胺的盐，取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
由于在生理条件下化合物中脱质子化的酸性部分例如羧基可为阴离子的，而这种带有的电荷然后可被内部带有阳离子的质子化了的或烷基化的碱性部分例如四价氮原子平衡抵消，所以应注意本发明化合物是潜在的内盐或两性离子。
除在文献中已知的或在实验程序中例证的标准方法外，可采用如下列方案中显示的反应制备本发明化合物。因此，下列说明性方案是为说明的目的而不是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Ⅰ、Ⅱ、Ⅲ、Ⅳ的定义下允许有多取代基的化合物上。
本发明所述化合物的制备方案
如方案所示当结构类型为I时，化合物可以由1,8-萘二甲酸酐为起始原料通过6步反应：
Figure PCTCN2016072266-appb-000002
Figure PCTCN2016072266-appb-000003
或由1,8-萘二甲酸酐为起始原料通过5步反应：
Figure PCTCN2016072266-appb-000004
如方案所示当结构类型为Ⅱ时，化合物可以由1,8-萘二甲酸酐为起始原料通过6步反应：
Figure PCTCN2016072266-appb-000005
Figure PCTCN2016072266-appb-000006
或由1,8-萘二甲酸酐为起始原料通过5步反应：
Figure PCTCN2016072266-appb-000007
如方案所示当结构类型为Ⅲ时，可以由1,8-萘二甲酸酐为起始原料通过6步反应合成：
Figure PCTCN2016072266-appb-000008
或由1,8-萘二甲酸酐为起始原料通过5步反应：
Figure PCTCN2016072266-appb-000010
如方案所示当结构类型为Ⅳ时，可以由1,8-萘二甲酸酐为起始原料通过5步反应合成：
Figure PCTCN2016072266-appb-000011
Figure PCTCN2016072266-appb-000012
以下结合具体实施例来进一步解释本发明，但实施例对发明不做任何形式的限定。
当结构类型为I时：
实施例1 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)丁烷-1-磺酰胺的合成：
Figure PCTCN2016072266-appb-000013
步骤1. 3-二氧代-2,3-二氢-1H-非那烯-2-基4-甲基苯磺酸酯的合成：
Figure PCTCN2016072266-appb-000014
在圆底烧瓶中加入1,8-萘二甲酸酐(11.9g，0.06mol)、盐酸羟胺(4.18g，0.06mol)和吡啶(70mL)，加热至回流1小时。冷却至80℃，快速加入4-甲苯磺酰氯(22.88g，0.12mol)，升温至回流反应1.5h。冷却至室温，将混合物倾倒入200g冰水中，搅拌有黄色沉淀析出。静置，抽滤，水洗三次，碳酸氢钠饱和溶液搅拌洗涤，抽滤，水洗三次，得到17g中间体(78％)。
步骤2.苯并[cd]吲哚-2(1H)-酮的合成：
Figure PCTCN2016072266-appb-000015
在圆底烧瓶中分别加入1,3-二氧代-2,3-二氢-1H-非那烯-2-基4-甲基苯磺酸酯(17g，0.048mol)，50mL乙醇，40mL水以及2.7mol/L的氢氧化钠溶液60mL，加热回流3h，冷却并减压除去乙醇，在75℃时滴入盐酸，调节PH至3，有黄色沉淀析出，抽滤，柱层析得6.65g黄色固体(82％)。MS(ESI),m/z:M+170.0。
步骤3. 1-乙基苯并[cd]吲哚-2(1H)-酮的合成：
Figure PCTCN2016072266-appb-000016
在圆底烧瓶中加入苯并[cd]吲哚-2(1H)-酮(6.65g，0.04mol)，100mL N,N-二甲基甲酰胺作为溶剂，冰浴下加入氢化钠(2.81g,0.18mol)，搅拌5min，滴入碘丙烷(7.33g，0.047mol)，低温滴加10min，室温反应，TLC监测反应；待反应完全后，冰浴下滴入水淬灭反应；用乙酸乙酯萃取三次，合并有机层，饱和氯化钠水溶液洗一次，无水硫酸钠干燥过夜，旋干，得到6.46g黄色固体(84％)。MS(ESI),m/z:M+198.0。
步骤4. 1-乙基-6-硝基苯并[cd]吲哚-2(1H)-酮的合成：
Figure PCTCN2016072266-appb-000017
在圆底烧瓶中加入1-乙基苯并[cd]吲哚-2(1H)-酮(500mg，2.53mmol)和冰醋酸(5mL)，将其置于冰浴中，缓慢滴入发烟硝酸(154mg，2.53mmol)。滴加完成后，升至室温至50℃反应1小时。冷却，水 洗，乙酸乙酯萃取三次，合并有机层，饱和氯化钠洗一遍，无水硫酸钠干燥，旋干，柱层析得1-乙基-6-硝基苯并[cd]吲哚-2(1H)-酮400mg(65％)。
步骤5. 6-氨基-1-乙基苯并[cd]吲哚-2(1H)-酮的合成：
Figure PCTCN2016072266-appb-000018
将铁粉(462mg，8.26mmol)和氯化铵(131mg，2.47mmol)溶于20mL水和2mL醋酸中，将其加热至50℃。将1-乙基-6-硝基苯并[cd]吲哚-2(1H)-酮(400mg，1.65mmol)溶于10mL N,N-二甲基甲酰胺中，反应半小时。冷却，加水，使用乙酸乙酯萃取三次，合并有机层，饱和氯化钠洗一遍，无水硫酸钠干燥，旋干，得到6-氨基-1-乙基苯并[cd]吲哚-2(1H)-酮316mg(90％)。
步骤6. N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)丁烷-1-磺酰胺的合成：
将6-氨基-1-乙基苯并[cd]吲哚-2(1H)-酮(80mg，0.38mmol)及丁烷-1-磺酰氯(89mg，0.57mmol)置于圆底烧瓶中，加入吡啶(5mL)作为溶剂，加热至80℃，反应2小时。冷却，水洗，乙酸乙酯萃取三次，合并有机层，饱和氯化钠洗一遍，无水硫酸钠干燥，旋干，柱层析得产物66mg(52％)。1H NMR(400MHz,CDCl3)δ8.21(d,J＝8.4Hz,1H),8.10(d,J＝7.2Hz,1H),7.90–7.69(m,1H),7.53(d,J＝7.6Hz,1H),6.88(d,J＝7.6Hz,1H),6.77(s,1H),3.97(q,J＝7.2Hz,2H),3.27–2.89(m,2H),1.94–1.75(m,2H),1.51–1.30(m,5H),0.90(t,J＝7.2Hz,3H).
实施例2 2-氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-氟苯磺酰胺的合成
Figure PCTCN2016072266-appb-000019
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.22(d,J＝8.4Hz,1H),8.06(d,J＝7.2Hz,1H),7.86(dd,J＝8.8,5.6Hz,1H),7.82–7.65(m,1H),7.33(dd,J＝8.0,2.4Hz,1H),7.26(s,1H),7.13(d,J＝7.6Hz,1H),7.00–6.83(m,1H),6.71(d,J＝7.6Hz,1H),3.91(q,J＝7.2Hz,2H),1.32(t,J＝7.2Hz,3H).
实施例3 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)噻吩-2-磺酰胺的合成
Figure PCTCN2016072266-appb-000020
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.03(d,J＝7.2Hz,1H),7.92(d,J＝8.4Hz,1H),7.74–7.58(m,1H),7.52(d,J＝5.2Hz,1H),7.41(d,J＝3.6Hz,1H),7.31(d,J＝7.6Hz,1H),7.01–6.93(m,1H),6.91(s,1H),6.82(d,J＝7.6Hz,1H),3.95(q,J＝7.2Hz,2H),1.36(t,J＝7.2Hz,3H).
实施例4 5-氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2-甲氧基苯磺酰胺(E172)的合成
Figure PCTCN2016072266-appb-000021
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.18(d,J＝8.4Hz,1H),8.05(d,J＝7.2Hz,1H),7.71(dd,J＝15.2,5.2Hz,2H),7.45(dd,J＝8.8,2.4Hz,1H),7.25(s,1H),7.13(d,J＝7.6Hz,1H),7.00(d,J＝8.8Hz,1H),6.72(d,J＝7.6Hz,1H),4.08(s,3H),3.91(q,J＝7.2Hz,2H),1.32(t,J＝7.2Hz,3H).
实施例5 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)环己烷磺酰胺的合成
Figure PCTCN2016072266-appb-000022
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.23(d,J＝8.4Hz,1H),8.09(d,J＝7.2Hz,1H),7.78(t,J＝7.6Hz,1H),7.55(d,J＝7.6Hz,1H),7.00–6.72(m,2H),3.96(q,J＝7.2Hz,2H),3.21–2.96(m,1H),2.23(d,J＝112.0Hz,2H),1.87(d,J＝7.6Hz,2H),1.65–1.61(m,4H),1.37(t,J＝7.2Hz,3H),1.19(d,J＝9.2Hz,2H).
实施例6 2-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸甲酯的合成
Figure PCTCN2016072266-appb-000023
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.27(s,1H),8.14(d,J＝8.4Hz,1H),8.01(d,J＝7.2Hz,1H),7.86(d,J＝7.2Hz,1H),7.72–7.49(m,3H),7.41(t,J＝7.6Hz,1H),7.33–7.14(m,2H),6.75(d,J＝7.6Hz,1H),4.12(s,3H),3.92(q,J＝7.2Hz,2H),1.34(t,J＝7.2Hz,3H).
实施例7 2-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸的合成
Figure PCTCN2016072266-appb-000024
2-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸甲酯的合成参见实施例6。
将2-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸甲酯(50mg，0.12mmol)用THF溶解，室温滴加2N氢氧化钠溶液0.5mL，室温反应过夜。旋去四氢呋喃。在冰浴下滴加浓盐酸，直至无沉淀析出，抽滤，得到33mg产物，收率69％。1H NMR(400MHz,d-DMSO)δ10.04(s,1H),8.18(d,J＝8.4Hz,1H),7.98(d,J＝7.2Hz,1H),7.75–7.66(m,2H),7.63(t,J＝7.6Hz,1H),7.57(d,J＝8.0Hz,1H),7.45(t,J＝7.6Hz,1H),7.22(d,J＝7.6Hz,1H),7.10(d,J＝7.6Hz,1H),3.87(q,J＝7.2Hz,2H),1.23(t,J＝7.2Hz,3H).
实施例8 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺的合成
Figure PCTCN2016072266-appb-000025
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.00(d,J＝7.2Hz,1H),7.90(d,J＝8.4Hz,1H),7.74(d,J＝7.6Hz,2H),7.60(t,J＝7.6Hz,1H),7.54–7.49(m,1H),7.39(t,J＝7.6Hz,2H),7.21(d,J＝7.6Hz,1H),7.06(s,1H),6.77(d,J＝7.6Hz,1H),3.93(q,J＝7.2Hz,2H),1.34(t,J＝7.2Hz,3H).
实施例9 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-氟苯磺酰胺的合成
Figure PCTCN2016072266-appb-000026
合成方法如实施例1。1H NMR(400MHz,d-DMSO)δ10.29(s,1H),8.03(dd,J＝16.4,7.6Hz,2H),7.84–7.63(m,3H),7.33(t,J＝8.8Hz,2H),7.13(s,2H),3.87(q,J＝7.2Hz,2H),1.23(t,J＝7.2Hz,3H).
实施例10 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-3-氟苯磺酰胺的合成
Figure PCTCN2016072266-appb-000027
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.03(d,J＝7.2Hz,1H),7.91(d,J＝8.4Hz,1H),7.65(t,J＝7.6Hz,1H),7.66–7.45(m,2H),7.38(dd,J＝13.2,8.0Hz,1H),7.25(d,J＝4.8Hz,1H),7.20(s,1H), 6.79(d,J＝7.6Hz,1H),3.94(q,J＝7.2Hz,2H),1.35(t,J＝7.2Hz,3H).
实施例11 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)乙磺酰胺的合成
Figure PCTCN2016072266-appb-000028
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.22(d,J＝8.4Hz,1H),8.10(d,J＝7.2Hz,1H),7.80(t,J＝7.6Hz,1H),7.54(d,J＝7.6Hz,1H),6.93–6.76(m,2H),3.97(q,J＝7.2Hz,2H),3.16(q,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H),1.37(t,J＝7.2Hz,3H).
