CN104530014B - Sulfamide compound of the dihydrobenzo of 2 oxo 1,2 [cd] indoles 6 and combinations thereof and application - Google Patents

Sulfamide compound of the dihydrobenzo of 2 oxo 1,2 [cd] indoles 6 and combinations thereof and application Download PDF

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CN104530014B
CN104530014B CN201410821535.5A CN201410821535A CN104530014B CN 104530014 B CN104530014 B CN 104530014B CN 201410821535 A CN201410821535 A CN 201410821535A CN 104530014 B CN104530014 B CN 104530014B
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indoles
oxo
ethyl
dihydrobenzos
sulfonamide
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CN104530014A (en
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许�永
薛晓纤
张岩
李静
金翔宇
罗小雨
宋宇
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Guangzhou Institute of Biomedicine and Health of CAS
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Guangzhou Institute of Biomedicine and Health of CAS
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Abstract

The present invention relates to a kind of sulfamide compound of 2 oxo 1,2 dihydrobenzo [cd] indoles 6 and combinations thereof and application.The invention provides the compound with the architectural feature of formula I as new vitamin A acid orphan nuclear receptor γ hypotypes (ROR γ) inhibitor, and the application of such compound and its pharmaceutically acceptable salt, isomers, racemic modification, pro-drug cocrystallization compound, hydrate, solvate in the medicine for treating or preventing the gamma regulated relevant diseases of ROR.Importantly, this kind of compound is probably used for the generation for reducing the immune factor related to immunological diseases and mitigates the generation of the symptom and cancer of immunologic derangement.

Description

2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfamide compounds and combinations thereof Thing and application
Technical field
The invention belongs to technical field of chemical medicine, more particularly to a kind of 2- oxos -1,2- dihydrobenzo [cd] indoles - 6- sulfonic acid amide derivatives and its pharmaceutically acceptable salt or stereoisomer and its prodrugs and preparation method, and should Class compound is preparing treatment by the application in the medicine of immune related diseases gamma regulated ROR.
Background technology
Retinoic acid-related orphan nuclear receptor (ROR) is one of member of nuclear receptor family, it can regulate and control a variety of physiology and Biochemical process.ROR families include three types ROR α, ROR β, and ROR γ.Three kinds of different ROR can be in different tissues It is middle to express and regulate and control different physiology courses.ROR α are mainly distributed on liver, skeletal muscle, skin, lung, adipose tissue, kidney, Thymus gland and brain .ROR β sphere of action very littles, mainly acting on central nervous system .ROR γ can express in many tissues, Including liver, animal tallow and skeletal muscle.Mammal lacks the phenomenon that ROR γ show blood glucose reduction.
ROR γ have two kinds of hypotypes：ROR γ 1 and ROR γ t (ROR γ 2).ROR γ 1 are in many tissues, such as：Thymus gland, muscle, Expressed in kidney and liver, and ROR γ t are then only expressed in immunocyte.ROR γ t are believed to modulating T cell auxiliary T The differentiation of cell 17 (Th17).Th17 is the cell of a kind of helper cell, and this cell can produce interleukin-17 (IL-17) With other cytohormones.It has been found that Th17 plays the effect of key in the immunological diseases fermentation of mouse, as encephalomyelitis and glue Former Induced Arthritis.In addition, Th17 have been found to human inflammation's disease and immunologic derangement, e.g., multiple sclerosis, wind Wet arthritis, psoriasis, clone's disease such as disease and asthma have relation.There is now document report ROR γ may be with prostate The generation of cancer is relevant with development.
ROR when no endogenous ligands connect also can controlling gene transcription, in the crystal knot of the ligand binding domain to ROR Find that cholesterol and cholesterol sulfonate can be entered in liganded pockets in structure test.Soon, it is found that some row hydroxyl courages are consolidated 01 derivatives can regulate and control ROR transcriptional activity, however, these cholesterol derivatives whether be ROR endogenous ligands it is also unclear Chu.And then there are some researches show a kind of small-molecule substance T1317 of synthesis can be combined with ROR γ and ROR α and regulate and control theirs Activity, but also other nuclear receptors (LXR α/βs, FXR, PXR) have effect to this compound with least four, so as to limit its conduct Treat the development of immunity disease medicine.Have now been found that a kind of ROR α selective inverse agonist SR3335, to ROR γ and ROR α have inverse agonist SR1001, the ROR γ of double action selective inverse agonist SR2211 and SR1555, and they are all The differentiation of IL-17 cell can be suppressed.GlaxoSmithKline PLC company has delivered a series of patents at present, mentions a kind of virtue Fragrant aminated compounds can suppress ROR acceptors.Also there are article report natural products digoxin and ursolic acid can be as ROR γ's Selective regulation material and the differentiation that IL-17 cell can be suppressed.But further investigations have shown that digoxin There is very strong side effect, ursolic acid also has effect to glucocorticoid receptor.These researchs all show to synthesize ROR γ selectivity Inhibitor has very big potential value as the medicine for suppressing IL-17 expression.
The content of the invention
One of the technical problem to be solved in the invention is to provide a kind of Novel 2-oxo -1,2- dihydrobenzos [cd] Yin Diindyl -6- sulfamide compounds.
The technical scheme for solving above-mentioned technical problem is as follows：
It is an object of the present invention to provide compound shown in a kind of formula (I), itself or its each optical isomer, using upper Acceptable cocrystallization compound, hydrate or solvate：
In formula：
R1Optionally certainly：
1)H；
2)C1~C5Alkyl；
3)C3~C6Cycloalkyl；
R2,R3Optionally certainly：
1)H；
2)C0~C4Alkylidene-R4；
3)C0~C4Alkylidene-R5- cycloalkyl；
4)C0~C4Alkylidene-R5- heterocyclic radical；
R described above4Optionally from-OR6、-COR6、-COOR6、-S(O)mR6、-S(O)mR6, wherein m is 0 or 2,
R6Optionally from C1~C3Alkyl；
The R5Optionally from-COR7、-COOR7, wherein R7Optionally from C1~C3Alkylidene；
The cycloalkyl optionally from phenyl, naphthyl, and the cycloalkyl by 0,1,2 or 3 optionally from halogen, methyl, second Base, propyl group, isopropyl, the tert-butyl group, trifluoromethyl, cyano group, carboxyl, nitro, amino, phenyl-diazenyl ,-CONH2、- COOR8、-COR8、-OR8、-NHCOR8、-NHCOOR8、-C6H5R9, morpholinyl, piperidyl, tetrahydrofuran base, Pyridyl residues take Generation, wherein R8Optionally from C1~C4Alkyl, phenyl, R9Optionally from C1~C4Alkyl, halogen, acetyl group, methoxyl group, ethyoxyl；
The heterocyclic radical is optionally from imidazole radicals, triazolyl, pyrazolyl, base, thienyl, oxazolyl, isoxazolyls, the pyrrole of muttering of barking Piperazine base, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, piperazinyl, nafoxidine base, piperidyl, morpholinyl, 1,3- dioxolanes Base, isoquinolyl, indoline base, 1H- indazolyls, 1H- benzos [d] imidazole radicals, 1H- indyls, benzo [d] [1,3] dioxa Cyclopentenyl, benzo [d] thiazolyl, H- pyrazoles -3 (2H) -one base, and the heterocyclic radical can be by 0,1,2 or 3 optionally from halogen Element, methyl, ethyl, propyl group, isopropyl, the tert-butyl group, trifluoromethyl, cyano group, carboxyl, nitro, amino, phenyl-diazenyl ,- CONH2、-COOR8、-COR8、-OR8、-NHCOR8、-NHCOOR8、-C6H5R9, morpholinyl, piperidyl, tetrahydrofuran base, pyridine radicals Group substitutes, wherein R8Optionally from C1~C4Alkyl, phenyl, R9Optionally from C1~C4Alkyl, halogen, acetyl group, methoxyl group, ethoxy Base；
R2And R3It is asynchronously H.
In one of the embodiments, the R1It is selected from：
1)H；
2) methyl, ethyl, propyl group, isopropyl, the tert-butyl group；
3) cyclopropyl, cyclobutyl, cyclohexyl.
In one of the embodiments, the R2, R3Optionally certainly：
1)C1-C3Alkylidene-R4, R4Optionally from-OR6、-COR6、-COOR6、-S(O)2R6、-S(O)2R6, R6Optionally from hydrogen, C1~C3Alkyl；
2)C0~C4Alkylidene-R5- cycloalkyl, R5Optionally from-COR7、-COOR7, wherein R7Optionally from C1~C3Alkylidene； Cycloalkyl is optionally from phenyl, naphthyl, wherein cycloalkyl described above can be by 0,1,2 or 3 optionally from fluorine, chlorine, bromine, fluoroform Base, carboxyl, phenyl-diazenyl ,-CONH2、-COOR8、-COR8、-OR8、-NHCOR8、-NHCOOR8、-C6H5R9, morpholinyl, piperazine Piperidinyl, tetrahydrofuran base, Pyridyl residues substitution, wherein R8Optionally from C1~C4 alkyl, phenyl, R9Optionally from methyl, ethyl, Isopropyl, the tert-butyl group, fluorine, chlorine, bromine, acetyl group, methoxyl group, ethyoxyl；
3)C0~C4Alkylidene-R5- heterocyclic radical, R5Optionally from-COR7、-COOR7, wherein R7Optionally from C1~C3Alkylidene； Heterocyclic radical optionally from imidazole radicals, pyrazolyl, bark mutter base, thienyl, oxazolyl, isoxazolyls, pyridine radicals, pyrimidine radicals, pyrrole radicals, Nafoxidine base, piperidyl, morpholinyl, 1,3- dioxolanyls, isoquinolyl, indoline base, 1H- indazolyls, 1H- benzos [d] imidazole radicals, 1H- indyls, benzo [d] [1,3] dioxa cyclopentenyl, benzo [d] thiazolyl, H- pyrazoles -3 (2H) -one Base, wherein heterocyclic radical described above can be by 0,1,2 or 3 optionally from fluorine, chlorine, bromine, methyl, ethyl, propyl group, isopropyl, tertiary fourth Base, trifluoromethyl, carboxyl ,-CONH2、-COOR8、-COR8、-OR8、-NHCOR8、-NHCOOR8、-C6H5R9, morpholinyl, piperidines Base, tetrahydrofuran base, Pyridyl residues substitution, wherein R8Optionally from C1~C4Alkyl, phenyl, R9Optionally from methyl, ethyl, different Propyl group, the tert-butyl group, fluorine, chlorine, bromine, acetyl group, methoxyl group, ethyoxyl.
Further, in one of the embodiments, R1It is selected from：
1)H；
2) ethyl；
R2, R3It is selected from：
1)H；
2) phenyl, it can be by 1 or 2 or 3 methoxyl groups, ethyoxyl, formoxyl, the tert-butyl group, morpholinyl, phenyl phenodiazine Alkenyl, phenoxy group, formamido, t-butyl carbamate substitution；
3) quinoline, isoquinolin, benzothiazole, it optionally can substitute by 0 or 1 ethyoxyl.
It is a further object of the present invention to provide the application of above-claimed cpd.
Concrete technical scheme is as follows：Above-claimed cpd or its pharmaceutically acceptable salt, isomers, racemic modification, precursor The application of medicine cocrystallization compound, hydrate, solvate in ROR γ acceptor inhibitors are prepared.
Above-claimed cpd or its pharmaceutically acceptable salt, isomers, racemic modification, pro-drug cocrystallization compound, Hydrate, solvate are preparing treatment encephalomyelitis, Collagen-induced Arthritis, multiple as ROR γ acceptor inhibitors Sclerosis, rheumatic arthritis, psoriasis, clone's disease, asthma and prostate cancer medicine in application.
It is a further object of the present invention to provide a kind of pharmaceutical composition.
Concrete technical scheme is as follows.
A kind of pharmaceutical composition as ROR γ acceptor inhibitors, its active component include above-claimed cpd or its medicine Acceptable salt, isomers, racemic modification, pro-drug cocrystallization compound, hydrate, solvate on.