实施例12 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-甲氧基苯磺酰胺的合成
Figure PCTCN2016072266-appb-000029
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.02(d,J＝7.2Hz,1H),7.95(d,J＝8.4Hz,1H),7.79–7.51(m,3H),7.20(d,J＝7.6Hz,1H),6.89(s,1H),6.84(d,J＝8.8Hz,2H),6.77(d,J＝7.6Hz,1H),3.93(q,J＝7.2Hz,2H),1.35(t,J＝7.2Hz,3H).
实施例13 4-氰基-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺的合成
Figure PCTCN2016072266-appb-000030
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.04(d,J＝7.2Hz,1H),7.89(d,J＝8.4Hz,1H),7.85(d,J＝8.4Hz,2H),7.74–7.57(m,3H),7.17(d,J＝7.6Hz,1H),7.11(s,1H),6.79(d,J＝7.6Hz,1H),3.94(q,J＝7.2Hz,2H),1.35(t,J＝7.2Hz,3H).
实施例14 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-硝基苯磺酰胺的合成
Figure PCTCN2016072266-appb-000031
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.25(d,J＝8.8Hz,2H),8.05(d,J＝7.2Hz,1H),7.92(d,J＝9.2Hz,3H),7.67(t,J＝7.6Hz,1H),7.17(d,J＝7.6Hz,1H),6.95(s,1H),6.79(d,J＝7.6Hz,1H),3.94(q,J＝7.2Hz,2H),1.36(t,J＝7.2Hz,3H).
实施例15 4-(叔丁基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺的合成
Figure PCTCN2016072266-appb-000032
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ7.99(d,J＝7.2Hz,1H),7.78(d,J＝8.4Hz,1H),7.63(d,J＝8.4Hz,2H),7.60–7.48(m,1H),7.37(d,J＝8.4Hz,2H),7.28(s,1H),6.80(d,J＝7.6Hz,2H),3.94(q,J＝7.2Hz,2H),1.36(t,J＝7.2Hz,3H),1.27(s,9H).
实施例16 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-(三氟甲氧基)苯磺酰胺的合成
Figure PCTCN2016072266-appb-000033
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.05(d,J＝7.2Hz,1H),7.86(d,J＝8.4Hz,1H),7.79(d,J＝8.8Hz,2H),7.71–7.53(m,1H),7.23(d,J＝7.6Hz,3H),6.87(s,1H),6.82(d,J＝7.6Hz,1H),3.97(q,J＝7.2Hz,2H),1.38(t,J＝7.2Hz,3H).
实施例17 3-氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2-氟苯磺酰胺的合成
Figure PCTCN2016072266-appb-000034
合成方法如实施例1。1H NMR(400MHz,d-DMSO)δ10.82(s,1H),8.12(d,J＝8.4Hz,1H),8.03(d,J＝6.8Hz,1H),7.82(dd,J＝17.6,10.0Hz,1H),7.76(d,J＝7.2Hz,1H),7.59(t,J＝7.2Hz,1H),7.28(t,J＝8.0Hz,1H),7.22(d,J＝7.6Hz,1H),7.13(d,J＝7.6Hz,1H),3.87(q,J＝7.2Hz,2H),1.23(t,J＝7.2Hz,3H).
实施例18 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-甲基苯磺酰胺的合成
Figure PCTCN2016072266-appb-000035
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.02(d,J＝7.2Hz,1H),7.93(d,J＝8.4Hz,1H),7.63(t,J＝8.4Hz,3H),7.19(dd,J＝7.6,5.2Hz,3H),6.85(s,1H),6.77(d,J＝7.6Hz,1H),3.93(q,J＝7.2Hz,2H),2.36(s,3H),1.35(t,J＝7.2Hz,3H).
实施例19 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2,4-二氟苯磺酰胺的合成
Figure PCTCN2016072266-appb-000036
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.14(d,J＝8.4Hz,1H),8.05(d,J＝7.2Hz,1H),7.75–7.70(m,2H),7.23(d,J＝7.6Hz,1H),7.07(s,1H),7.01–6.91(m,1H),6.87(dd,J＝11.6,5.2Hz,1H),6.75(d,J＝7.6Hz,1H),3.92(q,J＝7.2Hz,2H),1.33(t,J＝7.2Hz,3H).
实施例20 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)丙烷-1-磺酰胺的合成
Figure PCTCN2016072266-appb-000037
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.22(d,J＝8.0Hz,1H),8.09(d,J＝6.8Hz,1H),7.79(t,J＝7.2Hz,1H),7.53(d,J＝7.2Hz,1H),6.99(s,1H),6.88(d,J＝7.2Hz,1H),3.97(q,J＝7.2Hz,2H),3.30–2.79(m,2H),1.91(dd,J＝14.8,7.2Hz,2H),1.37(t,J＝6.8Hz,3H),1.02(t,J＝7.2Hz,3H).
实施例21 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)环戊烷磺酰胺的合成
Figure PCTCN2016072266-appb-000038
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.25(d,J＝8.0Hz,1H),8.08(d,J＝6.8Hz,1H),7.77(t,J＝7.2Hz,1H),7.58(d,J＝7.2Hz,1H),7.16(s,1H),6.86(d,J＝7.2Hz,1H),3.96(q,J＝7.2Hz,2H),3.51–3.46(m,1H),2.13–2.03(m,4H),1.95–1.78(m,4H),1.36(t,J＝7.2Hz,3H).
实施例22 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-(三氟甲基)苯磺酰胺的合成
Figure PCTCN2016072266-appb-000039
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.04(d,J＝6.8Hz,1H),7.96–7.73(m,3H),7.68–7.62(m,3H),7.18(d,J＝7.6Hz,1H),6.88(s,1H),6.79(d,J＝7.2Hz,1H),3.94(q,J＝7.2Hz,2H),1.36(t,J＝7.2Hz,3H).
实施例23 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-3-(甲基磺酰基)苯磺酰胺的合成
Figure PCTCN2016072266-appb-000040
合成方法如实施例1。1H NMR(400MHz,d-DMSO)δ10.49(s,1H),8.14(d,J＝9.6Hz,2H),8.00(d,J＝7.2Hz,2H),7.93(d,J＝7.6Hz,1H),7.77(t,J＝7.6Hz,1H),7.69(t,J＝7.6Hz,1H),7.13(s,2H),3.87(d,J＝7.2Hz,2H),3.17(s,3H),1.23(t,J＝6.8Hz,3H).
实施例24 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)萘-2-磺酰胺的合成
Figure PCTCN2016072266-appb-000041
合成方法如实施例1。1H NMR(400MHz,d-DMSO)δ10.61(s,1H),8.80(d,J＝8.4Hz,1H),8.15(d,J＝8.0Hz,1H),8.04(d,J＝7.6Hz,1H),7.98(d,J＝7.2Hz,1H),7.92(t,J＝7.6Hz,2H),7.72–7.65(m,2H),7.53–7.49(m,2H),7.09(d,J＝7.6Hz,1H),7.02(d,J＝7.6Hz,1H),3.82(q,J＝7.2Hz,2H),1.18(t,J＝7.2Hz,3H).
实施例25 甲基-4-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸甲酯的合成
Figure PCTCN2016072266-appb-000042
合成方法如实施例1。1H NMR(400MHz,d-DMSO)δ10.46(s,1H),8.04(d,J＝8.4Hz,3H),8.00(d,J＝7.2Hz,1H),7.80(d,J＝8.4Hz,2H),7.70(t,J＝7.6Hz,1H),7.11(s,2H),3.87(q,J＝7.2Hz,5H),1.23(t,J＝7.2Hz,3H).
实施例26 4-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸的合成
Figure PCTCN2016072266-appb-000043
合成方法如实施例7。1H NMR(400MHz,d-DMSO)δ13.41(s,1H),10.44(s,1H),8.17–7.92(m,4H),7.77(d,J＝8.0Hz,2H),7.70(t,J＝7.6Hz,1H),7.11(s,2H),3.86(q,J＝7.2Hz,2H),1.23(t,J＝7.2Hz,3H).
实施例27 3-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸甲酯的合成
Figure PCTCN2016072266-appb-000044
合成方法如实施例1。1H NMR(400MHz,d-DMSO)δ10.43(s,1H),8.22(s,1H),8.12(d,J＝7.6Hz,1H),8.04–7.98(m,2H),7.86(d,J＝7.6Hz,1H),7.70–7.61(m,2H),7.11(s,2H),3.93–3.77(m,5H),1.22(t,J＝7.1Hz,3H).
实施例28 3-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸的合成
Figure PCTCN2016072266-appb-000045
合成方法如实施例7。1H NMR(400MHz,d-DMSO)δ13.27(s,1H),10.39(s,1H),8.21(s,1H),8.10(d,J＝7.6Hz,1H),8.01–7.98(m,2H),7.84(d,J＝7.6Hz,1H),7.68(t,J＝7.6Hz,1H),7.61(t,J＝7.6Hz,1H),7.11(s,2H),3.86(q,J＝7.2Hz,2H),1.22(t,J＝7.2Hz,3H).
实施例29 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2,3-二氢苯并[b][1,4]二氧杂环己烯-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000046
合成方法如实施例1。1H NMR(400MHz,d-DMSO)δ10.14(s,1H),8.10(d,J＝8.4Hz,1H),8.01(d,J＝6.8Hz,1H),7.73(t,J＝7.6Hz,1H),7.26–7.00(m,4H),6.91(d,J＝8.4Hz,1H),4.25(d,J＝9.2Hz,4H),3.87(q,J＝7.2Hz,2H),1.23(t,J＝7.2Hz,3H).
实施例30 2-溴-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺的合成
Figure PCTCN2016072266-appb-000047
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.26(d,J＝8.4Hz,1H),8.05(d,J＝7.2Hz,1H),7.87(d,J＝7.6Hz,1H),7.80(d,J＝7.6Hz,1H),7.73(t,J＝7.6Hz,1H),7.40(t,J＝7.6Hz,1H),7.36–7.28(m,2H),7.11(d,J＝7.6Hz,1H),6.69(d,J＝7.6Hz,1H),3.90(q,J＝7.2Hz,2H),1.31(t,J＝7.2Hz,3H).
实施例31 5-溴-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2-甲氧基苯磺酰胺的合成
Figure PCTCN2016072266-appb-000048
合成方法如实施例1。1H NMR(400MHz,d-DMSO)δ10.29(s,1H),8.24(d,J＝8.4Hz,1H),8.02(d,J＝6.8Hz,1H),7.79(t,J＝7.6Hz,1H),7.71(d,J＝8.8Hz,1H),7.61(s,1H),7.24(d,J＝7.6Hz,1H),7.15(d,J＝8.8Hz,1H),7.10(d,J＝7.6Hz,1H),3.98–3.57(m,5H),1.22(t,J＝7.2Hz,3H).
实施例32 2,6-二氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺的合成
Figure PCTCN2016072266-appb-000049
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.17(d,J＝8.0Hz,1H),8.05(d,J＝7.2Hz,1H),7.73(t,J＝7.6Hz,1H),7.50(s,1H),7.45(d,J＝8.0Hz,2H),7.38–7.29(m,1H),7.22(d,J＝7.6Hz,1H),6.74(d,J＝7.6Hz,1H),3.92(q,J＝7.2Hz,2H),1.33(t,J＝7.2Hz,3H).
实施例33 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2,3-二甲氧基苯磺酰胺的合成
Figure PCTCN2016072266-appb-000050
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.23(d,J＝8.4Hz,1H),8.04(d,J＝7.2Hz,1H),7.72(t,J＝7.6Hz,1H),7.27(d,J＝4.4Hz,1H),7.22(s,1H),7.11(d,J＝7.6Hz,1H),7.02(s,2H),6.70(d,J＝7.6Hz,1H),4.07(s,3H),3.90(q,J＝7.2Hz,2H),3.67(s,3H),1.31(t,J＝7.2Hz,3H).
实施例34 3,5-二氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺的合成
Figure PCTCN2016072266-appb-000051
合成方法如实施例1。1H NMR(400MHz,d-DMSO)δ10.52(s,1H),8.05(t,J＝8.0Hz,2H),7.93(s,1H),7.76(t,J＝7.6Hz,1H),7.60(s,2H),7.29–6.97(m,2H),3.88(q,J＝7.2Hz,2H),1.23(t,J＝7.2Hz,3H).
实施例35 2,3-二氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺的合成
Figure PCTCN2016072266-appb-000052
合成方法如实施例1。1H NMR(400MHz,d-DMSO)δ10.77(s,1H),8.24(d,J＝8.0Hz,1H),8.03(d,J＝6.8Hz,1H),7.89(d,J＝8.0Hz,1H),7.80(dd,J＝7.6,4.0Hz,2H),7.42(t,J＝8.0Hz,1H),7.18(d,J＝7.6Hz,1H),7.09(d,J＝7.6Hz,1H),3.85(q,J＝7.2Hz,2H),1.21(t,J＝7.2Hz,3H).
实施例36 甲基4-((N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)甲基)苯甲酸甲酯的合成
Figure PCTCN2016072266-appb-000053
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.10(d,J＝6.8Hz,1H),7.95(t,J＝8.4Hz,3H),7.74(t,J＝7.6Hz,1H),7.52(d,J＝7.6Hz,1H),7.36(d,J＝8.0Hz,2H),6.87(d,J＝7.6Hz,1H),6.82(s,1H),4.43(s,2H),3.97(q,J＝7.2Hz,2H),3.91(s,3H),1.38(t,J＝7.2Hz,3H).
实施例37 4-((N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)甲基)苯甲酸(E210)的合成
Figure PCTCN2016072266-appb-000054
合成方法如实施例7。1H NMR(400MHz,d-DMSO)δ12.92(s,1H),9.96(s,1H),8.31(d,J＝8.4Hz,1H),8.08(d,J＝6.8Hz,1H),7.86–7.80(m,3H),7.48(d,J＝7.6Hz,1H),7.43(d,J＝8.0Hz,2H),7.19(d,J＝7.6Hz,1H),4.59(s,2H),3.92(q,J＝6.8Hz,2H),1.27(t,J＝7.2Hz,3H).
实施例38 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-1-(3-氟苯基)甲磺酰胺的合成
Figure PCTCN2016072266-appb-000055
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.10(d,J＝7.2Hz,1H),7.96(d,J＝8.4Hz,1H),7.74(t,J＝7.6Hz,1H),7.52(d,J＝7.6Hz,1H),7.32–7.13(m,2H),7.04(t,J＝10.4Hz,3H),6.91–6.66(m,2H),4.37(s,2H),3.98(q,J＝7.2Hz,2H),1.38(t,J＝7.2Hz,3H).
实施例39 甲基3-((N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)甲基)苯甲酸甲酯的合成
Figure PCTCN2016072266-appb-000056
合成方法如实施例1。1H NMR(400MHz,d-DMSO)δ9.94(s,1H),8.27(d,J＝8.4Hz,1H),8.07(d,J＝6.8Hz,1H),7.88(d,J＝7.8Hz,1H),7.86–7.82(m,2H),7.60(d,J＝7.6Hz,1H),7.51–7.35(m,2H),7.17(d,J＝7.6Hz,1H),4.61(s,2H),3.92(d,J＝7.2Hz,2H),3.79(s,3H),1.27(t,J＝7.2Hz,3H).
实施例40 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-1-(4-(三氟甲基)苯基)甲磺酰胺的合成
Figure PCTCN2016072266-appb-000057
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.09(d,J＝6.8Hz,1H),7.97(d,J＝8.0Hz,1H),7.73(t,J＝7.6Hz,1H),7.51(t,J＝6.4Hz,3H),7.40(d,J＝7.6Hz,2H),6.94(s,1H),6.86(d,J＝7.6Hz,1H),4.44(s,2H),3.97(q,J＝7.2Hz,2H),1.38(t,J＝7.2Hz,3H).
实施例41 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-1-(对甲苯基)甲磺酰胺的合成
合成方法如实施例1。1H NMR(400MHz,d-DMSO)δ9.84(s,1H),8.32(d,J＝8.4Hz,1H),8.07(d,J＝6.8Hz,1H),7.82(t,J＝7.6Hz,1H),7.47(d,J＝7.6Hz,1H),7.20–7.18(m,3H),7.11(d,J＝7.6Hz,2H),4.42(s,2H),3.92(q,J＝7.2Hz,2H),2.28(s,3H),1.27(t,J＝7.2Hz,3H).
实施例42 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-1-(2-氟苯基)甲磺酰胺的合成
Figure PCTCN2016072266-appb-000059
合成方法如实施例1。1H NMR(400MHz,d-DMSO)δ10.03(s,1H),8.34(d,J＝8.4Hz,1H),8.08(d,J＝6.8Hz,1H),7.84(t,J＝7.6Hz,1H),7.50(d,J＝7.6Hz,1H),7.41(t,J＝7.2Hz,2H),7.20–7.16(m,3H),4.53(s,2H),3.93(q,J＝7.2Hz,2H),1.27(t,J＝7.2Hz,3H).
实施例43 1-(4-氯苯基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)甲磺酰胺的合成
Figure PCTCN2016072266-appb-000060
合成方法如实施例1。1H NMR(400MHz,d-DMSO)δ9.92(s,1H),8.31(d,J＝8.4Hz,1H),8.07(d,J＝6.8Hz,1H),7.83(t,J＝7.6Hz,1H),7.48(d,J＝7.6Hz,1H),7.35(q,J＝8.4Hz,4H),7.18(d,J＝7.6Hz,1H),4.51(s,2H),3.92(q,J＝7.2Hz,2H),1.27(t,J＝7.2Hz,3H).
实施例44 1-(4-氰基苯基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)甲磺酰胺的合成
Figure PCTCN2016072266-appb-000061
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ10.01(s,1H),8.29(d,J＝8.0Hz,1H),8.08(d,J＝6.8Hz,1H),7.83(t,J＝7.6Hz,1H),7.78(d,J＝8.0Hz,2H),7.52–7.46(m,3H),7.19(d,J＝7.6Hz,1H),4.64(s,2H),3.92(q,J＝6.8Hz,2H),1.27(t,J＝7.2Hz,3H).
实施例45 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-1-(4-氟苯基)甲磺酰胺的合成
Figure PCTCN2016072266-appb-000062
合成方法如实施例1。1H NMR(400MHz,CDCl3)δ8.10(d,J＝7.2Hz,1H),7.96(d,J＝8.4Hz,1H),7.84–7.68(m,1H),7.51(d,J＝7.6Hz,1H),7.25(d,J＝9.2Hz,1H),6.98(t,J＝8.4Hz,2H),6.87(d,J＝7.6Hz,1H),6.71(s,1H),4.36(s,2H),3.98(q,J＝7.2Hz,2H),1.39(t,J＝7.2Hz,3H).
结构类型为Ⅱ时：
实施例46 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-氟苯甲酰胺的合成
Figure PCTCN2016072266-appb-000063
6-氨基-1-乙基苯并[cd]吲哚-2(1H)-酮的合成参见实施例1。
将6-氨基-1-乙基苯并[cd]吲哚-2(1H)-酮(100mg，0.47mmol)和对氟苯甲酸(98mg，0.7mmol)溶于二氯甲烷(20mL)中，加入HATU(269mg，0.71mmol)和DIPEA(183mg，1.41mmol)混合物室温反应过夜。加水，使用二氯甲烷萃取三次，合并有机层，饱和氯化钠洗一遍，无水硫酸钠干燥，旋干，柱层析，得到N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-氟苯甲酰胺90mg(57％)。1H NMR(400MHz,CDCl3)δ8.20(s,1H),8.03–7.96(m,4H),7.81(d,J＝7.6Hz,1H),7.68(t,J＝7.6Hz,1H),7.20(t,J＝8.4Hz,2H),6.87(d,J＝7.6Hz,1H),3.96(q,J＝7.2Hz,2H),1.37(t,J＝7.2Hz,3H).
实施例47 2-(4-氯苯基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)乙酰胺的合成
Figure PCTCN2016072266-appb-000064
合成方法如实施例46。1H NMR(400MHz,d-DMSO)δ10.23(s,1H),8.28(d,J＝8.0Hz,1H),8.06(d,J＝6.8Hz,1H),7.83(t,J＝7.6Hz,1H),7.76(d,J＝7.6Hz,1H),7.61–7.26(m,4H),7.16(d,J＝7.6Hz,1H),3.90(q,J＝7.2Hz,2H),3.82(s,2H),1.25(t,J＝7.2Hz,3H).
实施例48 2-(3,4-二甲氧基苯基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)乙酰胺的合成
Figure PCTCN2016072266-appb-000065
合成方法如实施例46。1H NMR(400MHz,CDCl3)δ8.01(d,J＝6.8Hz,1H),7.87(d,J＝7.6Hz,1H),7.62(t,J＝7.6Hz,1H),7.55(s,1H),7.50(d,J＝8.0Hz,1H),6.98–6.94(m,3H),6.85(d,J＝7.6Hz,1H),3.96–3.92(m,8H),3.82(s,2H),1.34(t,J＝7.2Hz,3H).
实施例49 2-(2,4-二氯苯基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)乙酰胺的合成
Figure PCTCN2016072266-appb-000066
合成方法如实施例46。1H NMR(400MHz,d-DMSO)δ10.29(s,1H),8.33(d,J＝8.0Hz,1H),8.07(d,J＝6.8Hz,1H),7.84(t,J＝7.6Hz,1H),7.74(d,J＝7.6Hz,1H),7.63(s,1H),7.52(d,J＝8.4Hz,1H),7.43(d,J＝8.4Hz,1H),7.17(d,J＝7.6Hz,1H),4.01(s,2H),3.91(q,J＝7.2Hz,2H),1.26(t,J＝7.2Hz,3H).
实施例50 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-3-苯基丙酰胺的合成
Figure PCTCN2016072266-appb-000067
合成方法如实施例46。1H NMR(400MHz,d-DMSO)δ9.95(s,1H),8.11(d,J＝8.4Hz,1H),8.05(d,J＝7.2Hz,1H),7.86–7.73(m,1H),7.71(d,J＝7.6Hz,1H),7.31(d,J＝4.0Hz,3H),7.23(s,1H),7.16(d,J＝7.6Hz,1H),3.91(q,J＝7.2Hz,2H),2.98(t,J＝7.6Hz,2H),2.79(t,J＝7.6Hz,2H),1.26(t,J＝7.2Hz,3H).
实施例51 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4,4,4-三氟丁酰胺的合成
Figure PCTCN2016072266-appb-000068
合成方法如实施例46。1H NMR(400MHz,d-DMSO)δ10.14(s,1H),8.32(d,J＝8.4Hz,1H),8.07(d,J＝6.8Hz,1H),7.83(t,J＝7.6Hz,1H),7.77(d,J＝7.6Hz,1H),7.18(d,J＝7.6Hz,1H),3.91(q,J＝7.2Hz,2H),2.88–2.71(m,2H),2.71–2.51(m,2H),1.26(t,J＝7.2Hz,3H).
实施例52 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)丙酰胺的合成
Figure PCTCN2016072266-appb-000069
合成方法如实施例46。1H NMR(400MHz,d-DMSO)δ9.92(s,1H),8.30(d,J＝8.4Hz,1H),8.06(d,J＝6.8Hz,1H),7.89–7.62(m,2H),7.16(d,J＝7.6Hz,1H),3.91(q,J＝7.2Hz,2H),2.46(q,J＝7.6Hz,2H),1.26(t,J＝7.2Hz,3H),1.16(t,J＝7.6Hz,3H).
实施例53 4-氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯甲酰胺的合成
Figure PCTCN2016072266-appb-000070
合成方法如实施例46。1H NMR(400MHz,d-DMSO)δ10.55(s,1H),8.20(d,J＝8.0Hz,1H),8.09(t,J＝8.8Hz,3H),7.81(t,J＝7.6Hz,1H),7.65(d,J＝8.4Hz,3H),7.23(d,J＝7.6Hz,1H),3.94(q,J＝7.2Hz,2H),1.29(t,J＝7.2Hz,3H).
实施例54 N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2-(对甲苯基)乙酰胺的合成
Figure PCTCN2016072266-appb-000071
合成方法如实施例46。1H NMR(400MHz,d-DMSO)δ10.19(s,1H),8.27(d,J＝8.0Hz,1H),8.06(d,J＝6.8Hz,1H),7.82(t,J＝7.6Hz,1H),7.75(d,J＝7.6Hz,1H),7.30(d,J＝7.6Hz,2H),7.16(d,J＝7.6Hz,3H),3.90(q,J＝7.2Hz,2H),3.75(s,2H),2.29(s,3H),1.25(t,J＝7.2Hz,3H).
实施例55 (E)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-3-(呋喃-2-基)丙烯酰胺的合成
Figure PCTCN2016072266-appb-000072
合成方法如实施例46。1H NMR(400MHz,d-DMSO)δ10.24(s,1H),8.43(d,J＝8.0Hz,1H),8.07(t,J＝7.6Hz,2H),7.84(d,J＝11.2Hz,2H),7.45(d,J＝11.2Hz,1H),7.20(d,J＝7.6Hz,1H),7.04–6.75(m,2H),6.64(s,1H),3.92(q,J＝6.8Hz,2H),1.27(t,J＝7.2Hz,3H).