The invention provides 2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamides with Formulas I architectural feature Compound.It has been investigated that such compound can effectively suppress ROR γ acceptors, so as to regulate and control Th17 differentiation, treatment brain can be used as Myelitis, Collagen-induced Arthritis, multiple sclerosis, rheumatic arthritis, psoriasis, clone's disease, asthma and forefront The medicine of the inflammation associated class disease such as gland cancer.
Brief description of the drawings
Fig. 1 illustrate inhibitory activity of the embodiment 1-91 compounds to ROR γ albumen.
Fig. 2 illustrate the embodiment 1-91 compounds inhibitory activity horizontal to ROR gamma cellses.
Embodiment
In chemicals of the present invention, as any variable (such as R1、R2Deng) occur more than once in any component, then Its definition occurred every time is independently of other definition occurred every time.Equally, it is allowed to the combination of substituent and variable, as long as this Combination makes compound stable.The line that loop system is included in from substituent represents that signified key may be connected to any annular atom that can substitute On.If loop system is polycyclic, it means that this key, which is connected only on any appropriate carbon atom of adjacent loops, is appreciated that this Field those of ordinary skill may be selected the compounds of this invention substituent and substitution pattern and provide chemically stable and can lead to Cross the compound that the method for art technology and following proposition is readily synthesized from readily available raw material.If instead of base certainly Body is exceeded a group substitution, it should be understood that these groups can be in identical carbon atoms or on different carbon atoms, as long as making structure Stable phrases " being optionally substituted by one or more substituents " are considered as " optionally being substituted " phase by least one substituent with phrase When and preferred embodiment will have 0-3 substituent in the case.
Terms used herein " alkyl " and " alkylidene " mean to include the side chain and straight chain with particular carbon atom number Saturated fat alkyl.For example, in " C1-C4 " alkyl " C1-C4 " definition include with straight or branched arrangement have 1,2, 3rd, 4, the group of carbon atom.For example, " C1-C4 " alkyl " specifically includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary fourth Base, isobutyl group.Term " cycloalkyl " refers to the monocyclic saturated fat alkyl with particular carbon atom number.Such as " cycloalkyl " includes Cyclopropyl, methyl-cyclopropyl, 2,2- dimethyl-cyclobutyls, 2- ethyI-cyclopentyls, cyclohexyl etc..
Unless otherwise defined, alkyl, cycloalkyl and heterocyclyl substituent can be unsubstituted or substitution.For example, (C1-C4) alkyl can be selected from OH, halogen, alkoxy, dialkyl amido or heterocyclic radical, such as morpholine by one, two or three The substituent substitution of base, piperidyl etc..
The present invention includes the free form of type I compound, also including its pharmaceutically acceptable salt and stereoisomer.This The specific exemplary compounds of some in text are the protonated salt of aminated compounds.Term " free form " refers to non-salt shape The aminated compounds of formula.The pharmaceutically-acceptable salts being included not only include the exemplary salt of specific compound described herein, Also the typical pharmaceutically acceptable salt of all type I compound free forms is included.Techniques known in the art separation can be used The free form of the compound specific salts.For example, can be by using appropriate alkali dilute aqueous solution such as NaOH dilute aqueous solutions, carbonic acid Potassium dilute aqueous solution, weak aqua ammonia and sodium acid carbonate dilute aqueous solution, which handle the salt, regenerates free form.Free form is in some physics Property for example in polar solvent each more or less distinguish with its in solubility by salt form, but is this acid of purpose of invention Each free form is suitable with its in terms of other pharmacy for salt and alkali salt.
It can synthesize the present invention's from containing the compounds of this invention of basic moiety or acidic moiety by conventional chemical processes Pharmaceutically acceptable salt.Generally, by ion-exchange chromatography or free alkali and stoichiometric amount or the required salt of excess are passed through The reaction in the combination of appropriate solvent or multi-solvents of the inorganic or organic acid of form prepares the salt of alkali compounds.Similar, The salt of acid compound is formed by being reacted with appropriate inorganic or organic base.
Therefore, the pharmaceutically acceptable salt of the compounds of this invention is included by alkaline the compounds of this invention and inorganic or have The conventional non-toxic salts for the compounds of this invention that machine acid reaction is formed.For example, conventional nontoxic salts include deriving from inorganic acid such as salt The salt of acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid etc., also include from organic acid such as acetic acid, propionic acid, butanedioic acid, second Alkyd, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, flutter acid, maleic acid, hydroxymaleic acid, phenylacetic acid, Glutamic acid, benzoic acid, salicylic acid, p-aminobenzene sulfonic acid, the benzoic acid of 2 one acetoxyl group one, fumaric acid, toluenesulfonic acid, methanesulfonic acid, The salt of the preparations such as ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid.
If the compounds of this invention is acid, appropriate " pharmaceutically acceptable salt " refers to by pharmaceutically acceptable Nontoxic alkali include salt prepared by inorganic base and organic base and derive from the salt of inorganic base including aluminium salt, ammonium salt, calcium salt, mantoquita, iron Salt, ferrous salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt etc..Particularly preferred ammonium salt, calcium salt, magnesium salts, sylvite And sodium salt.Salt derived from pharmaceutically acceptable organic nontoxic alkali, the alkali includes the salt of primary amine, secondary amine and tertiary amine, substituted Amine include naturally occurring substitution amine, cyclic amine and deacidite for example arginine, glycine betaine, caffeine, choline, N, N'- dibenzyl-ethylenediamin, diethylamine, 2- DEAE diethylaminoethanols, DMAE, ethylaminoethanol, monoethanolamine, second Diamines, N-ethylmorpholine, N-ethylpiperidine, gucosamine, Glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, Methyl glucose osamine, morpholine, piperazine, piperidines, croak smack one's lips, more polyimide resins, procaine, purine, theobromine, triethylamine, trimethylamine, Tripropyl amine (TPA), tromethamine etc..
Because the acidic moiety such as carboxyl of deprotonation in compound in physiological conditions can be anion, and it is this The electric charge carried then can be by internal protonated or alkylation the basic moiety such as quaternary nitrogen atom with cation Balance is offset, it is noted that the compounds of this invention is potential inner salt or amphion.
In addition to known in the literature or the illustration in experimental arrangement standard method, it can use as shown in following scheme Reaction prepare the compounds of this invention.Therefore, following illustrative approach is to be the purpose illustrated without being limited to listed chemical combination Thing or any specific substituent.The substituent number shown in scheme not necessarily meets number used in claim, And for clarity, showing monosubstituted base to be connected under the hereinbefore definition of Formulas I allows to have in the compound of multi-substituent.
Scheme
The compound as shown in scheme can be that initiation material is synthesized by the reaction of 5 steps by 1,8- naphthalic anhydrides.
Compound and its pharmaceutically acceptable salt involved by the application can be following for treating according to following method Disease and the Other diseases do not listed below：1) encephalomyelitis；2) Collagen-induced Arthritis；3) multiple sclerosis； 4) rheumatic arthritis；5) psoriasis；6) disease is cloned；7) asthma；8) prostate cancer.
Further aspect of the present invention provides a kind of pharmaceutical composition, including formula of the present invention (I) compound and it is a kind of or Several pharmaceutically acceptable auxiliary materials.Composition of the present invention can be liquid, semiliquid or solid form, according to suitable Prepared in the mode of method of administration used..Compound of the present invention is applicable to various methods of administration when in use, bag Include but be not limited to following approach, oral, cheek, suction, sublingual, rectum, vagina, it is intracisternal or intrathecal, pass through lumbar puncture, warp Urethra, through skin or parenteral (including intravenous injection, intramuscular injection, subcutaneous, row intracutaneous injection, intraperitoneal, intrathecal, operation are implanted into) Deng.
Orally administered composition can be solid, gel or liquid.The example of solid pharmaceutical preparation includes but is not limited to tablet, capsule Agent, granule and bulk powder.These preparations can selectively contain adhesive, diluent, disintegrant, lubricant, glidant, Sweetener and flavouring etc..The example of adhesive includes but is not limited to microcrystalline cellulose, glucose solution, mucialga of arabic gummy, bright Sol solution, sucrose and gelatinized corn starch；The example of lubricant includes but is not limited to talcum, starch, magnesium stearate, calcium stearate, tristearin Acid；The example of diluent includes but is not limited to lactose, sucrose, starch, mannitol, Dicalcium Phosphate；The example of glidant includes But it is not limited to silica；The example of disintegrant includes but is not limited to Ac-Di-Sol, primojel, algae Acid, cornstarch, farina, methylcellulose, agar and carboxymethyl cellulose.
The present composition is given with parenteral, typically based on injection, including subcutaneous, intramuscular or intravenous injection.Note Any conventionally form can be made into by penetrating agent, such as liquid solution or suspension, be suitable for being dissolved or suspended in liquid before injection In solid form or emulsion.Example available for the carrier of the pharmaceutical acceptable of injection of the present invention includes but is not limited to Aqueous carrier, non-aqueous carrier, antimicrobial, isotonic agent, buffer, antioxidant, suspension and dispersant, emulsifying agent, chelating Agent and other pharmaceutically acceptable materials.The example of aqueous carrier includes sodium chloride injection, woods form parenteral solution, isotonic Portugal Grape sugar parenteral solution, Sterile Water Injection, glucose and Lactated ringer's injection；The example of non-aqueous carrier comes including plant Fixing oil, cottonseed oil, corn oil, sesame oil and the peanut oil in source；The example of antimicrobial includes metacresol, benzylalcohol, neoprene Alcohol, benzalkonium chloride etc.；The example of isotonic agent includes sodium chloride and glucose；Buffer includes phosphate and citrate.
Inventive composition can also be prepared into sterile freeze drying powder injection, and compound is dissolved in into buffer solution of sodium phosphate, its In containing glucose or other suitable excipient, it is then under standard conditions well known by persons skilled in the art that solution is sterile Filtering, is followed by freeze-drying, obtains required preparation.
The present invention will be further described for following examples, but the embodiment is not intended to limit the protection model of the present invention Enclose.
Embodiment 1
1- ethyl-2-oxos-N- (2- oxos -2- (pyrrolidines -1- substitutions) ethyl) -1,2- dihydrobenzos [cd] indoles - 6- sulfonamide (E1)
(1-ethyl-2-oxo-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1,2-dihydrobenzo [cd]indole-6-sulfonamide)(E1)
Non- that alkene -2- bases 4- toluene sulfonic acide esters of step 1.1,3- dioxo -2,3- dihydros -1H-
(1,3-dioxo-2,3-dihydro-1H-phenalen-2-yl 4-methylbenzenesulfonate)
Added in round-bottomed flask 1,8- naphthalic anhydrides (1-1) (11.9g, 0.06mol), hydroxylamine hydrochloride (4.18g, 0.06mol) with pyridine (70mL), backflow 1 hour is heated to.Be cooled to 80 DEG C, rapidly join 4- toluene sulfochlorides (22.88g, 0.12mol), it is warming up to back flow reaction 1.5 hours.Room temperature is cooled to, mixture is poured into 200g frozen water, stirring has yellow Precipitation.Stand, filter, washing three times, saturated solution of sodium bicarbonate agitator treating, is filtered, and washing three times, is obtained in 17g Mesosome 1-2 (78%).
Step 2. benzo [cd] indoles -2 (1H) -one (benzo [cd] indol-2 (1H)-one)
Be separately added into compound 1-2 (17g, 0.048mol) in round-bottomed flask, 50mL ethanol, 40mL water and 2.7mol/L sodium hydroxide solution 60mL, is heated to reflux 3h, cools down and ethanol is removed under reduced pressure, and hydrochloric acid is instilled at 75 DEG C, adjusts PH to 3 is saved, there is yellow mercury oxide precipitation, is filtered, column chromatography obtains 6.65g yellow solids 1-3 (82%).