结构类型为Ⅲ时：
实施例56 1-乙基-6-((3-苯丙基)氨基)苯并[cd]吲哚-2(1H)-酮的合成
Figure PCTCN2016072266-appb-000073
6-氨基-1-乙基苯并[cd]吲哚-2(1H)-酮的合成参见实施例1。
将6-氨基-1-乙基苯并[cd]吲哚-2(1H)-酮(100mg，0.47mmol)和(3-氯丙基)苯(73mg，0.47mmol)溶于乙腈(20mL)中，加入碳酸钾(195mg，1.41mmol)。混合物70℃反应过夜。加水，使用乙酸乙酯萃取三次，合并有机层，饱和氯化钠洗一遍，无水硫酸钠干燥，旋干，柱层析，得到产物60mg(38％)。1H NMR(400MHz,CDCl3)δ8.06(d,J＝7.2Hz,1H),7.84(d,J＝8.0Hz,1H),7.63(t,J＝7.6Hz,1H),7.32(t,J＝7.6Hz,2H),7.26–7.04(m,3H),6.77(d,J＝7.6Hz,1H),6.34(d,J＝7.2Hz,1H),4.24(s,1H),3.94(q,J＝7.2Hz,2H),3.30(t,J＝6.8Hz,2H),2.83(t,J＝7.2Hz,2H),2.21–2.03(m,2H),1.36(t,J＝7.2Hz,3H).
实施例57 1-乙基-6-((3-吗啉代丙基)氨基)苯并[cd]吲哚-2(1H)-酮的合成
Figure PCTCN2016072266-appb-000074
合成方法如实施例56。1H NMR(400MHz,CDCl3)δ8.07(d,J＝7.6Hz,2H),7.66(t,J＝7.6Hz,1H),6.79(d,J＝7.6Hz,1H),6.35(d,J＝7.6Hz,1H),5.81(s,1H),3.95(q,J＝7.2Hz,2H),3.82(t,J＝4.4Hz,4H),3.35(t,J＝6.0Hz,2H),2.60–2.54(m,6H),2.02–1.87(m,2H),1.36(t,J＝7.2Hz,3H).
实施例58 1-乙基-6-((4-甲氧基苄基)氨基)苯并[cd]吲哚-2(1H)-酮的合成
Figure PCTCN2016072266-appb-000075
合成方法如实施例56。1H NMR(400MHz,d-DMSO)δ8.51(d,J＝8.0Hz,1H),7.98(d,J＝7.2Hz,1H),7.71(t,J＝7.6Hz,1H),7.33(d,J＝8.4Hz,2H),7.05(s,1H),6.88(d,J＝8.4Hz,3H),6.21(d,J＝7.6Hz,1H),4.40(d,J＝4.4Hz,2H),3.82(q,J＝7.2Hz,2H),3.70(d,J＝8.8Hz,3H),1.20(t,J＝7.2Hz,3H).
实施例59 1-乙基-6-((4-甲基苄基)氨基)苯并[cd]吲哚-2(1H)-酮的合成
Figure PCTCN2016072266-appb-000076
合成方法如实施例56。1H NMR(400MHz,d-DMSO)δ8.52(d,J＝8.0Hz,1H),7.99(d,J＝6.8Hz,1H),7.71(t,J＝7.6Hz,1H),7.29(d,J＝7.6Hz,2H),7.12(d,J＝7.6Hz,3H),6.87(d,J＝7.6Hz,1H),6.17(d,J＝7.6Hz,1H),4.42(s,2H),3.81(q,J＝7.2Hz,2H),2.26(s,3H),1.20(t,J＝7.2Hz,3H).
实施例60 1-乙基-6-((4-(三氟甲基)苄基)氨基)苯并[cd]吲哚-2(1H)-酮的合成
Figure PCTCN2016072266-appb-000077
合成方法如实施例56。1H NMR(400MHz,d-DMSO)δ8.52(d,J＝8.0Hz,1H),8.00(d,J＝6.8Hz,1H),7.74(t,J＝7.6Hz,1H),7.69(d,J＝8.0Hz,2H),7.63(d,J＝8.0Hz,2H),7.26(s,1H),6.87(d,J＝7.6Hz,1H),6.14(d,J＝7.6Hz,1H),4.58(d,J＝5.2Hz,2H),3.81(q,J＝7.2Hz,2H),1.20(t,J＝7.2Hz,3H).
实施例61 6-((4-氯苄基)氨基)-1-乙基苯并[cd]吲哚-2(1H)-酮的合成
Figure PCTCN2016072266-appb-000078
合成方法如实施例56。1H NMR(400MHz,d-DMSO)δ8.51(d,J＝8.4Hz,1H),8.00(d,J＝6.8Hz,1H),7.73(t,J＝7.6Hz,1H),7.43(d,J＝8.4Hz,2H),7.37(d,J＝8.4Hz,2H),7.18(t,J＝6.0Hz,1H),6.88(d,J＝7.6Hz,1H),6.15(d,J＝7.6Hz,1H),4.47(d,J＝6.0Hz,2H),3.82(q,J＝7.2Hz,2H),1.20(t,J＝7.2Hz,3H).
实施例62 1-乙基-6-((4-氟苄基)氨基)苯并[cd]吲哚-2(1H)-酮的合成
Figure PCTCN2016072266-appb-000079
合成方法如实施例56。1H NMR(400MHz,CDCl3)δ8.07(d,J＝7.2Hz,1H),8.00(d,J＝8.2Hz,1H),7.66(t,J＝7.6Hz,1H),7.41(dd,J＝8.4,5.6Hz,2H),7.06(t,J＝8.4Hz,2H),6.75(d,J＝7.6Hz,1H),6.38(d,J＝7.6Hz,1H),4.66(s,1H),4.45(s,2H),3.94(q,J＝7.2Hz,2H),1.35(t,J＝7.2Hz,3H).
结构类型为Ⅳ时：
实施例63 N-((1-乙酰基哌啶-4-取代)甲基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000080
1-乙基苯并[cd]吲哚-2(1H)-酮的合成参见实施例1。
步骤1. 1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰氯的合成：
Figure PCTCN2016072266-appb-000081
将1-乙基苯并[cd]吲哚-2(1H)-酮(6.46g，0.03mol)用100mL氯仿作为反应溶剂，冰浴下滴加氯磺酸(11.5g，0.1mol)，搅拌10min，升温至50℃，反应6h；将反应混合物倒入冰水中，搅拌至无气体逸出，用二氯甲烷萃取水层三次，合并有机层，饱和氯化钠水溶液洗一次，无水硫酸钠干燥，柱层析，得到5.75g黄绿色粉末状固体(59％)。MS(ESI),m/z:M+297.1。
将1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰氯(100mg，0.34mmol)溶于10mL二氯甲烷中，加入1-(4-(氨基甲基)哌啶-1-基)乙酮(64mg，0.41mmol)滴加5mL的吡啶，80℃反应1h，反应完全后，稀盐酸洗，乙酸乙酯萃取三次，合并有机层，饱和氯化钠水溶液洗一次，无水硫酸钠干燥，柱层析石油醚:乙酸乙酯＝4:1-2:1，得到92mg黄绿色粉末状固体，收率65％
1H-NMR(400MHz,d-DMSO)δ8.69(d,J＝8.4Hz,1H),8.16(d,J＝6.8Hz,1H),8.07(d,J＝7.6Hz,1H),7.96(t,J＝7.2Hz,1H),7.86(t,J＝6.0Hz,1H),7.31(d,J＝7.6Hz,1H),4.24(d,J＝8.0Hz,1H),3.93(q,J＝ 6.8Hz,2H),3.69(d,J＝12.4Hz,1H),2.87(t,J＝13.2Hz,1H),2.64(t,J＝6.0Hz,2H),2.36(t,J＝12.0Hz,1H).1.92(s,3H),1.56–1.51(m,3H),1.28(t,J＝7.2Hz,3H).MS(ESI),m/z:M+417.0；M-415.0.
实施例64 1-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)环己烷甲酰胺的合成
Figure PCTCN2016072266-appb-000082
合成方法如实施例63。1H-NMR(400MHz,d-DMSO)δ8.58(d,J＝8.4Hz,1H),8.15(d,J＝7.2Hz,1H),8.09(d,J＝7.6Hz,1H),7.96(t,J＝8.0Hz,1H),7.31(d,J＝7.6Hz,1H),3.92(q,J＝6.8Hz,2H),3.26–3.21(m,4H),1.25(t,J＝7.2Hz,3H),1.01–0.98(m,6H).MS(ESI),m/z:M-400.8.
实施例65 1-乙基-N-((3-异丙基-4,5-二氢异恶唑-5-取代)甲基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000083
合成方法如实施例63。1H-NMR(400MHz,d-DMSO)δ8.70(d,J＝8.0Hz,1H),8.14–8.09(m,2H),8.06(d,J＝7.6Hz,1H),7.94(t,J＝7.6Hz,1H),7.29(d,J＝7.2Hz,1H),4.43–4.39(m,1H),3.93(q,J＝6.8Hz,2H),2.84–2.83(m,2H),2.48(s,3H),1.26(t,J＝6.8Hz,1H),0.98(s,6H).MS(ESI),m/z:M-400.0.
实施例66 N-((3,5-二甲基-4,5-二氢异恶唑-5-基)甲基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000084
合成方法如实施例63。1H-NMR(400MHz,d-DMSO)δ8.72(d,J＝8.4Hz,1H),8.15–8.10(m,2H),8.07(d,J＝7.6Hz,1H),7.94(t,J＝7.2Hz,1H),7.30(d,J＝7.6Hz,1H),3.93(q,J＝7.2Hz,2H),2.85–2.82(m,3H),2.58(s,1H),1.75(s,3H),1.27–1.22(m,4H),1.17(s,2H).MS(ESI),m/z:M-386.0.
实施例67 N-(4-乙酰基苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000085
1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰氯合成方法如实施例63。
取1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰氯(100mg,0.338mmol)，和1-(4-氨基苯基)乙酮(55mg，0.41mmol)溶于3mL吡啶中。室温反应过夜，反应完全后，水洗，乙酸乙酯萃取三次，合并有机层，10％盐酸50mL洗一次，饱和氯化钠水溶液洗一次，无水硫酸钠干燥，柱层析，得到80mg黄绿色粉末状固体，收率60％。1H-NMR(400MHz,d-DMSO)δ10.82(s,1H),8.69(d,J＝8.4Hz,1H),8.19(d,J＝7.6Hz,1H),8.09(d,J＝7.2Hz,1H),7.94(t,J＝8.0Hz,1H),7.58–7.53(m,2H),7.31(d,J＝5.6Hz,2H),7.25(d,J＝7.6Hz,1H),3.86(q,J＝6.8Hz,2H),2.43(s,3H),1.22(t,J＝6.8Hz,3H).MS(ESI),m/z:M+395.0；M-393.0.
实施例68 N-(2-氯苄基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000086
合成方法如实施例63。1H-NMR(400MHz,d-DMSO)δ8.68(d,J＝8.0Hz,1H),8.13(d,J＝7.2Hz,1H),8.04(d,J＝7.6Hz,1H),7.92(t,J＝7.2Hz,1H),7.27–7.29(m,3H),7.12–7.02(m,2H),4.12(s,2H),3.93(q,J＝7.2Hz,1H),1.27(t,J＝7.2Hz,3H).MS(ESI),m/z:M-399.0.
实施例69 1-乙基-N-(2-氟苄基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000087
合成方法如实施例63。1H-NMR(400MHz,d-DMSO)δ8.64(d,J＝8.4Hz,1H),8.41(s,1H),8.12(d,J＝6.8Hz,1H),8.03(d,J＝8.0Hz,1H),7.91(t,J＝7.2Hz,1H),7.21(d,J＝7.6Hz,1H),7.15(t,J＝8.0Hz,1H),7.07–7.05(m,1H),7.91–7.83(m,2H),4.06(s,2H),3.92(q,J＝7.2Hz,2H),1.29(t,J＝7.2Hz,3H).MS(ESI),m/z:M-383.0.
实施例70 N-(1-乙酰基-4-取代)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000088
合成方法如实施例63。1H-NMR(400MHz,d-DMSO)δ8.70(d,J＝8.4Hz,1H),8.16–8.11(m,2H),8.02(d,J＝7.6Hz,1H),7.94(q,J＝7.2Hz,1H),7.30(d,J＝8.0Hz,1H),4.01(q,J＝6.8Hz,1H),3.93(q,J＝7.2Hz,2H),3.58(d,J＝14.0Hz,1H),3.33–3.19(m,1H),2.97–2.90(m,1H),2.62–2.55(m,1H),1.88(s,3H),1.49(d,J＝10.0Hz,2H),1.28(t,J＝7.2Hz,3H),1.27–1.22(m,2H).MS(ESI),m/z:M+402.1；M-400.1.