MS(ESI),m/z:M+170.0
Step 3.1- ethyls benzo [cd] indoles -2 (1H) -one (1-ethylbenzo [cd] indol-2 (1H)-one)
Compound 1-3 (6.65g, 0.039mol) is added in round-bottomed flask and adds 100mLN, dinethylformamide is made For solvent, sodium hydride (2.81g, 0.117mol) is added under ice bath, stirs 5min, instills iodopropane (7.33g, 0.047mol), 10min, room temperature reaction, TLC monitoring reactions is added dropwise in low temperature；Water quenching is instilled after question response is complete, under ice bath to go out reaction；With acetic acid second Ester is extracted three times, merges organic layer, and saturated sodium-chloride water solution is washed once, and anhydrous sodium sulfate drying is overnight, is spin-dried for, and obtains 6.46g yellow solids 1-4 (84%).MS(ESI),m/z:M+198.0
Step 4.1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonic acid chlorides
(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonyl chloride)
By compound 1-4 (6.46g, 0.033mol) by the use of 100mL chloroforms as reaction dissolvent, chlorosulfonic acid is added dropwise under ice bath (11.5g, 0.099mol), 10min is stirred, be warming up to 50 DEG C, react 6h；Reactant mixture is poured into frozen water, stirred to nothing Gas escapes, and with dichloromethane aqueous layer extracted three times, merges organic layer, saturated sodium-chloride water solution is washed once, anhydrous sodium sulfate Dry, column chromatography, obtain 5.75g yellow greenish powder shape solid 1-5 (59%).MS(ESI),m/z:M+297.1
Step 5.1- ethyl-2-oxos-N- (2- oxos-2- (pyrrolidines-1-substitution) ethyl)-1,2- dihydrobenzos [cd] Indoles -6- sulfonamide (E1)
(1-ethyl-2-oxo-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1,2-dihydrobenzo [cd]indole-6-sulfonamide)(E1)
1- ethyl-2-oxos -1,2- dihydrobenzo [cd] indoles -6- sulfonic acid chlorides (100mg, 0.34mmol) are dissolved in 10ml In dichloromethane, add 2- amino -1- (pyrrolidin-1-yl) ethyl ketone (52mg, 0.41mmol) and 2mlDIPEA, room temperature reaction is added dropwise 5h, after reaction completely, washing, dichloromethane is extracted three times, merges organic layer, and saturated sodium-chloride water solution is washed once, anhydrous sulphur Sour sodium is dried, column chromatography DCM:Methanol=100:1-20:1, obtain 92mg yellow greenish powder shape solids, yield 70%.
1H-NMR (400MHz, d-DMSO) δ 8.70 (d, J=8.4Hz, 1H), 8.13 (d, J=10.8Hz, 1H), 8.07 (d, J=7.6Hz, 1H), 7.96-7.89 (m, 2H), 7.28 (d, J=7.2Hz, 1H), 3.91 (q, J=7.2Hz, 2H)), 3.66 (d, J=5.6Hz, 1H), 3.25 (t, J=6.5Hz, 2H), 3.00 (t, J=6.7Hz, 2H), 1.75-1.72 (m, 2H), 1.62- 1.58 (m, 2H), 1.25 (t, J=6.9Hz, 3H) .MS (ESI), m/z:M+388.0；M-386.0.
Embodiment 2
N- ((1- Acetylpiperidins -4- substitutions) methyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulphurs Acid amides (E2)
(N-((1-acetylpiperidin-4-yl)methyl)-1-ethyl-2-oxo-1,2-dihydrobenzo [cd]indole-6-sulfonamide)(E2)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.69 (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.
Embodiment 3
1- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) cyclohexane carboxamide (E3)
(N-(1-acetylcyclohexyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E3)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.58 (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.
Embodiment 4
1- ethyls-N- (2- (ethylsulfonyl) ethyl) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E4)
(1-ethyl-N-(2-(ethylsulfonyl)ethyl)-2-oxo-1,2-dihydrobenzo[cd]indole- 6-sulfonamide)(E4)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.67 (d, J=8.4Hz, 1H), 8.17-8.10 (m, 2H), 7.97 (t, J= 8.0Hz, 1H), 7.35 (d, J=7.6Hz, 1H), 3.95 (q, J=6.8Hz, 2H), 3.18-3.04 (m, 6H), 1.26 (t, J= 6.8Hz, 3H), 1.13 (t, J=7.2Hz, 2H) .MS (ESI), m/z:M-395.0.
Embodiment 5
N- ((3,5- dimethyl -4,5- dihydro-isoxazoles -5- substitutions) methyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E5)
(1-ethyl-N-((4-methylmorpholin-2-yl)methyl)-2-oxo-1,2-dihydrobenzo [cd]indole-6-sulfonamide)(E5)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.68 (d, J=8.4Hz, 1H), 8.16 (d, J=7.2Hz, 1H), 8.06 (d, J=7.6Hz, 1H), 7.99 (t, J=6.0Hz, 1H), 7.92 (t, J=7.6Hz, 1H), 7.28 (d, J=7.6Hz, 1H), 3.93 (q, J=7.2Hz, 1H), 3.54 (d, J=10.8Hz, 2H), 3.18 (t, J=10.4Hz, 1H), 2.82 (t, J=6.0Hz, 2H), 2.49-2.39 (m, 2H), 1.98 (s, 3H) .1.75 (t, J=8.4Hz, 1H), 1.44 (t, J=10.8Hz, 1H), 1.27- 1.23(m,4H).MS(ESI),m/z:M-388.1.
Embodiment 6
1- ethyls-N- ((3- isopropyl -4,5- dihydro-isoxazoles -5- substitutions) methyl) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E6)
(1-ethyl-N-((3-isopropyl-4,5-dihydroisoxazol-5-yl)methyl)-2-oxo-1,2- dihydrobenzo[cd]indole-6-sulfonamide)(E6)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.70 (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.
Embodiment 7
N- ((3,5- dimethyl -4,5- dihydro-isoxazole -5- bases) methyl) -1- ethyl-2-oxo -1,2- dihydrobenzos (cd] indoles -6- sulfonamide (E7)
(N-((3,5-dimethyl-4,5-dihydroisoxazol-5-yl)methyl)-1-ethyl-2-oxo-1,2- dihydrobenzo[cd]indole-6-sulfonamide)(E7)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.72 (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.
Embodiment 8
1- ethyls-N- ((5- methyl isophthalic acid H- indazole -3- bases) methyl) -2- oxo -1,2- dihydrobenzos (cd] indoles -6- sulphurs Acid amides (E8)
(1-ethyl-N-((5-methyl-1H-indazol-3-yl)methyl)-2-oxo-1,2-dihydrobenzo [cd]indole-6-sulfonamide)(E8)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 12.49 (s, 1H), 8.59 (d, J=8.4Hz, 1H), 8.39 (t, J= 5.6Hz, 1H), 8.03 (d, J=7.2Hz, 1H), 7.83 (q, J=7.2Hz, 1H), 7.76 (d, J=7.6Hz, 1H), 7.07 (d, J=8.4Hz, 1H), 6.97 (d, J=7.6Hz, 1H), 6.87 (s, 1H), 6.81 (d, J=8.4Hz, 1H), 4.33 (d, J= 5.6Hz, 2H), 3.85 (q, J=7.2Hz, 2H), 1.98 (s, 3H), 1.27 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M+ 421.0；M-419.0.
Embodiment 9
1- ethyls-N- ((4- methyl -6- (trifluoromethyl) pyrimidines -2- substitutions) methyl) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E9)
(1-ethyl-N-((4-methyl-6-(trifluoromethyl)pyrimidin-2-yl)methyl)-2- oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E9)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.72 (t, J=6.4Hz, 1H), 8.61 (d, J=8.4Hz, 1H), 8.08 (d, J=6.8Hz, 1H), 7.89-7.84 (m, 2H), 7.43 (s, 1H), 7.07 (d, J=7.6Hz, 1H), 4.36 (d, J=6.4Hz, 1H), 3.87 (q, J=7.2Hz, 2H), 2.09 (s, 3H), 1.22 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M-449.0.
Embodiment 10
The tert-butyl group (3- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) phenyl) amino first Tert-butyl acrylate (E10)
(tert-butyl(3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamido)phenyl)carbamate)(E10)
1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonic acid chlorides synthetic method such as embodiment 1.
Take 1- ethyl-2-oxos -1,2- dihydrobenzo [cd] indoles -6- sulfonic acid chlorides (60mg, 0.203mmol), DAMP (5mg, 0.041mmol) and the tert-butyl group (3- aminophenyls) t-butyl carbamate (85mg, 0.406mmol) are dissolved in 10mLDMF In, add triethylamine 2mL.Overnight, after reaction completely, washing, ethyl acetate extracts three times, merges organic layer for room temperature reaction, 10% hydrochloric acid 50mL is washed once, and saturated sodium-chloride water solution is washed once, anhydrous sodium sulfate drying, column chromatography, it is yellowish green to obtain 54mg Color pulverulent solids, yield 58%.
1H-NMR (400MHz, d-DMSO) δ 8.58 (d, J=8.4Hz, 1H), 8.17 (d, J=8.0Hz, 1H), 8.00 (d, J=7.2Hz, 1H), 7.68 (d, J=7.6Hz, 1H), 7.17 (s, 1H), 7.01 (t, J=8.2Hz, 2H), 6.83 (d, J= 7.6Hz, 1H), 6.73 (d, J=7.2Hz, 1H), 6.63 (s, 1H), 3.91 (dd, J=14.2Hz, 7.0Hz, 2H), 1.43 (s, 9H), 1.25 (t, J=7.0Hz, 3H) .MS (ESI), m/z:M-446.1.
Embodiment 11
N- (3,4- Dimethoxyphenyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E11)
(N-(3,4-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E11)
Synthetic method such as embodiment 10.
1H-NMR (400MHz, d-DMSO) δ 8.55 (d, J=8.4Hz, 1H), 8.04 (t, J=3.6Hz, 2H), 7.72 (t, J=7.4Hz, 1H), 7.36-7.23 (m, 1H), 6.82 (d, J=7.6Hz, 1H), 6.64 (s, 1H), 6.55 (d, J=8.8Hz, 1H), 6.41 (d, J=8.4Hz, 1H), 3.93 (dd, J=14.0Hz, 6.8Hz, 2H), 3.73 (s, 3H), 3.65 (s, 3H), 1.24 (t, J=7.0Hz, 3H) .MS (ESI), m/z:M+413.1；M-411.0.
Embodiment 12
1- ethyls-N- ((1- methyl -5- (trifluoromethyl) -1H- benzo [d] imidazoles -2- substitutions) methyl) -2- oxo -1, 2- dihydrobenzos [cd] indoles -6- sulfonamide (E12)
(1-ethyl-N-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E12)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.70 (t, J=6.0Hz, 1H), 8.56 (d, J=8.4Hz, 1H), 7.96 (d, J=7.2Hz, 1H), 7.91 (d, J=7.6Hz, 1H), 7.85 (t, J=8.0Hz, 1H), 7.49 (s, 1H), 7.35 (s, 1H), 6.95 (d, J=7.6Hz, 1H), 4.41 (d, J=5.6Hz, 2H), 3.73 (q, J=7.2Hz, 2H), 3.51 (s, 3H), 1.14 (t, J=7.2Hz, 3H)
MS(ESI),m/z:M+489.0；M-487.0.
Embodiment 13
1- ethyls-N- ((the fluoro- 1H- indoles -2- substitutions of 5-) methyl) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulphurs Acid amides (E13)
(1-ethyl-N-((5-fluoro-1H-indol-2-yl)methyl)-2-oxo-1,2-dihydrobenzo [cd]indole-6-sulfonamide)(E13)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 10.78 (s, 1H) 8.68 (d, J=8.4Hz, 1H), 8.33 (t, J=5.6Hz, 1H), 8.04-8.01 (m, 2H), 7.88 (d, J=7.6Hz, 1H), 7.16 (d, J=7.6Hz, 1H), 7.09 (t, J=4.8Hz, 1H), 6.94 (dd, J=2.4Hz, J=2.0Hz, 1H), 6.77-6.72 (m, 1H), 5.94 (s, 1H), 4.13 (d, J=5.6Hz, 2H), 3.87 (q, J=7.2Hz, 2H), 1.23 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M-422.0.