实施例71 叔丁基4-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)哌啶-1-甲酸叔丁酯的合成
Figure PCTCN2016072266-appb-000089
合成方法如实施例63。1H-NMR(400MHz,d-DMSO)δ8.68(d,J＝8.4Hz,1H),8.15–8.10(m,2H),7.98–7.92(m,2H),7.29(d,J＝7.6Hz,1H),3.93(d,J＝7.2Hz,2H),3.67–3.64(m,2H),3.18(s,1H),2.69(s,2H),1.47–1.44(m,2H),1.32(s,9H),1.32–1.25(m,3H),1.17–1.51(m,2H).MS(ESI),m/z:M-458.0.
实施例72 N-环戊基-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000090
合成方法如实施例63。1H-NMR(400MHz,d-DMSO)δ8.72(d,J＝8.4Hz,1H),8.14(d,J＝6.8Hz,1H),8.09(d,J＝7.6Hz,1H),7.95(t,J＝7.6Hz,1H),7.80(d,J＝7.2Hz,1H),7.26(d,J＝7.6Hz,1H),3.95(q,J＝7.2Hz,2H),3.44(q,J＝6.4Hz,1H),1.51–1.46(m,4H),1.28–1.22(m,7H).MS(ESI),m/z:M-343.0.
实施例73 1-((1-乙基-2-氧代-1-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)甲基)环戊烷羧酸甲酯的合成
Figure PCTCN2016072266-appb-000091
合成方法如实施例63。1H-NMR(400MHz,d-DMSO)δ8.63(d,J＝8.4Hz,1H),8.17(d,J＝7.6Hz,1H),8.11(d,J＝7.2Hz,1H),7.86(t,J＝8.0Hz,1H),6.93(d,J＝7.6Hz,1H),5.36(t,J＝6.8Hz,1H),4.04–3.96(m,4H),2.92(d,J＝7.2Hz,2H),1.93–1.89(m,2H),1.71(s,2H),1.58–1.54(m,6H),1.39(t,J＝7.2Hz,3H),1.16(t,J＝7.2Hz,3H).MS(ESI),m/z:M-429.0.
实施例74 1-((1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)甲基)环戊烷羧酸的合成
Figure PCTCN2016072266-appb-000092
1-((1-乙基-2-氧代-1-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)甲基)环戊烷羧酸甲酯的合成方法参见实施例73。
将1-((1-乙基-2-氧代-1-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)甲基)环戊烷羧酸甲酯(100mg，0.23mmol)用THF溶解，室温滴加2N氢氧化钠溶液0.5mL，室温反应过夜。旋去四氢呋喃。在冰浴下滴加浓盐酸，直至无沉淀析出，抽滤，得到86mg产物，收率93％。1H-NMR(400MHz,d-DMSO)δ8.63(d,J＝8.4Hz,1H),8.17(d,J＝7.6Hz,1H),8.11(d,J＝7.2Hz,1H),7.86(t,J＝8.0Hz,1H),6.93(d,J＝7.6Hz,1H),5.36(t,J＝6.8Hz,1H),3.92(m,3H),2.83(s,2H),1.81(m,2H),1.45(m,6H),1.25(m,4H).
实施例75 N-(4-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)苯基)乙酰胺的合成
Figure PCTCN2016072266-appb-000093
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ10.33(s,1H),9.79(s,1H),8.68(d,J＝8.0Hz,1H),8.10(dd,J＝14.4,6.8Hz,2H),7.92(t,J＝7.2Hz,1H),7.34(d,J＝7.6Hz,2H),7.23(d,J＝7.6Hz,1H),6.94(d,J＝7.6Hz,2H),3.88(d,J＝6.8Hz,2H),1.95(s,3H),1.23(t,J＝7.2Hz,3H).
实施例76 2-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)苯甲酸的合成
Figure PCTCN2016072266-appb-000094
合成方法如实施例74。1H NMR(400MHz,d-DMSO)δ11.96(s,1H),8.52(d,J＝8.4Hz,1H),8.26(d,J＝7.6Hz,1H),8.13(d,J＝7.2Hz,1H),8.02–7.84(m,1H),7.80(d,J＝7.2Hz,1H),7.63–7.41(m,2H),7.28(d,J＝7.6Hz,1H),7.02(t,J＝7.6Hz,1H),3.89(q,J＝7.2Hz,2H),1.23(t,J＝7.2Hz,3H).
实施例77 1-乙基-N-(4-氟苯基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000095
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ10.48(s,1H),8.64(d,J＝8.4Hz,1H),8.13–8.07(m,2H),8.00–7.79(m,1H),7.25(d,J＝7.6Hz,1H),7.17–6.83(m,4H),3.89(q,J＝7.2Hz,2H),1.25(t,J＝7.2Hz,3H).
实施例78 N-丁基-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000096
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ8.69(d,J＝8.4Hz,1H),8.15(d,J＝7.2Hz,1H),8.08(d,J＝7.6Hz,1H),8.01–7.85(m,1H),7.77(t,J＝6.0Hz,1H),7.31(d,J＝7.6Hz,1H),3.94(q,J＝7.2Hz,2H),2.75(dd,J＝13.2,6.8Hz,2H),1.35–1.21(m,5H),1.19–1.12(m,2H),0.70(t,J＝7.2Hz,3H).
实施例79 N-(2-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)乙基)乙酰胺的合成
Figure PCTCN2016072266-appb-000097
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ8.65(d,J＝8.2Hz,1H),8.14(d,J＝6.4Hz,1H),8.06(d,J＝7.2Hz,1H),7.94(t,J＝7.2Hz,1H),7.87(s,1H),7.76(s,1H),7.30(d,J＝7.2Hz,1H),3.93(d,J＝6.8Hz,2H),3.01(d,J＝5.6Hz,2H),2.77(s,2H),1.65(s,3H),1.26(t,J＝6.4Hz,3H).
实施例80 1-乙基-N-(2-(甲基磺酰基)乙基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000098
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ8.64(d,J＝8.4Hz,1H),8.16–8.10(m,3H),7.96(t,J＝7.6Hz,1H),7.33(d,J＝7.6Hz,1H),3.94(q,J＝6.8Hz,2H),3.23(t,J＝6.8Hz,2H),3.14(t,J＝6.8Hz,2H),2.97(s,3H),1.27(t,J＝7.2Hz,3H).
实施例81 1-乙基-2-氧代-N-(2-(2-氧代咪唑烷-1-基)乙基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000099
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ8.66(d,J＝8.0Hz,1H),8.14(d,J＝6.4Hz,1H),8.08(d,J＝7.2Hz,1H),7.92(d,J＝6.4Hz,2H),7.29(d,J＝7.2Hz,1H),6.23(s,1H),3.93(d,J＝6.4Hz,2H),3.18(d,J＝7.2Hz,2H),3.09–3.02(m,4H),2.86–2.84(m,2H),1.26(t,J＝7.2Hz,3H).
实施例82 叔丁基(4-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)丁基)氨基甲酸叔丁酯的合成
Figure PCTCN2016072266-appb-000100
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ8.67(d,J＝8.4Hz,1H),8.13(d,J＝6.8Hz,1H),8.06(d,J＝7.6Hz,1H),7.93(t,J＝7.6Hz,1H),7.76(s,1H),7.29(d,J＝7.6Hz,1H),6.67(s,1H),3.92(d,J＝7.2Hz,2H),2.91–2.64(m,4H),1.26(s,9H),1.25–1.24(m,4H),1.24(t,J＝7.2Hz,3H).
实施例83 N-(5-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)吡啶-2-基)乙酰胺的合成
Figure PCTCN2016072266-appb-000101
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ10.48(s,1H),10.34(s,1H),8.62(d,J＝8.4Hz,1H),8.12(d,J＝7.6Hz,1H),8.06(d,J＝7.6Hz,1H),7.99–7.70(m,3H),7.41(d,J＝8.8Hz,1H),7.23(d,J＝7.6Hz,1H),3.88(q,J＝6.8Hz,2H),1.98(d,J＝8.4Hz,3H),1.22(t,J＝7.2Hz,3H).
实施例84 叔丁基-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)吡咯烷-1-甲酸叔丁酯的合成
Figure PCTCN2016072266-appb-000102
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.62(d,J＝8.4Hz,1H),8.23(d,J＝7.6Hz,1H),8.13(d,J＝7.2Hz,1H),7.85(t,J＝7.6Hz,1H),6.95(d,J＝7.6Hz,1H),5.10(d,J＝7.2Hz,1H),4.00(q,J＝7.2Hz,2H),3.86(d,J＝4.8Hz,1H),3.48–3.30(m,2H),3.29–3.26(m,1H),3.07–3.03(m,1H),1.94–1.87(m,2H),1.48–1.29(m,12H).
实施例85 叔丁基-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)氮杂环丁烷-1-甲酸叔丁酯的合成
Figure PCTCN2016072266-appb-000103
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.60(d,J＝8.4Hz,1H),8.14(d,J＝7.6Hz,1H),8.12(d,J＝6.8Hz,1H)7.85(t,J＝7.6Hz,1H),6.92(d,J＝7.6Hz,1H),5.31(d,J＝8.8Hz,1H),4.11(d,J＝8.0Hz,1H),4.01–3.95(m,4H),3.56(s,2H),1.44–1.30(m,12H).
实施例86 N-(2-环己基乙基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000104
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.64(d,J＝8.4Hz,1H),8.19(d,J＝7.6Hz,1H),8.12(d,J＝7.2Hz,1H),7.84(t,J＝7.2Hz,1H),6.93(d,J＝7.5Hz,1H),4.41(t,J＝6.0Hz,1H),3.99(q,J＝7.2Hz,2H),2.97(dd,J＝13.2,6.8Hz,2H),1.39–1.37(m,4H),1.28–1.25(m,6H),1.13–1.08(m,2H),1.02–0.97(m,2H),0.96–0.89(m,2H).
实施例87 1-乙基-2-氧代-N-(吡咯烷-3-基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000105
叔丁基-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)吡咯烷-1-甲酸叔丁酯的合成参见实施例84。
将叔丁基-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)吡咯烷-1-甲酸叔丁酯(50mg，0.112mmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(0.5mL)。室温反应2小时，水洗，二氯甲烷萃取三次，合并有机层，饱和氯化钠洗一遍，无水硫酸钠干燥，旋干，用乙酸乙酯和石油醚重结晶，得到产物37mg(95％)。1H NMR(400MHz,d-DMSO)δ8.74(s,1H),8.65(d,J＝8.4Hz,1H),8.29(d,J＝6.0Hz,1H),8.18(d,J＝7.2Hz,1H),8.13(d,J＝7.6Hz,1H),8.03–7.86(m,1H),7.34(d,J＝7.6Hz,1H),3.94(q,J＝7.2Hz,1H),3.74(dd,J＝12.0,6.0Hz,1H),3.18–3.12(m,1H),3.11–2.99(m,1H),2.93–2.89(m,1H),1.90–1.83(m,1H),1.69–1.66(m,1H),1.27(t,J＝7.2Hz,2H).
实施例88 N-(氮杂环丁烷-3-基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000106
合成方法如实施例87。1H NMR(400MHz,d-DMSO)δ8.78(d,J＝7.6Hz,1H),8.61(d,J＝8.4Hz,2H),8.18(d,J＝7.2Hz,1H),8.10(d,J＝7.6Hz,1H),7.99(t,7.2Hz,1H),7.33(d,J＝7.6Hz,1H),3.94(q,J＝7.2Hz,2H),3.86(t,J＝9.2Hz,2H),3.66(s,2H),1.27(t,J＝7.2Hz,3H).
实施例89 1-N-乙基-N-己基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000107
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ8.68(d,J＝8.4Hz,1H),8.14(d,J＝7.2Hz,1H),8.07(d,J＝7.6Hz,1H),8.00–7.83(m,1H),7.76(t,J＝6.0Hz,1H),7.29(d,J＝7.6Hz,1H),3.93(q,J＝7.2Hz,2H),2.75(dd,J＝12.8,6.4Hz,2H),1.35–1.12(m,6H),1.09–0.88(m,6H),0.67(t,J＝6.8Hz,3H).
实施例90 1-乙基-2-氧代-N-(2-(吡咯烷-1-基)乙基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000108
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ8.68(d,J＝8.2Hz,1H),8.17(d,J＝6.8Hz,1H),8.12(d,J＝7.6Hz,1H),7.96(t,J＝7.6Hz,1H),7.33(d,J＝7.6Hz,1H),4.00–3.88(m,2H),3.18–3.02(m,3H),2.85(s,4H),1.73(s,3H),1.28(t,J＝7.2Hz,3H).
实施例91 1-乙基-2-氧代-N-(2-(四氢-2H-吡喃-4-基)乙基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000109
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ8.69(d,J＝8.4Hz,1H),8.16(d,J＝7.2Hz,1H),8.08(d,J＝7.6Hz,1H),7.96(t,J＝7.6Hz,1H),7.78(s,1H),7.30(d,J＝7.6Hz,1H),3.93(t,J＝7.2Hz,2H),3.63(dd,J＝11.2,3.6Hz,2H),2.89(t,J＝11.2Hz,2H),2.80(d,J＝4.8Hz,2H),1.35–1.10(m,8H),0.90–0.86(m,2H).
实施例92 1-乙基-2-氧代-N-(四氢呋喃-3-基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000110
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ8.69(d,J＝8.4Hz,1H),8.16(d,J＝6.0Hz,2H),8.11(d,J＝7.6Hz,1H),7.95(t,J＝7.6Hz,1H),7.32(d,J＝7.6Hz,1H),3.94(q,J＝7.2Hz,2H),3.72(s,1H),3.64(dd,J＝14.4,7.2Hz,1H),3.59–3.44(m,2H),1.81–1.76(m,1H),1.53(dd,J＝12.4,6.0Hz,1H),1.27(t,J＝7.2Hz,3H).
实施例93 N-(2-(4-氯苯氧基)乙基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000111
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.61(d,J＝8.4Hz,1H),8.19(d,J＝7.6Hz,1H),8.09(d,J＝7.2Hz,1H),7.82(t,J＝7.6Hz,1H),7.10(d,J＝8.8Hz,2H),6.88(d,J＝7.6Hz,1H),6.51(d,J＝8.8Hz,2H),5.08(t,J＝6.0Hz,1H),3.97(q,J＝7.2Hz,2H),3.88(t,J＝5.2Hz,2H),3.37(dd,J＝10.8,5.2Hz,2H),1.38(t,J＝7.2Hz,3H).
实施例94 N，1-二乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000112
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.65(d,J＝8.4Hz,1H),8.20(d,J＝7.6Hz,1H),8.12(d,J＝6.8Hz,1H),7.84(t,J＝7.6Hz,1H),6.93(d,J＝7.6Hz,1H),4.52(s,1H),3.99(q,J＝7.2Hz,2H),3.02(t,J＝7.2Hz,2H),1.39(t,J＝7.2Hz,3H),1.08(t,J＝7.2Hz,3H).
实施例95 1-乙基-2-氧代-正戊基-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000113
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.64(d,J＝8.4Hz,1H),8.18(d,J＝7.6Hz,1H),8.11(d,J＝6.8Hz,1H),7.84(t,J＝7.6Hz,1H),6.92(d,J＝7.6Hz,1H),4.54(d,J＝6.0Hz,1H),3.99(q,J＝ 7.2Hz,2H),2.94(q,J＝6.8Hz,2H),1.40(q,J＝7.2Hz,5H),1.16(d,J＝6.4Hz,4H),0.75(t,J＝7.2Hz,3H).
实施例96 1-N-乙基-N-甲基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000114
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.64(d,J＝8.4Hz,1H),8.19(d,J＝7.6Hz,1H),8.12(d,J＝7.2Hz,1H),7.83(t,J＝7.6Hz,1H),6.94(d,J＝7.6Hz,1H),4.49(d,J＝5.2Hz,1H),3.99(q,J＝7.2Hz,2H),2.65(d,J＝5.2Hz,3H),1.39(t,J＝7.2Hz,3H).
实施例97 N-环己基-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺
Figure PCTCN2016072266-appb-000115
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.61(d,J＝8.4Hz,1H),8.20(d,J＝7.6Hz,1H),8.11(d,J＝7.2Hz,1H),7.84(t,J＝7.2Hz,1H),6.92(d,J＝7.6Hz,1H),4.52(d,J＝7.6Hz,1H),3.99(q,J＝7.2Hz,2H),3.29–2.92(m,1H),1.75–1.63(m,2H),1.58–1.50(m,1H),1.49–1.46(m,1H),1.40(t,J＝7.2Hz,3H),1.25-1.05(m,6H).
实施例98 叔丁基-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2016072266-appb-000116
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.60(d,J＝8.4Hz,1H),8.21(d,J＝7.6Hz,1H),8.11(d,J＝7.2Hz,1H),7.84(t,J＝7.6Hz,1H),6.92(d,J＝7.6Hz,1H),4.87(s,1H),3.98(q,J＝7.2Hz,2H),3.47–3.16(m,4H),3.02(dd,J＝13.2,7.2Hz,1H),1.67–1.53(m,2H),1.47–1.25(m,14H).
实施例99 1-N-乙基-N-异丁基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000117
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.64(d,J＝8.4Hz,1H),8.18(d,J＝7.6Hz,1H),8.11(d,J＝7.2Hz,1H),7.84(t,J＝7.6Hz,1H),6.92(d,J＝7.6Hz,1H),4.61(t,J＝6.4Hz,1H),3.99(q,J＝7.2Hz,2H),2.75(t,J＝6.4Hz,2H),1.67(dt,J＝13.2,6.8Hz,1H),1.39(t,J＝7.2Hz,3H),0.81(d,J＝6.8Hz,6H).
实施例100 1-乙基-2-氧代基-N-丙基-1,2-二氢苯并[cd]吲哚-6-磺酰胺
Figure PCTCN2016072266-appb-000118
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.65(d,J＝8.4Hz,1H),8.18(d,J＝7.6Hz,1H),8.10(d,J＝7.2Hz,1H),7.92–7.68(m,1H),6.92(d,J＝7.6Hz,1H),4.66(t,J＝6.0Hz,1H),3.98(q,J＝7.2Hz,2H),2.91(dd,J＝13.2,6.8Hz,2H),1.46(dt,J＝14.4,7.2Hz,2H),1.39(t,J＝7.2Hz,3H),0.80(t,J＝7.2Hz,3H).
实施例101 1-乙基-N-(3-(4-甲基哌嗪-1-基)丙基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000119
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ8.68(d,J＝8.4Hz,1H),8.16(d,J＝6.8Hz,1H),8.08(d,J＝7.2Hz,1H),7.95(t,J＝7.6Hz,1H),7.78(s,1H),7.31(d,J＝7.6Hz,1H),3.94(q,J＝7.2Hz,2H), 2.79(d,J＝5.6Hz,2H),2.23–1.86(m,11H),1.48–1.33(m,2H),1.28(t,J＝7.2Hz,3H).
实施例102 1-乙基-2-氧代-N-(2-(哌啶-1-基)乙基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000120
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ8.68(d,J＝8.4Hz,1H),8.15(d,J＝6.8Hz,1H),8.10(d,J＝7.6Hz,1H),7.94(t,J＝7.6Hz,1H),7.67(s,1H),7.30(d,J＝7.6Hz,1H),3.94(q,J＝7.2Hz,2H),2.88(t,J＝6.4Hz,2H),2.23–2.11(m,2H),2.10–2.01(m,3H),1.30–1.22(m,7H),0.94–0.65(m,2H).
实施例103 N-(4,4-二乙氧基丁基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000121
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ8.67(d,J＝8.4Hz,1H),8.14(d,J＝6.8Hz,1H),8.06(d,J＝7.6Hz,1H),7.93(t,J＝7.6Hz,1H),7.79(t,J＝5.2Hz,1H),7.29(d,J＝7.6Hz,1H),4.18(s,1H),3.92(q,J＝6.8Hz,2H),3.42–3.31(m,2H),3.23–3.17(m,2H),2.78(d,J＝5.2Hz,2H),1.35–1.21(m,7H),0.95(t,J＝6.8Hz,6H).
实施例104 乙基-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)丙酸甲酯的合成
Figure PCTCN2016072266-appb-000122
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.61(d,J＝8.4Hz,1H),8.19(d,J＝7.6Hz,1H),8.12(d,J＝7.2Hz,1H),7.96–7.69(m,1H),6.93(d,J＝7.6Hz,1H),5.35(t,J＝6.4Hz,1H),4.01–3.96(m,4H),3.19(dd,J＝12.4,6.4Hz,2H),2.48(t,J＝6.0Hz,2H),1.39(t,J＝7.2Hz,3H),1.18(t,J＝7.2Hz,3H).
实施例105 1-乙基-N-((1-乙基吡咯烷-2-基)甲基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E-148)的合成
Figure PCTCN2016072266-appb-000123
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.68(d,J＝8.4Hz,1H),8.12(dd,J＝10.4,7.2Hz,2H),7.96–7.78(m,1H),6.90(d,J＝7.6Hz,1H),3.98(q,J＝7.2Hz,2H),3.67(d,J＝5.6Hz,1H),3.46(s,1H),3.37(dd,J＝14.4,7.6Hz,2H),3.19(dd,J＝14.4,3.2Hz,1H),2.87(s,1H),2.76(s,1H),2.15–1.80(m,5H),1.38(t,J＝7.2Hz,6H).
实施例106 1-乙基-N-(1-甲基哌啶-4-基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000124
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ8.68(d,J＝8.4Hz,1H),8.14(d,J＝7.2Hz,1H),8.09(d,J＝7.6Hz,1H),7.93(dd,J＝12.4,5.6Hz,2H),7.29(d,J＝7.6Hz,1H),3.93(q,J＝7.2Hz,2H),2.93(s,1H),2.58(d,J＝11.2Hz,2H),2.06(s,3H),1.82(s,2H),1.44(d,J＝10.4Hz,2H),1.38–1.35(m,2H),1.27(t,J＝7.2Hz,3H).
实施例107 N-环庚基-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000125
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.63(d,J＝8.4Hz,1H),8.21(d,J＝7.6Hz,1H),8.13(d,J＝7.2Hz,1H),7.93–7.60(m,1H),6.94(d,J＝7.6Hz,1H),4.55(d,J＝8.0Hz,1H),4.01(q,J＝7.2 Hz,2H),3.50–3.20(m,1H),1.73–1.69(m,2H),1.55–0.99(m,15H).
实施例108 1-乙基-2-氧代-N-(四氢-2H-吡喃-4-基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000126
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.61(d,J＝8.4Hz,1H),8.21(d,J＝7.6Hz,1H),8.12(d,J＝7.2Hz,1H),7.93–7.77(m,1H),6.92(d,J＝7.6Hz,1H),4.65(d,J＝8.0Hz,1H),3.99(q,J＝7.2Hz,2H),3.82(d,J＝12.0Hz,2H),3.44–3.34(m,1H),3.30(t,J＝10.8Hz,2H),1.69(d,J＝13.2Hz,2H),1.51–1.35(m,5H).
实施例109 叔丁基4-(2-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)乙基)哌嗪-1-甲酸叔丁酯的合成
Figure PCTCN2016072266-appb-000127
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.63(d,J＝8.4Hz,1H),8.19(d,J＝7.6Hz,1H),8.12(d,J＝7.2Hz,1H),7.93–7.75(m,1H),6.93(d,J＝7.6Hz,1H),5.35(s,1H),3.99(q,J＝7.2Hz,2H),3.28–3.10(m,4H),2.98(s,2H),2.41–2.23(m,2H),2.16–2.04(m,4H),1.47–1.30(m,12H).
实施例110 N-环己基-1-甲基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000128
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ8.70(d,J＝8.4Hz,1H),8.14(d,J＝7.6Hz,1H),8.11(d,J＝7.2Hz,1H),8.02–7.89(m,1H),7.85(d,J＝7.6Hz,1H),7.23(d,J＝7.6Hz,1H),3.38(s,3H),2.94(s,1H),1.57–1.33(m,5H),1.04–0.88(m,5H).
实施例111 N-丁基-1-甲基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000129
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ8.68(d,J＝8.4Hz,1H),8.15(d,J＝7.2Hz,1H),8.08(d,J＝7.6Hz,1H),7.99–7.83(m,1H),7.77(s,1H),7.25(d,J＝7.6Hz,1H),3.39(s,3H),2.74(d,J＝3.2Hz,2H),1.27(dd,J＝14.8,7.2Hz,2H),1.15(dd,J＝14.8,7.2Hz,2H),0.70(t,J＝7.2Hz,3H).