Embodiment 14
1- ethyls-N- ((5- methoxyl group-1H- indoles-2-substitution) methyl)-2- oxo base-1,2- dihydrobenzos [cd] Yin Diindyl -6- sulfonamide (14)
(1-ethyl-N-((5-methoxy-1H-indol-2-yl)methyl)-2-oxo-1,2-dihydrobenzo [cd]indole-6-sulfonamide)(E14)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 10.51 (s, 1H), 8.65 (d, J=12.4Hz, 1H), 8.26 (t, J= 6.0Hz, 1H), 8.05-8.01 (m, 2H), 7.87 (t, J=7.6Hz, 1H), 7.14 (d, J=7.6Hz, 1H), 7.02 (d, J= 8.4Hz, 1H), 6.68 (s, 1H), 6.56 (dd, J=1.6Hz, J=1.6Hz, 1H), 5.82 (s, 1H), 4.11 (d, J= 6.0Hz, 2H), 3.86 (q, J=7.2Hz, 2H), 3.66 (s, 1H) .1.28 (t, J=6.8Hz, 3H) .MS (ESI), m/z:M+ 436.0；M-434.0.
Embodiment 15
1- ethyls-N- (3- methyl isophthalic acids-(pyridine -3- substitutions) butyl) -2- oxo -1,2- dihydrobenzo [cd] indoles -6- Sulfonamide (E15)
(1-ethyl-N-(3-methyl-1-(pyridin-3-yl)butyl)-2-oxo-1,2-dihydrobenzo [cd]indole-6-sulfonamide)(E15)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.53 (d, J=8.4Hz, 1H), 8.44 (d, J=9.2Hz, 1H), 8.05 (d, J=7.2Hz, 1H), 7.99 (s, 1H), 7.92-7.82 (m, 3H), 7.21 (d, J=7.6Hz, 1H), 7.05 (d, J=7.6Hz, 1H), 6.65 (dd, J=4.8Hz, J=4.8Hz, 2H), 4.17 (q, J=9.2Hz, 1H), 9.91-3.80 (m, 2H), 1.57- 1.50 (m, 1H), 1.45-1.39 (m, 1H) .0.76 (d, J=5.6Hz, 3H), 0.69 (d, J=6.4Hz, 3H) .MS (ESI), m/ z:M-442.1.
Embodiment 16
1-N- (4- chloro- 3- (trifluoromethyl) phenyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulphonyl Amine (E16)
(N-(4-chloro-3-(trifluoromethyl)phenyl)-1-ethyl-2-oxo-1,2- dihydrobenzo[cd]indole-6-sulfonamide)(E16)
Synthetic method such as embodiment 10.
1H-NMR (400MHz, d-DMSO) δ 11.12 (s, 1H), 8.65 (d, J=8.4Hz, 1H), 8.19 (d, J= 7.6Hz, 1H), 8.14 (d, J=6.8Hz, 1H), 7.96 (t, J=7.8Hz, 1H), 7.53 (d, J=8.8Hz, 1H), 7.46 (d, J=1.6Hz, 1H), 7.31 (dd, J=14.2Hz, 8.2Hz, 2H), 3.89 (dd, J=14.2Hz, 7.0Hz, 2H), 1.23 (t, J =7.0Hz, 3H)
MS(ESI),m/z:M+457.0；M-453.0.
Embodiment 17
N- (4- acetylphenyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E17)
(N-(4-acetylphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E17)
Synthetic method such as embodiment 10.
1H-NMR (400MHz, d-DMSO) δ 10.82 (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.
Embodiment 18
N- (benzo [d] [1,3] dioxole-5-substituent methyl)-1- ethyl-2-oxo-1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E18)
(N-(benzo[d][1,3]dioxol-5-ylmethyl)-1-ethyl-2-oxo-1,2-dihydrobenzo [cd]indole-6-sulfonamide)(E18)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.62 (d, J=8.4Hz, 1H), 8.31 (t, J=6.4Hz, 1H), 8.11 (d, J=6.8Hz, 1H), 8.01 (d, J=7.6Hz, 1H), 7.90 (t, J=7.6Hz, 1H), 7.21 (d, J=7.6Hz, 1H), 6.54 (d, J=7.6Hz, 1H), 6.46 (d, J=7.6Hz, 2H), 5.80 (s, 2H), 3.91 (d, J=6.8Hz, 1H), 1.27 (t, J= 6.8Hz,3H).MS(ESI),m/z:M+411.0；M-409.1.
Embodiment 19
1- ethyls-N- (4- morphlinophenyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E19)
(1-ethyl-N-(4-morpholinophenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E19)
Synthetic method such as embodiment 10.
1H-NMR (400MHz, d-DMSO) δ 10.08 (s, 1H), 8.65 (d, J=8.4Hz, 1H), 8.11 (d, J= 6.8Hz, 1H), 8.00 (d, J=7.6Hz, 1H), 7.86 (t, J=8.4Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 6.87 (d, J=8.8Hz, 2H), 6.70 (d, J=9.2Hz, 2H), 3.87 (q, J=6.8Hz, 2H), 3.62-3.60 (m, 4H), 2.91- 2.89 (m, 4H), 1.22 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M+438.0；M-436.0.
Embodiment 20
1- ethyl-2-oxos-N- (pyridine -2- ylmethyls) -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E20)
(1-ethyl-2-oxo-N-(pyridin-2-ylmethyl)-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E20)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.66 (d, J=8.4Hz, 1H), 8.49 (t, J=6.0Hz, 1H), 8.21 (d, J=4.4Hz, 1H), 8.11 (d, J=6.8Hz, 1H), 8.02 (d, J=7.6Hz, 1H), 7.91 (t, J=8.0Hz, 1H), 7.50-7.46 (m, 1H), 7.20-7.15 (m, 2H), 7.05-7.02 (m, 1H), 4.11 (d, J=6.4Hz, 2H), 3.89 (q, J =7.2Hz, 2H), 1.26 (t, J=6.8Hz, 3H) .MS (ESI), m/z:M+368.0；M-366.0.
Embodiment 21
1- ethyls-N- (4- methyl-benzyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E21)
(1-ethyl-N-(4-methylbenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E21)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.64 (d, J=8.4Hz, 1H), 8.33 (t, J=6.4Hz, 1H), 8.11 (d, J=7.2Hz, 1H), 8.01 (d, J=7.6Hz, 1H), 7.88 (t, J=7.6Hz, 1H), 7.19 (t, J=7.6Hz, 1H), 6.89 (d, J=8.0Hz, 2H), 6.81 (d, J=8.0Hz, 2H), 3.94-3.87 (m, 4H), 2.10 (s, 3H), 1.26 (t, J= 7.2Hz,3H).MS(ESI),m/z:M-379.0.
Embodiment 22
N- (4- (tert-butyl group) benzyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E22)
(N-(4-(tert-butyl)benzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E22)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.62 (d, J=8.8Hz, 1H), 8.35 (t, J=6.4Hz, 1H), 8.09 (d, J=6.8Hz, 1H), 7.88 (d, J=7.6Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 7.00 (d, J=8.0Hz, 2H), 6.92 (d, J=8.4Hz, 2H), 3.97 (d, J=6.4Hz, 2H), 3.87 (q, J=6.8Hz, 2H), 1.25 (t, J=7.2Hz, 3H), 1.10(s,9H).MS(ESI),m/z:M-421.2.
Embodiment 23
1- ethyls-N- (4- fluorobenzene ethyl) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E23)
(1-ethyl-N-(4-fluorophenethyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E23)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.55 (d, J=8.4Hz, 1H), 8.09 (d, J=6.8Hz, 1H), 7.99 (d, J=7.6Hz, 1H), 7.89-7.85 (m, 2H), 7.20 (d, J=7.6Hz, 1H), 6.97-6.94 (m, 2H), 6.74 (t, J= 8.8Hz, 2H), 3.90 (q, J=6.8Hz, 2H), 3.02 (q, J=6.8Hz, 2H), 2.57 (t, J=6.8Hz, 2H), 1.26 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M-397.0.
Embodiment 24
N- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] Indoles -6- sulfonamide (E24)
(N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-ethyl-2-oxo-1,2- dihydrobenzo[cd]indole-6-sulfona mide)(E24)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.68 (d, J=8.4Hz, 1H), 8.16 (d, J=6.8Hz, 1H), 8.09- 8.03 (m, 2H), 7.95-9-7.91 (m, 1H), 7.29 (d, J=7.6Hz, 1H), 3.98-9.90 (m, 2H), 3.84 (q, J= 6.0Hz, 1H), 3.54 (q, J=5.6Hz, 1H), 2.84 (t, J=6.0Hz, 2H), 1.27 (t, J=7.2Hz, 3H), 1.14 (s, 3H),1.11(s,3H).MS(ESI),m/z:M-389.1.
Embodiment 25
1- ethyls-N- (2- morpholinoethyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E25)
(1-ethyl-N-(2-morpholinoethyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E25)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.68 (d, J=8.4Hz, 1H), 8.15 (d, J=6.8Hz, 1H), 8.09 (d, J=7.6Hz, 1H), 7.95 (q, J=7.2Hz, 1H), 7.71 (s, 1H), 7.29 (d, J=7.6Hz, 1H), 3.93 (q, J= 7.2Hz, 2H), 3.25 (t, J=4.4,4H), 2.89 (s, 2H), 2.19 (t, J=6.4Hz, 2H), 2.07 (d, J=4.0Hz, 4H), 1.26 (t, J=8.8Hz, 3H)
MS(ESI),m/z:M+390.1；M-388.1.
Embodiment 26
1- ethyls-N- (4- methoxy-benzyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E26)
(1-ethyl-N-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E26)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.63 (d, J=8.4Hz, 1H), 8.28 (t, J=6.4Hz, 1H), 8.11 (d, J=6.8Hz, 1H), 8.00 (d, J=7.6Hz, 1H), 7.90 (q, J=7.2Hz, 1H), 7.21 (d, J=7.6Hz, 1H), 6.94 (d, J=8.4Hz, 2H), 6.57 (d, J=8.8Hz, 2H), 2.93-3.88 (m, 5H), 3.60 (s, 3H), 1.27 (t, J= 7.2Hz,3H).MS(ESI),m/z:[M+H]-,395.1.
Embodiment 27
1- ethyls-N- (3- methyl-benzyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E27)
(1-ethyl-N-(3-methylbenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E27)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.65 (d, J=8.4Hz, 1H), 8.34 (t, J=6.4Hz, 1H), 8.11 (d, J=7.2Hz, 1H), 7.99 (d, J=7.6Hz, 1H), 7.91 (t, J=8.0Hz, 1H), 7.19 (d, J=7.6Hz, 1H), 6.93 (t, J=7.6Hz, 1H), 6.84-6.80 (m, 2H), 6.71 (s, 1H), 3.98 (d, J=6.4Hz, 2H), 3.90 (q, J= 6.8Hz, 2H), 1.98 (s, 3H), 1.27 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M-379.1.