实施例112 N-环己基-2-氧代-1-丙基-1,2-二氢苯并[cd]吲哚-6-磺酰胺
Figure PCTCN2016072266-appb-000130
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.62(d,J＝8.4Hz,1H),8.18(d,J＝7.2Hz,1H),8.11(d,J＝7.2Hz,1H),7.83(t,7.2Hz,1H),6.91(d,J＝7.6Hz,1H),4.57(d,J＝7.6Hz,1H),3.89(t,J＝7.2Hz,2H),3.31–3.03(m,1H),1.82(dt,J＝14.8,7.2Hz,2H),1.74–1.64(m,2H),1.57–1.56(m,2H),1.48(d,J＝12.4Hz,1H),1.17–1.08(m,4H),1.02(t,J＝7.2Hz,3H).
实施例113 2-氧代-N，1-二丙基-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000131
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.64(d,J＝8.4Hz,1H),8.18(d,J＝7.6Hz,1H),8.11(d,J＝7.2Hz,1H),7.94–7.66(m,1H),6.92(d,J＝7.6Hz,1H),4.60(t,J＝6.0Hz,1H),3.89(t,J＝7.2Hz, 2H),2.92(dd,J＝13.6,6.8Hz,2H),1.78(dt,J＝14.4,7.2Hz,2H),1.44(dt,J＝14.4,7.2Hz,2H),1.01(t,J＝7.2Hz,3H),0.81(t,J＝7.2Hz,3H).
实施例114 N-丁基-2-氧代-1-丙基-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000132
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.64(d,J＝8.4Hz,1H),8.18(d,J＝7.6Hz,1H),8.12(d,J＝7.2Hz,1H),7.84(dd,J＝8.2,7.2Hz,1H),6.92(d,J＝7.6Hz,1H),4.51(t,J＝6.0Hz,1H),3.90(t,J＝7.2Hz,2H),2.94(dd,J＝13.2,6.8Hz,2H),1.88–1.70(m,2H),1.50–1.33(m,2H),1.23(dt,J＝14.4,7.2Hz,3H),1.01(t,J＝7.2Hz,3H),0.78(t,J＝7.2Hz,3H).
实施例115 N-丁基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000133
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ11.13(s,1H),8.68(d,J＝8.4Hz,1H),8.11(d,J＝7.2Hz,1H),8.03(d,J＝7.6Hz,1H),7.98–7.87(m,1H),7.74(t,J＝5.6Hz,1H),7.06(d,J＝7.6Hz,1H),2.74(dd,J＝13.2,6.8Hz,2H),1.35–1.19(m,2H),1.19–0.98(m,2H),0.69(t,J＝7.2Hz,3H).
实施例116 N-丁基-1-异丁基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000134
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ8.69(d,J＝8.4Hz,1H),8.16(d,J＝7.2Hz,1H),8.06(d,J＝7.6Hz,1H),8.03–7.83(m,1H),7.77(t,J＝6.0Hz,1H),7.30(d,J＝7.6Hz,1H),3.72(d,J＝7.2Hz,2H),2.76(dd,J＝12.8,6.8Hz,2H),2.15(dt,J＝13.2,6.8Hz,1H),1.37–1.21(m,2H),1.18–1.10(m,2H),0.93(s,3H),0.91(s,3H),0.68(t,J＝7.2Hz,3H).
实施例117 N-环己基-1-异丁基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000135
合成方法如实施例67。1H NMR(400MHz,d-DMSO)8.70(d,J＝8.4Hz,1H),8.12(d,J＝7.2Hz,1H),8.08(d,J＝7.6Hz,1H),8.08–7.93(m,1H),7.85(t,J＝6.0Hz,1H),7.30(d,J＝7.6Hz,1H),3.71(d,J＝7.2Hz,2H),2.94(s,1H),2.08–1.96(m,1H),1.47–1.36(m,5H),1.05–0.90(m,5H).
实施例118 N-环己基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000136
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ11.10(s,1H),8.69(d,J＝8.4Hz,1H),8.09(d,J＝6.8Hz,1H),8.04(d,J＝7.6Hz,1H),7.96–7.87(m,1H),7.81(d,J＝7.6Hz,1H),7.04(d,J＝7.6Hz,1H),2.93(s,1H),1.58–1.30(m,5H),1.06–0.98(m,5H).
实施例119 N-(3-乙酰基苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000137
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ10.82(s,1H),8.70(d,J＝8.4Hz,1H),8.19(d,J＝7.6Hz,1H),8.13(d,J＝6.8Hz,1H),7.95(t,J＝7.6Hz,1H),7.65–7.46(m,2H),7.39–7.24(m,3H),3.88(q,J＝6.8Hz,2H),2.45(s,3H),1.22(t,J＝7.2Hz,3H).13C NMR(500MHz,d-DMSO)δ197.1,166.6,143.4,138.0, 137.5,133.5,130.7,129.6,128.9,127.4,126.0,125.2,124.8,123.9,123.8,123.2,117.7,103.9,34.6,26.5,13.5.
实施例120 N-(4-氯苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000138
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.54(d,J＝8.4Hz,1H),8.09(d,J＝7.6Hz,2H),7.79(t,J＝7.6Hz,1H),7.13(d,J＝8.4Hz,2H),6.94(d,J＝8.4Hz,2H),6.90(s,1H),6.85(d,J＝7.6Hz,1H),3.95(q,J＝7.2Hz,2H),1.36(t,J＝7.2Hz,3H).
实施例121 1-乙基-2-氧代-N-苯基-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000139
合成方法如实施例67。1H NMR(400MHz,d-DMSO)δ10.56(s,1H),8.69(d,J＝8.4Hz,1H),8.16–8.11(m,2H),7.93(t,J＝7.6Hz,1H),7.26(d,J＝7.6Hz,1H),7.16(t,J＝7.6Hz,2H),7.04(d,J＝7.6Hz,2H),6.94(t,J＝7.2Hz,1H),3.89(q,J＝7.2Hz,2H),1.23(t,J＝7.2Hz,3H).
实施例122 N-(2-氯苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000140
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.51(d,J＝8.4Hz,1H),8.14(d,J＝7.6Hz,1H),8.07(d,J＝7.2Hz,1H),7.77(t,J＝7.6Hz,1H),7.66(d,J＝8.4Hz,1H),7.22(t,J＝7.6Hz,1H),7.13(d,J＝7.6Hz,2H),6.99(t,J＝7.6Hz,1H),6.84(d,J＝7.6Hz,1H),3.94(q,J＝7.2Hz,2H),1.35(t,J＝7.2Hz,3H).
实施例123 N-(3-氯苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成
Figure PCTCN2016072266-appb-000141
合成方法如实施例67。1H NMR(400MHz,CDCl3)δ8.55(d,J＝8.4Hz,1H),8.16(d,J＝7.6Hz,1H),8.10(d,J＝7.2Hz,1H),7.80(t,J＝7.6Hz,1H),7.16–7.01(m,3H),6.93–6.82(m,2H),3.96(d,J＝7.2Hz,2H),1.37(t,J＝7.2Hz,3H).
实施例124
体外活性实验：本发明采用AlphaScreen检测技术验证本发明化合物的对BRD4(1)蛋白抑制能力。
1、实验目的
测定本发明化合物对BRD4(1)蛋白的抑制活性。
2、实验材料
目的蛋白BRD4(1)500nM；实验缓冲液(10×)MOPS(500mM)，CHAPS(0.5mM)，NaF(500mM)，BSA(1mg/mL)，PH7.4；试剂盒中供体微珠50μg/mL,受体微珠50μg/mL；BRD4(1)配体，短肽H4KAc4-botin(SGRG{Lys-Ac}GG{Lys-Ac}GLG{Lys-Ac}GGA{Lys-Ac}RHR{Lys(biotin)})50nM；150μL反应体系中：BRD4(1):15μL，实验缓冲液：15μL，去离子水：15μL，小分子化合物：15μL，供体微珠：15μL，受体微珠：15μL；阳性抑制剂：(+)-JQ1。
3、实验方法
将蛋白、短肽加入反应溶液中，20℃孵育1.5小时，加入供体和受体微珠，避光孵育1小时。转移至384孔板，每孔转移40μL液体，通过PE Envison2104多功能检测酶标仪，激发波长：680nM，发射波长520-620nM检测读数。
实施例125
体外活性实验，本发明采用TSA检测技术验证本发明化合物的对BRD4(1)蛋白抑制能力。
1、实验目的
测定本发明化合物对BRD4(1)蛋白的抑制活性。
2、实验材料
目的蛋白BRD4(1)100μM；小分子化合物400μM；实验缓冲液(10×)HEPES(50mM)，NaCl(150mM)，甘油10％，pH7.5；染料，
Figure PCTCN2016072266-appb-000142
Orange(SIGMA)(500×)；反应体系中：蛋白2μL，染料2μL，小分子化合物：10μL，实验缓冲液2μL，去离子水4μL，阳性抑制剂：(+)-JQ1。
3、实验方法
按上述体积将各组分加入到BIO-RAD 96孔黑色PCR板，冰上避光孵育30分钟，用CFX-96荧光定量PCR仪进行检测。程序为溶解曲线，30-80℃，每5秒升高0.5℃，最终测得温度变化值。
实施例124采用AlphaScreen检测技术验证结果及实施例125采用TSA检测技术验证结果见表1～4：
表1.式Ⅰ类结构活性列表
Figure PCTCN2016072266-appb-000143
Figure PCTCN2016072266-appb-000144
表2.式Ⅱ类结构活性列表
化合物 Alphascreen(μM) TSA(℃)
实施例46 >20 3
实施例47 >20 0
实施例48 >20 3.6
实施例49 >20 0
实施例50 >20 1
实施例51 >20 2.4
实施例52 14.51 4
实施例53 >20 0
实施例54 >20 0
实施例55 >20 0
表3.式Ⅲ类结构活性列表
化合物 Alphascreen(μM) TSA(℃)
实施例56 >20 0
实施例57 11.18 4
实施例58 2.7 2
实施例59 >20 1
实施例60 1.77 2
实施例61 >20 2
实施例62 2.49 2
表4.式Ⅳ类结构活性列表
Figure PCTCN2016072266-appb-000145
Figure PCTCN2016072266-appb-000146
四个表中的部分化合物表现出与阳性对照JQ1相当的活性，虽然较JQ1略低，但也显示出较强的活性。特别是实施例1、2、3、4、5、8、9、10、17、18、19、20、21、30、31、78、97、99和100所介绍的化合物与阳性化合物相当，且对比阳性化合物具有结构稳定和容易制备的优点。表1～4分子水平活性数据表明，这些化合物可以有效结合具有bromodomain结构域的蛋白。因此充分表明这类化合物具有成为治疗癌症、细胞增值性紊乱、炎症疾病及自身免疫疾病、败血症和病毒感染等疾病的潜力。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (10)

  1. 一种2-氧代-1,2-二氢苯并[cd]吲哚类化合物或其药学上可接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物或溶剂合物，其特征在于，具有式Ⅰ、Ⅱ、Ⅲ或Ⅳ所示的结构：
    Figure PCTCN2016072266-appb-100001
    式Ⅰ中，R1任选自：H或C1～C4直链或支链烷基；R2任选自：C1～C7烷基、C1～C4亚烷基-R6或C0～C4亚烷基-R7-环基；所述的R6任选自-OR8、-COR8、-CONHR8、-COOR8、-S(O)mR8、-S(O)mR8、-NHCOOR8、-NHCOR8或-NH2，其中m为0或2，R8任选自氢或C1～C3烷基；所述R7任选自-COR9、-COOR9、-OR9或不选，其中R9任选自C1～C3亚烷基；所述的环基任选自C3～C10环烷基、苯基或杂环基；
    式Ⅱ中，R1任选自：H或C1～C4直链或支链烷基；R3任选自：C1～C7烷基、C1～C4亚烷基-R6或C0～C4亚烷基-R7-环基；所述的R6任选自-OR8、-COR8、-CONHR8、-COOR8、-S(O)mR8或-S(O)mR8，其中m为0或2，R8任选自氢、C1～C3烷基；所述R7任选-COR9、-COOR9、-OR9或不选，其中R9任选自C1～C3亚烷基；所述的环基任选自C3～C10环烷基、苯基或杂环基；
    式Ⅲ中，R1任选自：H或C1～C4直链或支链烷基；R4任选自：C1～C7烷基、C1～C4亚烷基-R6或C0～C4亚烷基-R7-环基；所述的R6任选自-OR8、-COR8、-CONHR8、-COOR8、-S(O)mR8、-S(O)mR8、-NHCOOR8或-NHCOR8，其中m为0或2，R8任选自氢或C1～C3烷基；所述R7任选自-COR9、-COOR9、-OR9或不选，其中R9任选自C1～C3亚烷基；所述的环基任选自C3～C10环烷基、苯基或杂环基；
    式Ⅳ中，R1任选自：H或C1～C4直链或支链烷基；R5任选自：C1～C7烷基、C1～C4亚烷基-R6或C0～C4亚烷基-R7-环基；以上所述的R6任选自-OR8、-COR8、-CONHR8、-COOR8、-S(O)mR8、-S(O)mR8、-NHCOOR8或-NHCOR8，其中m为0或2，R8任选自氢、C1～C3烷基；所述R7任选自-COR9、-COOR9、-OR9或不选，其中R9任选自C1～C3亚烷基；所述的环基任选自C3～C10环烷基、苯基或杂环基。
  2. 根据权利要求1所述的2-氧代-1,2-二氢苯并[cd]吲哚类化合物或其药学上可接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物或溶剂合物，其特征在于，式Ⅰ、Ⅱ、Ⅲ和Ⅳ中所述R1选自：H、甲基、乙基、丙基、异丙基或叔丁基。
  3. 根据权利要求1所述的2-氧代-1,2-二氢苯并[cd]吲哚类化合物或其药学上可接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物或溶剂合物，其特征在于，
    在式Ⅰ中，所述C0～C4亚烷基-R7-环基中的环基任选自：环丙烷、环丁烷、环戊烷、环己烷、环庚烷、苯基、萘基，氮杂环丁烷、氧杂环丁烷、氮杂环戊烷、氧杂环戊烷、氮杂环己烷、氧杂环己烷、氮杂环己基、咪唑-2-酮基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、嘧啶基、吡咯基、哌嗪基、四氢吡咯基、哌啶基、吗啉基、1,3-二氧戊环基或苯并[d]噻唑基，且所述环烷基被0、1、2或3个任选自卤素、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、氰基、硝基、氨基、酰胺、-COOR10、-COR10、-OR10、-NHCOR10、-NHCOOR10、-C6H5R11、吗啉基、哌啶基、四氢呋喃基或吡啶基基团取代，其中R10任选自氢、C1～C4烷基、苯基，R11任选自C1～C4烷基、卤素、乙酰基、甲氧基或乙氧基；
    在式Ⅱ中，所述C0～C4亚烷基-R7-环基中的环基任选自：环丙烷、环丁烷、环戊烷、环己烷、环庚烷、苯基、氮杂环丁烷、氧杂环丁烷、氮杂环戊烷、氧杂环戊烷、氮杂环己烷、氧杂环己烷、氮杂环己基、吠喃基、噻吩基、噁唑基、异噁唑基、嘧啶基、吡咯基、四氢吡咯基、哌啶基、吗啉基、1,3-二氧戊环基或苯并[d]噻唑基，且所述环烷基被0、1、2或3个任选自卤素、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、氰基、羧基、硝基、氨基、-CONH2、-COOR10、-COR10、-OR10、-NHCOR10、-NHCOOR10、-C6H5R11、吗啉基、哌啶基、四氢呋喃基或吡啶基基团取代，其中R10任选自氢、C1～C4烷基或苯基，R11任选自C1～C4烷基、卤素、乙酰基、甲氧基或乙氧基；
    在式Ⅲ中，所述C0～C4亚烷基-R7-环基中的环基任选自：环丙烷、环丁烷、环戊烷、环己烷、环庚烷、苯基、氮杂环丁烷、氧杂环丁烷、氮杂环戊烷、氧杂环戊烷、氮杂环己烷、氧杂环己烷、氮杂环己基、 咪唑-2-酮基、咪唑基、吠喃基、噻吩基、噁唑基、异噁唑基、嘧啶基、吡咯基、哌嗪基、四氢吡咯基、哌啶基、吗啉基、1,3-二氧戊环基或苯并[d]噻唑基，且所述环烷基被0、1、2或3个任选自卤素、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、氰基、硝基、氨基、-CONH2、-COOR10、-COR10、-OR10、-NHCOR10、-NHCOOR10、-C6H5R11、吗啉基、哌啶基、四氢呋喃基或吡啶基基团取代，其中R10任选自氢、C1～C4烷基、苯基，R11任选自C1～C4烷基、卤素、乙酰基、甲氧基或乙氧基；
    在式Ⅳ中，所述C0～C4亚烷基-R7-环基中的环基任选自：环丙烷、环丁烷、环戊烷、环己烷、环庚烷、苯基、氮杂环丁烷、氧杂环丁烷、氮杂环戊烷、氧杂环戊烷、氮杂环己烷、氧杂环己烷、氮杂环己基、咪唑-2-酮基、吠喃基、噻吩基、噁唑基、异噁唑基、吡咯基、哌嗪基、四氢吡咯基、哌啶基、吗啉基、1,3-二氧戊环基或1H-吲哚基，且所述杂环基可被0、1、2或3个任选自卤素、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、硝基、氨基、酰胺、-COOR9、-COR9、-OR9、-NHCOR9、-NHCOOR9、-C6H5R10、吗啉基、哌啶基、四氢呋喃基、吡啶基基团取代，其中R9任选自C1～C4烷基、苯基，R10任选自氢、C1～C4烷基、卤素、乙酰基、甲氧基或乙氧基。