Embodiment 28
N- ((6- chloropyridines -3- substitutions) methyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E28)
(N-((6-chloropyridin-3-yl)methyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd] indole-6-sulfonamide)(E28)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.57 (d, J=8.4Hz, 1H), 8.48 (t, J=6.4Hz, 1H), 8.11 (d, J=6.8Hz, 1H), 7.98-7.97 (m, 2H), 7.90 (q, J=7.2Hz, 1H), 7.44-7.41 (m, 1H), 7.21 (d, J= 7.6Hz, 1H), 7.03 (d, J=8.0Hz, 1H), 4.06 (d, J=6.4Hz, 1H), 3.91 (q, J=7.2Hz, 2H), 1.27 (t, J=8.8Hz, 3H) .MS (ESI), m/z:M-400.0
Embodiment 29
1- ethyls-N- (the fluoro- 4- methyl-benzyls of 3-) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E29)
(1-ethyl-N-(3-fluoro-4-methylbenzyl)-2-oxo-1,2-dihydrobenzo[cd] indole-6-sulfonamide)(E29)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.64 (d, J=8.4Hz, 1H), 8.40 (s, 1H), 8.13 (d, J=6.8Hz, 1H), 8.00 (d, J=7.6Hz, 1H), 7.86 (t, J=8.0Hz, 1H), 7.14 (d, J=7.6Hz, 1H), 6.86 (t, J= 8.8Hz, 1H), 6.65 (t, J=6.4Hz, 1H), 3.97 (s, 2H), 3.90 (q, J=7.2Hz, 2H), 1.96 (s, 3H), 1.27 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M-397.1.
Embodiment 30
N- (the chloro- 6- luorobenzyls of 2-) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E30)
(N-(2-chloro-6-fluorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd] indole-6-sulfonamide)(E30)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.63 (d, J=8.4Hz, 1H), 8.37 (t, J=6.0Hz, 1H), 8.10 (d, J=6.8Hz, 1H), 8.04 (d, J=7.6Hz, 1H), 7.86 (q, J=6.8Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 7.13-7.07 (m, 1H), 6.98 (d, J=8.0Hz, 1H), 6.85 (d, J=8.8Hz, 1H), 4.13 (d, J=4.8Hz, 1H), 3.92 (q, J=6.8Hz, 1H), 1.27 (t, J=6.8Hz, 3H)
MS(ESI),m/z:M-417.0.
Embodiment 31
N- (4- chlorobenzene ethyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E31)
(N-(4-chlorophenethyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E31)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.55 (d, J=8.0Hz, 1H), 8.11 (d, J=7.2Hz, 1H), 7.98 (d, J=7.6Hz, 1H), 7.89-7.85 (m, 2H), 7.21 (d, J=7.6Hz, 1H), 6.95 (s, 4H), 3.94 (q, J=7.2Hz, 2H), 3.08 (q, J=6.8Hz, 2H), 2.59 (t, J=6.8Hz, 2H), 1.29 (t, J=7.2Hz, 3H) .MS (ESI), m/z: M-413.0.
Embodiment 32
1- ethyls-N- (4- luorobenzyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E32)
(1-ethyl-N-(4-fluorobenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E32)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.64 (d, J=8.4Hz, 1H), 8.40 (t, J=6.4Hz, 1H), 8.13 (d, J=6.8Hz, 1H), 8.02 (d, J=7.6Hz, 1H), 7.89 (q, J=7.2Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 7.10-7.07 (m, 2H), 6.89-6.83 (m, 2H), 4.01 (d, J=6.4Hz, 2H), 3.88 (q, J=7.2Hz, 2H), 1.27 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M-383.0.
Embodiment 33
N- (2- chlorobenzyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E33)
(N-(2-chlorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E33)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.68 (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.
Embodiment 34
1- ethyls-N- (3- morphoinopropyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E34)
(1-ethyl-N-(3-morpholinopropyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E34)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.69 (d, J=8.0Hz, 1H), 8.17 (d, J=6.8Hz, 1H), 8.07 (d, J=7.6Hz, 1H), 7.94 (t, J=8.0Hz, 1H), 7.79 (s, 1H), 7.31 (d, J=7.6Hz, 1H), 3.95 (q, J= 7.2Hz, 2H), 3.37 (s, 4H), 2.82 (d, J=5.2Hz, 2H), 2.06-2.02 (m, 6H), 1.42 (t, J=6.8Hz, 2H), 1.28 (t, J=6.8Hz, 3H) .MS (ESI), m/z:M+403.5；M-402.1.
Embodiment 35
1- ethyls-N- (2- luorobenzyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E35)
(1-ethyl-N-(2-fluorobenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E35)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.64 (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.
Embodiment 36
N- (1- acetyl group-4-substitution)-1- ethyl-2-oxo-1,2- dihydrobenzos [cd] indoles-6-sulfonamide (E36)
(N-(1-acetylpiperidin-4-yl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole- 6-sulfonamide)(E36)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.70 (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.
Embodiment 37
1- ethyls-N- (2- methyl-benzyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E37)
(1-ethyl-N-(2-methylbenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E37)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.70 (d, J=8.4Hz, 1H), 8.22 (s, 1H), 8.13 (d, J=6.8Hz, 1H), 8.06 (d, J=7.6Hz, 1H), 7.94-7.90 (m, 1H), 7.25 (d, J=7.6Hz, 1H), 7.09 (d, J=7.2Hz, 1H), 6.99-6.92 (m, 3H), 3.98-3.90 (m, 4H), 2.09 (s, 3H), 1.28 (t, J=6.8Hz, 3H) .MS (ESI), m/ z:M-379.1.
Embodiment 38
1- ethyls-6- ((4- (pyridin-4-yl methyl) piperazine-1-substitution) sulfonyl) benzo [cd] indoles-2 (1H) -one (E38)
(1-ethyl-6-((4-(pyridin-4-ylmethyl)piperazin-1-yl)sulfonyl)benzo[cd] indol-2(1H)-one)(E38)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.64 (d, J=8.4Hz, 1H), 8.40-8.38 (m, 2H), 8.16 (d, J= 7.2Hz, 1H), 8.07 (d, J=7.6Hz, 1H), 7.94 (dd, J=7.2Hz；J=7.2Hz, 1H), 7.38 (d, J=7.6Hz, 1H), 7.16 (d, J=6.8Hz, 2H), 3.94 (q, J=6.8Hz, 2H), 3.44 (s, 2H), 3.00 (s, 4H), 2.40-2.38 (m, 4H), 1.29 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M+437.5；M-436.1.
Embodiment 39
N- (2- chlorobenzene ethyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E39)
(N-(2-chlorophenethyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E39)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.60 (d, J=8.4Hz, 1H), 8.14 (d, J=7.2Hz, 1H), 8.06 (d, J=7.6Hz, 1H), 8.00 (t, J=5.6Hz, 1H), 7.91 (t, J=8.0Hz, 1H), 7.26 (d, J=7.6Hz, 1H), 7.18 (d, J=7.6Hz, 1H), 7.11 (d, J=6.8Hz, 1H), 7.05-6.97 (m, 2H), 3.93 (q, J=7.2Hz, 2H), 3.06 (q, J=6.4Hz, 2H), 2.69 (t, J=7.2Hz, 2H), 1.29 (t, J=7.2Hz, 3H) MS (ESI), m/z:M-413.1.
Embodiment 40
1- ethyl-2-oxos-N- (4- (trifluoromethyl) benzyl) -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E40)
(1-ethyl-2-oxo-N-(4-(trifluoromethyl)benzyl)-1,2-dihydrobenzo[cd] indole-6-sulfonamide)(E40)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.60 (d, J=8.4Hz, 1H), 8.52 (s, 1H), 8.10 (d, J=6.8Hz, 1H), 7.99 (d, J=7.2Hz, 1H), 7.88 (t, J=7.6Hz, 1H), 7.32 (d, J=8.0Hz, 2H), 7.22 (d, J= 8.0Hz, 2H), 7.15 (d, J=7.6Hz, 1H), 4.15 (s, 2H), 3.89 (d, J=7.2Hz, 2H), 1.25 (t, J=6.8Hz, 3H).MS(ESI),m/z:M-433.0.
Embodiment 41
N- (double (trifluoromethyl) benzyls of 3,5-) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E41)
(N-(3,5-bis(trifluoromethyl)benzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo [cd]indole-6-sulfonamide)(E41)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.66 (t, J=6.0Hz, 1H), 8.57 (d, J=8.4Hz, 1H), 8.08 (d, J=7.2Hz, 1H), 7.95 (d, J=7.6Hz, 1H), 7.85 (t, J=7.6Hz, 1H), 7.62 (s, 3H), 7.10 (d, J= 7.6Hz, 1H), 4.34 (d, J=6.0Hz, 2H), 3.87 (q, J=7.2Hz, 2H), 1.22 (t, J=6.8Hz, 3H) .MS (ESI),m/z:M-501.0.
Embodiment 42
1- ethyls-N- (4- fluoro- 3- (trifluoromethyl) benzyl) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E42)
(1-ethyl-N-(4-fluoro-3-(trifluoromethyl)benzyl)-2-oxo-1,2- dihydrobenzo[cd]indole-6-sulfonamide)(E42)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.59 (d, J=8.4Hz, 1H), 8.51 (t, J=6.0Hz, 1H), 8.10 (d, J=7.2Hz, 1H), 7.94-7.87 (m, 2H), 7.39 (s, 1H), 7.17-7.10 (m, 3H), 4.15 (d, J=6.4Hz, 2H), 3.89 (q, J=6.8Hz, 2H), 1.23 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M-451.0.
Embodiment 43
N- (the bromo- 2- luorobenzyls of 4-) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E43)
(N-(4-bromo-2-fluorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole- 6-sulfonamide)(E43)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.66 (d, J=8.4Hz, 1H), 8.13 (d, J=5.6Hz, 1H), 8.05 (d, J=7.6Hz, 1H), 7.95 (t, J=7.6Hz, 1H), 7.38 (q, J=5.6Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 6.96 (t, J=7.2Hz, 1H), 6.87-8-6.83 (m, 1H), 4.11 (s, 2H), 3.92 (q, J=6.8Hz, 2H), 1.25 (t, J= 6.8Hz,3H).MS(ESI),m/z:M-460.9.
Embodiment 44
1- ethyl-2-oxos-N- (3,4,5- trifluoro-benzyls) -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E44)
(1-ethyl-2-oxo-N-(3,4,5-trifluorobenzyl)-1,2-dihydrobenzo[cd]indole- 6-sulfonamide)(E44)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.60 (d, J=8.0Hz, 1H), 8.50 (s, 1H), 8.12 (d, J=6.8Hz, 1H), 8.00 (d, J=7.6Hz, 1H), 7.91 (t, J=7.6Hz, 1H), 7.21 (d, J=7.6Hz, 1H), 6.85 (t, J= 8.0Hz, 1H), 4.06 (s, 2H), 3.91 (q, J=6.8Hz, 2H), 1.25 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M- 419.0.
Embodiment 45
N- (2,5- dichloro benzyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E45)
(N-(2,5-dichlorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E45)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.68 (d, J=8.4Hz, 1H), 8.28 (t, J=5.2Hz, 1H), 8.12- 8.09 (m, 1H), 7.88 (t, J=8.0Hz, 1H), 7.26 (d, J=7.6Hz, 1H), 7.19 (d, J=7.2Hz, 2H), 7.18- 7.11 (m, 1H), 4.25 (d, J=5.2Hz, 2H), 3.93 (q, J=7.2Hz, 2H), 1.27 (t, J=7.2Hz, 3H) .MS (ESI),m/z:M-433.0.
Embodiment 46
N- (2,4 difluorobenzene base) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E46)
(N-(2,4-difluorophenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E46)
Synthetic method such as embodiment 10.
1H-NMR (400MHz, d-DMSO) δ 8.22 (d, J=8.0Hz, 1H), 8.10 (d, J=6.8Hz, 1H), 7.94 (d, J=8.4Hz, 1H), 7.67 (t, J=7.6Hz, 1H), 7.41-7.34 (m, 1H), 7.32-7.28 (m, 1H), 7.26-7.22 (m, 1H), 3.95 (q, J=7.2Hz, 2H), 1.29 (t, J=6.8Hz, 3H) .MS (ESI), m/z:M-387.0.
Embodiment 47
1- ethyls-N- ((1- ethyl-2-oxo-1-1,2- dihydrobenzos [cd] indoles-6-substitution) sulfonyl)-N- (5- Fluoro-2-methylbenzene base) -2- oxo 1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E47)
(1-ethyl-N-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)sulfonyl)- N-(5-fluoro-2-methylphenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide) (E47)
Synthetic method such as embodiment 10.