  4. 根据权利要求1所述的2-氧代-1,2-二氢苯并[cd]吲哚类化合物或其药学上可接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物或溶剂合物，其特征在于，所述的化合物选自下述化合物中的任一一种：
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)丁烷-1-磺酰胺；
    2-氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-氟苯磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)噻吩-2-磺酰胺；
    5-氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2-甲氧基苯磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)环己烷磺酰胺；
    2-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸甲酯；
    2-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-氟苯磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-3-氟苯磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)乙磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-甲氧基苯磺酰胺；
    4-氰基-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-硝基苯磺酰胺；
    4-(叔丁基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-(三氟甲氧基)苯磺酰胺；
    3-氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2-氟苯磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-甲基苯磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2,4-二氟苯磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)丙烷-1-磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)环戊烷磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-(三氟甲基)苯磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-3-(甲基磺酰基)苯磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)萘-2-磺酰胺；
    甲基-4-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸甲酯；
    4-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸；
    3-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸甲酯；
    3-(N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)苯甲酸；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd〕吲哚-6-基)-2,3-二氢苯并[b][1,4]二氧杂环己烯-6-磺酰胺；
    2-溴-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺；
    5-溴-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2-甲氧基苯磺酰胺；
    2,6-二氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2,3-二甲氧基苯磺酰胺；
    3,5-二氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺；
    2,3-二氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯磺酰胺；
    甲基4-((N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)甲基)苯甲酸甲酯；
    4-((N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)甲基)苯甲酸；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-1-(3-氟苯基)甲磺酰胺；
    甲基3-((N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)氨磺酰)甲基)苯甲酸甲酯；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-1-(4-(三氟甲基)苯基)甲磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-1-(对甲苯基)甲磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-1-(2-氟苯基)甲2磺酰胺；
    1-(4-氯苯基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)甲磺酰胺；
    1-(4-氰基苯基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)甲磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-1-(4-氟苯基)甲磺酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4-氟苯甲酰胺；
    2-(4-氯苯基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)乙酰胺；
    2-(3,4-二甲氧基苯基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)乙酰胺；
    2-(2,4-二氯苯基)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)乙酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-3-苯基丙酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-4,4,4-三氟丁酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)丙酰胺；
    4-氯-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)苯甲酰胺；
    N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-2-(对甲苯基)乙酰胺；
    (E)-N-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)-3-(呋喃-2-基)丙烯酰胺；
    1-乙基-6-((3-苯丙基)氨基)苯并[cd]吲哚-2(1H)-酮；
    1-乙基-6-((3-吗啉代丙基)氨基)苯并[cd]吲哚-2(1H)-酮；
    1-乙基-6-((4-甲氧基苄基)氨基)苯并[cd]吲哚-2(1H)-酮；
    1-乙基-6-((4-甲基苄基)氨基)苯并[cd]吲哚-2(1H)-酮；
    1-乙基-6-((4-(三氟甲基)苄基)氨基)苯并[cd]吲哚-2(1H)-酮；
    6-((4-氯苄基)氨基)-1-乙基苯并[cd]吲哚-2(1H)-酮；
    1-乙基-6-((4-氟苄基)氨基)苯并[cd〕吲哚-2(1H)-酮；
    N-((1-乙酰基哌啶-4-取代)甲基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)环己烷甲酰胺；
    1-乙基-N-((3-异丙基-4,5-二氢异恶唑-5–取代)甲基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-E-7磺酰胺；
    N-((3,5-二甲基-4,5-二氢异恶唑-5-基)甲基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-(4-乙酰基苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-(2-氯苄基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-乙基-N-(2-氟苄基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-(1-乙酰基-4–取代)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    叔丁基4-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)哌啶-1-甲酸叔丁酯；
    N-环戊基-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-((1-乙基-2-氧代-1-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)甲基)环戊烷羧酸甲酯；
    1-((1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)甲基)环戊烷羧酸；
    N-(4-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)苯基)乙酰胺；
    2-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)苯甲酸；
    1-乙基-N-(4-氟苯基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-丁基-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-(2-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)乙基)乙酰胺；
    1-乙基-N-(2-(甲基磺酰基)乙基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-乙基-2-氧代-N-(2-(2-氧代咪唑烷-1-基)乙基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    叔丁基(4-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)丁基)氨基甲酸叔丁酯；
    N-(5-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)吡啶-2-基)乙酰胺；
    叔丁基-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)吡咯烷-1-甲酸叔丁酯；
    叔丁基-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)氮杂环丁烷-1-甲酸叔丁酯；
    N-(2-环己基乙基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-乙基-2-氧代-N-(吡咯烷-3-基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-(氮杂环丁烷-3-基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-N-乙基-N-己基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-乙基-2-氧代-N-(2-(吡咯烷-1-基)乙基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-乙基-2-氧代-N-(2-(四氢-2H-吡喃-4-基)乙基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-乙基-2-氧代-N-(四氢呋喃-3-基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-(2-(4-氯苯氧基)乙基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N，1-二乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-乙基-2-氧代-正戊基-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-N-乙基-N-甲基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-环己基-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    叔丁基-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)哌啶-1-羧酸叔丁酯；
    1-N-乙基-N-异丁基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-乙基-2-氧代基-N-丙基-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-乙基-N-(3-(4-甲基哌嗪-1-基)丙基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-乙基-2-氧代-N-(2-(哌啶-1-基)乙基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-(4,4-二乙氧基丁基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    乙基-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)丙酸甲酯；
    1-乙基-N-((1-乙基吡咯烷-2-基)甲基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-乙基-N-(1-甲基哌啶-4-基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-环庚基-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-乙基-2-氧代-N-(四氢-2H-吡喃-4-基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    叔丁基4-(2-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)乙基)哌嗪-1-甲酸叔丁酯；
    N-环己基-1-甲基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-丁基-1-甲基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-环己基-2-氧代-1-丙基-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    2-氧代-N，1-二丙基-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-丁基-2-氧代-1-丙基-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-丁基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-丁基-1-异丁基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-环己基-1-异丁基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-环己基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-(3-乙酰基苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-(4-氯苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    1-乙基-2-氧代-N-苯基-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-(2-氯苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺；
    N-(3-氯苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺。
  5. 一种药物组合物，其特征在于，含有权利要求1～4任一项所述的2-氧代-1,2-二氢苯并[cd]吲哚类化合物或其药学上可接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物或溶剂合物。
  6. 权利要求1～4任一项所述的2-氧代-1,2-二氢苯并[cd]吲哚类化合物或其药学上可接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物或溶剂合物在制备BET bromodomain受体抑制剂中的应用；或在制备治疗癌症、细胞增值性紊乱疾病、炎症疾病及自身免疫疾病、败血症或病毒感染的药物中的应用。
  7. 根据权利要求6所述的应用，其特征在于，所述的癌症为：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。
  8. 根据权利要求6所述的应用，其特征在于，所述的细胞增值性紊乱疾病包括：良性软组织肿瘤、脑和脊髓肿瘤、眼睑和轨道肿瘤、肉芽肿、脂肪瘤、脑膜瘤、多发性内分泌瘤、鼻息肉、垂体肿瘤、泌乳素瘤、脂溢性角质的、胃息肉、甲状腺结节、肝血管瘤、声带结节、息肉、囊肿、藏毛病、皮肤纤维瘤、皮拉尔囊肿或化脓性肉芽肿。
  9. 根据权利要求6所述的应用，其特征在于，所述的炎症疾病包括：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。
  10. 根据权利要求6所述的应用，其特征在于，所述的病毒感染包括：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。
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