1H-NMR (400MHz, d-DMSO) δ 8.23 (d, J=8.0Hz, 2H), 8.12 (d, J=6.8Hz, 2H), 8.03 (d, J=8.4Hz, 2H), 7.74 (t, J=7.6Hz, 2H), 7.38 (d, J=8.0Hz, 2H), 7.31 (d, J=5.6Hz, 2H), 6.64 (d, J=8.8Hz, 1H), 3.98 (d, J=7.2Hz, 4H), 1.77 (s, 3H), 1.31 (t, J=7.2Hz, 3H) .MS (ESI), m/ z:M-643.70.
Embodiment 48
N- (1- benzyl piepridines-4-substitution)-1- ethyl-2-oxo-1,2- dihydrobenzos [cd] indoles-6- sulfonamide (E48)
(N-(1-benzylpiperidin-4-yl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole- 6-sulfonamide)(E48)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.70 (d, J=8.0Hz, 1H), 8.13-8.08 (m, 2H), 7.95-7.91 (m, 2H), 7.27-7.22 (m, 3H), 7.14 (d, J=6.8Hz, 3H), 3.91 (d, J=6.8Hz, 2H), 3.30 (s, 2H), 2.95 (s, 1H), 2.57-2.50 (m, 2H) 1.78 (t, J=6.8Hz, 3H), 1.45-1.42 (m, 2H), 1.33-1.24 (m, 5H).MS(ESI),m/z:M+450.2；M-448.2.
Embodiment 49
6- ((4- (2- chlorphenyls) piperazine -1- substitutions) sulfonyl) -1- ethyls benzo [cd] indoles -2 (1H) -one (E49)
(6-((4-(2-chlorophenyl)piperazin-1-yl)sulfonyl)-1-ethylbenzo[cd] indol-2(1H)-one)(E49)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.69 (d, J=8.4Hz, 1H), 8.17 (d, J=6.8Hz, 1H), 8.12 (d, J=7.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.38 (d, J=7.6Hz, 1H), 7.13 (t, J=8.0Hz, 1H), 6.88 (s, 1H), 6.81 (d, J=8.4Hz, 1H), 6.75 (d, J=7.6Hz, 1H), 3.95 (q, J=6.8Hz, 2H), 3.20 (s, 4H), 3.09 (s, 4H), 1.28 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M-445.0.
Embodiment 50
N- ([1,1'- biphenyl]-3-substitution)-1- ethyl-2-oxo-1,2- dihydrobenzos [cd] indoles-6- sulfonamide (E50)
(N-([1,1'-biphenyl]-3-yl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E50)
Synthetic method such as embodiment 10.
1H-NMR (400MHz, d-DMSO) δ 10.7 (s, 1H), 8.74 (d, J=8.4Hz, 1H), 8.21 (d, J=7.6Hz, 1H), 8.08 (d, J=6.8Hz, 1H), 7.92 (t, J=7.6Hz, 1H), 7.41 (s, 4H), 7.26-7.22 (m, 5H), 7.05 (d, J=6.8Hz, 1H), 3.86 (d, J=6.8Hz, 2H), 1.22 (t, J=6.8Hz, 3H) .MS (ESI), m/z:M-427.0.
Embodiment 51
Tert-butyl group 4- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) piperidines -1- formic acid The tert-butyl ester (E51)
(tert-butyl4-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido) piperidine-1-carboxylate)(E51)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.68 (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.
Embodiment 52
N- (3- chlorobenzene ethyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (52)
(N-(3-chlorophenethyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E52)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.55 (d, J=8.4Hz, 1H), 8.12 (d, J=6.8Hz, 1H), 8.01 (d, J=7.6Hz, 1H), 7.88-7.85 (m, 2H), 7.25 (d, J=7.6Hz, 1H), 7.03-6.99 (m, 3H), 6.92 (d, J= 6.8Hz, 1H), 3.95 (q, J=7.2Hz, 2H), 3.08 (q, J=6.0Hz, 3H), 2.62 (t, J=6.4Hz, 2H), 1.30 (t, J=6.8Hz, 3H) .MS (ESI), m/z:M-413.0.
Embodiment 53
N- benzhydryls -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E53)
(N-benzhydryl-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide) (E53)
Synthetic method such as embodiment 10.
1H-NMR (400MHz, d-DMSO) δ 8.63 (d, J=8.0Hz, 1H), 8.02 (d, J=6.8Hz, 1H), 7.95 (d, J=7.2Hz, 1H), 7.82 (t, J=8.0Hz, 1H), 7.38 (d, J=7.6Hz, 1H), 7.27 (t, J=7.2Hz, 1H), 7.16 (t, J=7.6Hz, 1H), 7.08-7.3-03 (m, 4H), 6.97-6.66 (m, 5H), 5.48 (s, 1H), 3.88 (q, J=6.8Hz, 2H), 1.23 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M-441.0.
Embodiment 54
N- cyclopenta -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E54)
(N-cyclopentyl-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E54)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.72 (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.
Embodiment 55
N- (3- (tert-butyl group) phenyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E55)
(N-(3-(tert-butyl)phenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E55)
Synthetic method such as embodiment 10.
1H-NMR (400MHz, d-DMSO) δ 8.49 (d, J=8.4Hz, 1H), 8.13 (d, J=7.6Hz, 1H), 8.05 (d, J=6.8Hz, 1H), 7.71 (t, J=7.6Hz, 1H), 7.08 (d, J=5.6Hz, 2H), 6.98 (s, 1H), 6.90 (s, 1H), 6.84 (d, J=7.2Hz, 2H), 3.94 (dd, J=14.2Hz, 7.4Hz, 2H), 1.34 (t, J=7.2Hz, 3H), 1.09 (s, 9H).MS(ESI),m/z:M-407.1
Embodiment 56
N- (2- (tert-butyl group) phenyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E56)
(N-(2-(tert-butyl)phenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E56)
1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonic acid chlorides synthetic method such as embodiment 1.
Take 1- ethyl-2-oxos -1,2- dihydrobenzo [cd] indoles -6- sulfonic acid chlorides (100mg, 0.338mmol), and 2- (tert-butyl group) aniline (92mg, 0.617mmol) is dissolved in 3mL pyridines.Room temperature reaction overnight, after reaction completely, is washed, acetic acid second Ester is extracted three times, merges organic layer, and 10% hydrochloric acid 50mL is washed once, and saturated sodium-chloride water solution is washed once, and anhydrous sodium sulfate is done It is dry, column chromatography, obtain 50mg yellow greenish powder shape solids, yield 36%.
1H-NMR (400MHz, d-DMSO) δ 9.37 (s, 1H), 8.76 (d, J=8.4Hz, 1H), 8.21 (d, J=7.2Hz, 1H), 8.05 (d, J=7.6Hz, 1H), 7.94 (t, J=8.0Hz, 1H), 7.44 (d, J=8.0Hz, 1H), 7.32 (d, J= 7.6Hz, 1H), 7.15 (t, J=7.6Hz, 1H), 6.90 (t, J=7.6Hz, 1H), 6.36 (d, J=7.6Hz, 1H), 3.97 (q, J=7.2Hz, 2H), 1.45 (s, 9H), 1.29 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M-407.1
Embodiment 57
2- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) methyl benzoate (E57)
(2-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)benzoate) (E57)
Synthetic method such as embodiment 56.
1H-NMR (400MHz, d-DMSO) δ 10.67 (s, 1H), 8.48 (d, J=8.4Hz, 1H), 8.22 (d, J= 7.6Hz, 1H), 8.10 (d, J=7.2Hz, 1H), 7.96 (t, J=7.6Hz, 1H), 7.75 (d, J=7.6Hz, 1H), 7.55- 7.48 (m, 2H), 7.27 (d, J=7.6Hz, 1H), 7.10 (t, J=7.2Hz, 1H), 3.88 (q, J=7.2Hz, 2H), 3.69 (s, 3H), 1.23 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M-409.1
Embodiment 58
N- (2- benzoylphenyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E58)
(N-(2-benzoylphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E58)
Synthetic method such as embodiment 56.
1H-NMR (400MHz, d-DMSO) δ 9.88 (s, 1H), 8.35 (d, J=7.6Hz, 1H), 7.91 (d, J=6.8Hz, 1H), 7.79 (d, J=7.6Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.55 (t, J=7.6Hz, 1H), 7.47-7.42 (m, 2H), 7.28 (t, J=7.6Hz, 1H), 7.19-7.17 (m, 3H), 7.06 (d, J=7.6Hz, 1H), 6.97 (d, J=7.6Hz, 1H), 3.81 (q, J=6.8Hz, 2H), 1.21 (t, J=6.8Hz, 3H) .MS (ESI), m/z:M-455.0
Embodiment 59
N- (2- acetylphenyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E59)
(N-(2-acetylphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E59)
Synthetic method such as embodiment 56.
1H-NMR (400MHz, d-DMSO) δ 11.67 (s, 1H), 8.44 (d, J=8.0Hz, 1H), 8.25 (d, J= 7.6Hz, 1H), 8.11 (d, J=7.2Hz, 1H), 7.95 (t, J=8.0Hz, 1H), 7.88 (d, J=8.0Hz, 1H), 7.50 (t, J=7.6Hz, 1H), 7.42 (d, J=8.4Hz, 1H), 7.28 (d, J=7.6Hz, 1H), 7.11 (t, J=7.6Hz, 1H), 3.89 (q, J=7.2Hz, 2H), 2.48 (s, 3H), 1.23 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M-393.0
Embodiment 60
1- ethyl-2-oxos-N- (pyridine -3- substitutions) -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E60)
1-ethyl-2-oxo-N-(pyridin-3-yl)-1,2-dihydrobenzo[cd]indole-6- sulfonamide(E60)
Synthetic method such as embodiment 56.
1H-NMR (400MHz, d-DMSO) δ 10.83 (s, 1H), 8.66 (d, J=8.4Hz, 1H), 8.26 (s, 1H), 8.18-8.16 (m, 2H), 8.13 (d, J=6.8Hz, 1H), 7.94 (t, J=7.6Hz, 1H), 7.47 (d, J=8.4Hz, 1H), 7.28 (d, J=7.6Hz, 1H), 7.23-7.20 (m, 1H), 3.89 (q, J=6.8Hz, 2H), 1.23 (t, J=6.8Hz, 3H) .MS(ESI),m/z:M-352.0
Embodiment 61
N- (3- acetylphenyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E61)
(N-(3-acetylphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E61)
Synthetic method such as embodiment 56.
1H-NMR (400MHz, d-DMSO) δ 10.80 (s, 1H), 8.69 (d, J=8.0Hz, 1H), 8.18 (d, J= 7.6Hz, 1H), 8.10 (d, J=6.8Hz, 1H), 7.93 (t, J=7.6Hz, 1H), 7.59 (s, 1H), 7.54 (d, J=3.6Hz, 1H), 7.34-7.31 (m, 2H), 7.25 (d, J=7.6Hz, 1H), 3.86 (dd, J=13.8Hz, 7.0Hz, 2H), 2.43 (s, 3H), 1.20 (t, J=7.2Hz, 3H)
Embodiment 62
N- (3- bromo- 5- (trifluoromethyl) phenyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E62)
(N-(3-bromo-5-(trifluoromethyl)phenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo [cd]indole-6-sulfonamide)(E62)
Synthetic method such as embodiment 56.
1H-NMR (400MHz, d-DMSO) δ 11.28 (s, 1H), 8.64 (d, J=8.4Hz, 1H), 8.23 (d, J= 7.6Hz, 1H), 8.14 (d, J=7.2Hz, 1H), 7.97 (t, J=7.6Hz, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.32 (t, J=7.6Hz, 2H), 3.89 (dd, J=14.0Hz, 6.8Hz, 2H), 1.22 (t, J=7.2Hz, 3H)
Embodiment 63
(E) -1- ethyl-2-oxos-N- (4- (phenyl-diazenyl) phenyl) -1,2- dihydrobenzos [cd] indoles -6- sulphurs Acid amides (E63)
((E)-1-ethyl-2-oxo-N-(4-(phenyldiazenyl)phenyl)-1,2-dihydrobenzo[cd] indole-6-sulfonamide)(E63)
Synthetic method such as embodiment 56.
1H-NMR (400MHz, d-DMSO) δ 11.10 (s, 1H), 8.74 (d, J=8.4Hz, 1H), 8.26 (d, J= 7.6Hz, 1H), 8.11 (d, J=7.2Hz, 1H), 7.95 (t, J=7.8Hz, 1H), 7.73 (t, J=9.0Hz, 4H), 7.50 (dd, J=14.6Hz, 7.0Hz, 3H), 7.27 (dd, J=8.0Hz, 4.0Hz, 3H), 3.86 (dd, J=14.0Hz, 6.8Hz, 2H), 1.20 (t, J=7.2Hz, 3H)
Embodiment 64
Ethyl 2- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) -3- (furans -2- bases) Ethyl propionate (E64)
(ethyl2-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3- (furan-2-yl)propanoate)(E64)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.58 (d, J=8.4Hz, 1H), 8.15 (d, J=7.6Hz, 1H), 8.10 (d, J=6.8Hz, 1H), 7.83 (t, J=7.6Hz, 1H), 7.09 (s, 1H), 6.88 (d, J=7.6Hz, 1H), 6.09 (s, 1H), 5.91 (s, 1H), 5.37 (d, J=9.2Hz, 1H), 4.24-4.19 (m, 1H), 3.98 (q, J=7.2Hz, 2H), 3.85 (q, J= 7.2Hz, 2H), 3.04-3.00 (m, 1H), 1.57 (s, 1H), 1.38 (t, J=7.2Hz, 3H), 1.00 (t, J=7.2Hz, 3H) .MS(ESI),m/z:M+443.1；M-441.1.
Embodiment 65
Ethyl -3- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide) -3- (5- methylfurans -2- Base) ethyl propionate (E65)
(ethyl3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3- (5-methylfuran-2-yl)propanoate)(E65)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.61 (d, J=8.4Hz, 1H), 8.52 (d, J=8.8Hz, 1H), 8.11 (d, J=6.8Hz, 1H), 7.97 (d, J=7.6Hz, 1H), 7.89 (d, J=7.2Hz, 1H), 7.21 (d, J=7.6Hz, 1H), 5.75 (s, 1H), 5.50 (s, 1H), 4.62 (q, J=7.6Hz, 1H), 3.95-3.85 (m, 4H), 2.70 (d, J=7.2Hz, 2H), 1.62 (s, 3H), 1.27 (t, J=6.8Hz, 3H), 1.06 (t, J=6.8Hz, 3H) .MS (ESI), m/z:M-455.1.
Embodiment 66
5- ((1- ethyl-2-oxos -1,2- dihydrobenzo [cd] indoles -6- sulfonamidos) methyl) thiophene -2-carboxylic acid The tert-butyl ester (E66)
(ethyl5-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido) methyl)thiophene-2-carboxylate)(E66)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.64 (d, J=8.4Hz, 2H), 8.14 (d, J=6.8Hz, 1H), 8.04 (d, J=7.6Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.36 (d, J=8.0Hz, 1H), 7.22 (d, J=7.6Hz, 1H), 6.84 (d, J=7.6Hz, 1H), 4.28 (d, J=6.0Hz, 2H), 4.17 (q, J=6.8Hz, 2H), 3.92 (q, J=6.8Hz, 2H), 1.27-1.20(m,6H).MS(ESI),m/z:M-443.0.
Embodiment 67
2- (1- ethyl-2-oxo-1,2- dihydrobenzos [cd] indoles-6- sulfonamidos)-3- (furans-2-substitution) third Sour (E67)
(2-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3-(furan- 2-yl)propanoic acid)(E67)
Ethyl 2- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) -3- (furans -2- bases) Ethyl propionate synthetic method such as embodiment 64.
By ethyl 2- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) -3- (furans -2- Base) ethyl propionate (130mg, 0.29mmol) dissolves with THF, and 2N sodium hydroxide solution 0.5mL are added dropwise in room temperature, react at room temperature Night.Tetrahydrofuran is removed in rotation.Concentrated hydrochloric acid is added dropwise under ice bath, until without Precipitation, filters, obtains 106mg products, yield 88%.
1H-NMR (400MHz, d-DMSO) δ 8.48 (d, J=8.4Hz, 1H), 8.09 (d, J=7.2Hz, 1H), 7.88 (d, J=7.2Hz, 1H), 7.68 (t, J=7.6Hz, 1H), 6.80-6.77 (m, 2H), 5.80 (s, 1H), 5.75 (s, 1H), 4.23 (s, 1H), 3.91-3.88 (m, 2H), 2.98-2.92 (m, 2H), 1.34 (t, J=7.6Hz, 3H) .MS (ESI), m/z:M- 413.0.
Embodiment 68
3- (1- ethyl-2-oxo-1,2- dihydrobenzos [cd] indoles-6- sulfonamidos)-3- (5- methylfurans-2- Substitution) propionic acid (E68)
(3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3-(5- methylfuran-2-yl)propanoicacid)(E68)
Synthetic method such as embodiment 67.
1H-NMR (400MHz, d-DMSO) δ 8.59 (d, J=8.4Hz, 1H), 8.11-8.03 (m, 2H), 7.82 (t, J= 8.0Hz, 1H), 6.84 (d, J=7.6Hz, 1H), 5.73 (s, 1H), 5.49 (s, 1H), 4.77 (s, 1H), 4.00-3.94 (m, 2H), 3.48 (s, 1H), 2.93-2.76 (m, 2H), 1.38 (t, J=7.2Hz, 3H) .MS (ESI), m/z:M-427.0.
Embodiment 69
1- ((1- ethyl-2-oxo -1-1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) methyl) cyclopentane-carboxylic acid Methyl esters (E68)
(ethyl1-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido) methyl)cyclopentane carboxylate)(E68)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.63 (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.
Embodiment 70
1- ethyls-N- (isoquinolin-8-substitution)-2- oxo-1,2- dihydrobenzos [cd] indoles-6- sulfonamide (E70)
(1-ethyl-N-(isoquinolin-7-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E70)
Synthetic method such as embodiment 56.
1H-NMR (400MHz, d-DMSO) δ 11.04 (s, 1H), 9.15 (s, 1H), 8.74 (d, J=8.4Hz, 1H), 8.32 (d, J=5.6Hz, 1H), 8.29 (d, J=8.0Hz, 1H), 8.09 (d, J=7.2Hz, 1H), 7.93 (t, J=7.6Hz, 1H), 7.78 (d, J=8.8Hz, 1H), 7.72 (s, 1H), 7.62 (d, J=6.0Hz, 1H), 7.47 (d, J=9.2Hz, 1H), 7.23 (d, J=8.0Hz, 1H), 3.84 (dd, J=14.0Hz, J=7.2Hz, 2H), 1.18 (t, J=7.20Hz, 3H)
Embodiment 71
Ethyl 4- (3,5- 3,5-dimethylphenyls) -3- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfenyls Amino) ethyl butyrate (E71)
(ethyl 4-(3,5-dimethylphenyl)-3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd] indole-6-sulfonamido)butanoate)(E71)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.54 (d, J=8.0Hz, 1H), 8.06 (d, J=7.2Hz, 1H), 7.88 (d, J=7.6Hz, 1H), 7.79 (t, J=8.0Hz, 1H), 6.66 (t, J=8.0Hz, 1H), 6.59 (s, 1H), 6.34 (d, J= 7.6Hz, 1H), 5.80 (d, J=7.2Hz, 1H), 4.96 (q, J=6.4Hz, 1H), 4.01-3.89 (m, 4H), 2.69 (dd, J= 6.4Hz, 2H), 2.06 (d, J=9.6Hz, 6H), 1.56 (s, 2H), 1.35 (t, J=7.2Hz, 3H), 1.13 (t, J=7.2Hz, 3H).
Embodiment 72
Ethyl 2- ((1- ethyl-2-oxo -1-1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) methyl) benzoic acid Methyl esters
(E72)
(ethyl 2-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido) methyl)benzoate)(E72)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.46 (d, J=8.4Hz, 1H), 8.02 (t, J=7.2Hz, 2H), 7.72 (t, J=8.0Hz, 1H), 7.58 (d, J=8.0Hz, 1H), 7.18 (t, J=7.2Hz, 1H), 7.10-7.07 (m, 2H), 6.74 (d, J =7.6Hz, 1H), 6.27 (t, J=6.8Hz, 1H), 4.39 (d, J=7.2Hz, 2H), 4.19 (q, J=7.6Hz, 2H), 3.95 (q, J=7.6Hz, 2H), 1.39 (t, J=7.2Hz, 3H), 1.30 (t, J=7.2Hz, 3H)
Embodiment 73
3- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide) ethyl butyrate (E73)
(ethyl 3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido) heptanoate)(E73)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.62 (d, J=8.4Hz, 1H), 8.20 (d, J=7.6Hz, 1H), 8.10 (d, J=7.2Hz, 1H), 7.83 (t, J=7.6Hz, 1H), 6.92 (d, J=7.6Hz, 1H), 5.40 (d, J=9.2Hz, 1H), 4.01-3.90 (m, 4H), 3.50 (d, J=4.4Hz, 1H), 2.36 (s, 2H), 1.49-1.43 (m, 1H), 1.39 (t, J= 7.2Hz, 4H), 1.14 (t, J=5.6Hz, 3H), 1.15-1.14 (m, 3H), 1.12-0.93 (m, 1H), 0.58 (t, J= 7.2Hz,3H).
Embodiment 74
2- ethyls -2- ((1- ethyl-2-oxos -1,2- dihydrobenzo [cd] indoles -6- sulfonamidos) methyl) butyric acid (E74)
(2-ethyl-2-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido) methyl)butanoic acid)(E74)
Synthetic method such as embodiment 67.
1H-NMR (400MHz, d-DMSO) δ 8.78 (d, J=8.4Hz, 1H), 8.14 (d, J=7.2Hz, 1H), 7.95 (d, J=7.6Hz, 1H), 7.65 (s, 1H), 7.34 (d, J=7.6Hz, 1H), 3.95 (q, J=7.2Hz, 2H), 2.85 (s, 2H), 1.50-1.38 (m, 4H), 1.27 (t, J=6.8Hz, 3H), 1.21 (s, 1H), 0.58 (t, J=7.2Hz, 4H)
Embodiment 75
5- ((1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) methyl) thiophene-2-carboxylic acid (E75)
(5-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl) thiophene-2-carboxylic acid)(E75)
Synthetic method such as embodiment 67.
1H-NMR (400MHz, d-DMSO) δ 8.64-8.608.64 (m, 2H), 8.11 (d, J=6.8Hz, 1H), 8.04 (d, J=7.2Hz, 1H), 7.93 (t, J=7.6Hz, 1H), 7.32 (d, J=7.2Hz, 1H), 7.22 (d, J=7.6Hz, 2H), 6.81 (s, 1H), 4.26 (d, J=5.6Hz, 2H), 3.92 (t, J=6.0Hz, 3H), 1.28-0.22 (m, 5H)
Embodiment 76
1- ((1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) methyl) cyclopentane-carboxylic acid (E76)
(1-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl) cyclopentanecarboxylic acid)(E76)
Synthetic method such as embodiment 67.
1H-NMR (400MHz, d-DMSO) δ 8.63 (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).
Embodiment 77
N- (the chloro- 4- luorobenzyls of 3-) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E77)
(N-(3-chloro-4-fluorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd] indole-6-sulfonamide)(E77)
Synthetic method such as embodiment 1.
1H-NMR(400MHz,CDCl3) δ 8.60 (d, J=8.4Hz, 1H), 8.09 (t, J=7.2Hz, 2H), 7.82 (t, J =7.8Hz, 1H), 6.98 (d, J=7.2Hz, 1H), 6.94 (d, J=4.4Hz, 1H), 6.88-6.83 (m, 2H), 4.10 (d, J =6.0Hz, 2H), 3.97 (dd, J=14.4Hz, 7.2Hz, 2H), 1.38 (t, J=7.2Hz, 3H)
Embodiment 78
4- (3,5- 3,5-dimethylphenyls) -3- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfenyl ammonia Base) butyric acid (E78)
(4-(3,5-dimethylphenyl)-3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole- 6-sulfonamido)butanoic acid)(E78)
Synthetic method such as embodiment 67.
1H-NMR (400MHz, d-DMSO) δ 8.53 (d, J=8.4Hz, 1H), 8.04 (d, J=6.8Hz, 1H), 7.85- 7.79 (m, 2H), 6.98 (d, J=7.6Hz, 1H), 6.67 (d, J=7.6Hz, 1H), 6.35 (s, 1H), 6.35 (d, J= 7.6Hz, 1H), 6.02 (d, J=7.6Hz, 1H), 4.80 (t, J=7.2Hz, 2H), 3.85 (s, 3H), 1.83 (s, 3H), 1.28- 1.22(m,7H).
Embodiment 79
2- ((1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) methyl) benzoic acid (E79)
(2-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl) benzoic acid)(E79)
Synthetic method such as embodiment 67.
1H-NMR (400MHz, d-DMSO) δ 8.65 (d, J=8.4Hz, 1H), 8.31 (s, 1H), 8.15 (d, J=6.8Hz, 1H), 8.02 (d, J=7.2Hz, 1H), 7.91 (t, J=8.0Hz, 1H), 7.69 (d, J=7.6Hz, 1H), 7.42 (d, J= 7.6Hz, 1H), 7.31 (t, J=7.2Hz, 1H), 7.23-7.18 (m, 2H), 4.40 (d, J=5.6Hz, 2H), 3.92 (d, J= 7.2Hz, 2H), 1.29 (t, J=6.8Hz, 3H)
Embodiment 80
N- (1- acetylindole -5- bases) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E80)
(N-(1-acetylindolin-5-yl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide)(E80)
Synthetic method such as embodiment 56.
1H-NMR (400MHz, d-DMSO) δ 10.31 (s, 1H), 8.70 (d, J=8.4Hz, 1H), 8.13 (d, J= 7.2Hz, 1H), 8.07 (d, J=7.6Hz, 1H), 7.92 (d, J=8.0Hz, 1H), 7.77 (d, J=7.2Hz, 1H), 7.91 (t, J=8.4Hz, 1H), 7.25 (d, J=7.6Hz, 1H), 6.91 (s, 1H), 6.77 (d, J=8.8Hz, 1H), 3.96 (t, J= 8.4Hz, 2H), 3.88 (q, J=6.8Hz, 2H), 2.97 (t, J=8.4Hz, 2H), 2.05 (s, 1H), 1.24 (t, J=7.2Hz, 3H).
Embodiment 81
3- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) enanthic acid (E81)
(3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)heptanoic acid)(E81)
Synthetic method such as embodiment 67.
1H-NMR (400MHz, d-DMSO) δ 8.69 (d, J=8.4Hz, 1H), 8.14 (d, J=6.8Hz, 1H), 8.07 (d, J=7.6Hz, 1H), 7.93 (t, J=7.2Hz, 1H), 7.28 (d, J=7.2Hz, 1H), 3.95 (d, J=6.8Hz, 2H), 2.26-2.18 (m, 2H), 1.27-1.20 (m, 6H), 0.79-0.63 (m, 4H), 0.34-0.31 (t, J=6.0Hz, 3H)
Embodiment 82
1- ethyls -6- ((4- (pyridine -2- ylmethyls) piperazine -1- substitutions) sulfonyl) benzo [cd] indoles -2 (1H) -one (E82)
(1-ethyl-6-((4-(pyridin-2-ylmethyl)piperazin-1-yl)sulfonyl)benzo[cd] indol-2(1H)-one)(E82)
Synthetic method such as embodiment 1.
1H-NMR (400MHz, d-DMSO) δ 8.65 (d, J=8.4Hz, 1H), 8.41 (d, J=4.4Hz, 1H), 8.18 (d, J=7.2Hz, 1H), 8.07 (d, J=7.6Hz, 1H), 7.94 (t, J=8.0Hz, 1H), 7.63 (t, J=7.6Hz, 1H), 7.38 (d, J=7.6Hz, 1H), 7.25 (d, J=8.0Hz, 1H), 7.16 (t, J=5.6Hz, 1H), 3.95 (q, J=7.2Hz, 2H), 3.54 (s, 2H), 3.01 (s, 4H), 2.43 (s, 4H), 1.29 (t, J=6.8Hz, 3H)
Embodiment 83
1- ethyl-2-oxos-N- (3,4,5- trimethoxyphenyls) -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E83)
1-ethyl-2-oxo-N-(3,4,5-trimethoxyphenyl)-1,2-dihydrobenzo[cd]indole- 6-sulfonamide(E83)
Synthetic method such as embodiment 67.
1HNMR(400MHz,CDCl3) δ 8.52 (d, J=8.4Hz, 1H), 8.09 (d, J=7.2Hz, 2H), 7.79 (d, J= 7.6Hz, 1H), 6.87-6.85 (m, 1H), 6.61 (d, J=8.4Hz, 3H), 6.68 (d, J=8.8Hz, 2H), 3.95 (q, J= 7.2Hz, 2H), 3.72 (s, 3H), 3.62 (s, 6H), 1.31 (t, J=7.2Hz, 3H)
Embodiment 84
1- ethyls-N- (4- methoxyphenyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E84)
1-ethyl-N-(4-methoxyphenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide(E84)
Synthetic method such as embodiment 67.
1H NMR(400MHz,CDCl3) δ 8.48 (d, J=8.4Hz, 1H), 8.09 (d, J=7.2Hz, 1H), 8.01 (d, J =7.6Hz, 1H), 7.85-7.63 (m, 1H), 6.87-6.81 (m, 3H), 6.68 (d, J=8.8Hz, 2H), 6.47 (s, 1H), 3.95 (q, J=7.2Hz, 2H), 3.71 (s, 3H), 1.36 (t, J=7.2Hz, 3H)
Embodiment 85
N- (3,4- Dimethoxyphenyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E85)
N-(3,4-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide(E85)
Synthetic method such as embodiment 1.
1HNMR(400MHz,CDCl3) δ 8.52 (d, J=8.4Hz, 1H), 8.07 (d, J=7.2Hz, 1H), 7.97 (d, J= 7.6Hz, 1H), 7.76 (t, J=7.6Hz, 1H), 7.42 (d, J=8.8Hz, 1H), 6.79 (d, J=7.6Hz, 1H), 6.68 (s, 1H), 6.43 (d, J=8.8Hz, 1H), 6.08 (d, J=6.8Hz, 1H), 3.94 (q, J=7.2Hz, 2H), 3.72 (s, 3H), 3.04 (s, 3H), 1.35 (t, J=7.2Hz, 3H)
Embodiment 86
1- ethyls-N- (3- methoxyphenyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E86)
1-ethyl-N-(3-methoxyphenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide(E86)
Synthetic method such as embodiment 67.
1HNMR(400MHz,CDCl3) δ 8.57 (d, J=8.4Hz, 1H), 8.15 (d, J=7.6Hz, 1H), 8.07 (d, J= 7.2Hz, 1H), 7.77 (t, J=7.6Hz, 1H), 7.04 (t, J=8.0Hz, 1H), 6.97 (s, 1H), 6.85 (d, J=7.6Hz, 1H), 6.74-6.58 (m, 2H), 6.54 (d, J=8.0Hz, 1H), 3.94 (q, J=7.2Hz, 2H), 3.68 (s, 3H), 1.35 (t, J=7.2Hz, 3H)
Embodiment 87
N- (3,5- Dimethoxyphenyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E87)
N-(3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide(E87)
Synthetic method such as embodiment 67.
1HNMR(400MHz,CDCl3) δ 8.59 (d, J=8.4Hz, 1H), 8.17 (d, J=7.6Hz, 1H), 8.07 (d, J= 7.2Hz, 1H), 7.90-7.70 (m, 1H), 6.92 (s, 1H), 6.86 (d, J=7.6Hz, 1H), 6.19 (s, 2H), 6.14 (s, 1H), 3.95 (q, J=7.2Hz, 2H), 3.64 (s, 6H), 1.36 (t, J=7.2Hz, 3H)
Embodiment 88
N- (4- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) phenyl) acetamide (E88)
N-(4-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)phenyl) acetamide(E88)
Synthetic method such as embodiment 67.
1H NMR (400MHz, d-DMSO) δ 10.33 (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).
Embodiment 89
2- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) benzoic acid (E89)
2-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)benzoic acid(E89)
Synthetic method such as embodiment 67.
1H NMR (400MHz, d-DMSO) δ 11.96 (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).
Embodiment 90
1- ethyls-N- (4- fluorophenyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide (E90)
1-ethyl-N-(4-fluorophenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide(E90)
Synthetic method such as embodiment 67.
1HNMR (400MHz, d-DMSO) δ 10.48 (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)
Embodiment 91
N- ((1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- bases) sulfonyl)-N- (4- methoxyphenyls) Pyrazinamide (E91)
N-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)sulfonyl)-N-(4- methoxyphenyl)isonicotina mide(E91)
The synthesis side of 1- ethyls-N- (4- methoxyphenyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide Method is referring to embodiment 83.
By 1- ethyls-N- (4- methoxyphenyls) -2- oxos -1,2- dihydrobenzo [cd] indoles -6- sulfonamide (100mg, 0.26mmol) dissolved with dichloromethane, room temperature add isonicotinic acid (34mg, 0.28mmol), HATU (148mg, 380mmol) and DIPEA (0.5mL), room temperature reaction is overnight.Washing, ethyl acetate extract three times, are associated with several layers of, saturated common salt washing one time, Anhydrous sodium sulfate drying.Column chromatography：Petroleum ether：Ethyl acetate=1:1, obtain product 23mg, yield 18%.1H NMR(400MHz, CDCl3) δ 8.53 (d, J=7.6Hz, 1H), 8.47 (s, 2H), 8.12 (d, J=8.4Hz, 1H), 8.06 (d, J=7.2Hz, 1H), 7.63 (t, J=7.6Hz, 1H), 7.16 (d, J=4.4Hz, 2H), 7.04 (t, J=7.6Hz, 3H), 6.77 (d, J= 8.4Hz, 2H), 4.03 (q, J=7.2Hz, 2H), 3.78 (s, 3H), 1.41 (t, J=7.2Hz, 3H)
Embodiment 92
External activity is tested：The present invention is using AlphaScreen detection techniques checking the compounds of this invention to ROR γ eggs White rejection ability.
1st, experiment purpose
Determine inhibitory activity of the compounds of this invention to ROR γ albumen.
2nd, experiment material
Destination protein ROR γ 100nM；Test buffer (10 ×) MOPS (500mM), CHAPS (0.5mM), NaF (500mM), BSA (1mg/mL), PH7.4；The μ g/mL of donor microballon 50 in kit, the μ g/mL of Acceptor beads 50；ROR γ excitements altogether The factor, small peptide SRC1-4 (QKPTSGPQTPQAQQKSLLQQLLTE) 20nM；In 150 μ L reaction systems：RORγ:15 μ L, experiment Buffer solution：15 μ L, deionized water：15 μ L, micromolecular compound：15 μ L, donor microballon：15 μ L, Acceptor beads：15μL；It is positive Inhibitor：T1317,SR2211,UA,Digoxin.
3rd, experimental method
Lucifuge is incubated 2 hours, is transferred to 384 orifice plates, and 40 μ L liquid are shifted per hole, by multi-functional detection ELIASA, is swashed Send out wavelength：680nM, launch wavelength 520-620nM detect reading.
4th, experimental result
The compounds of this invention E1-E82 is as shown in Figure 1 to the inhibitory activity data of ROR γ albumen.
Active IC of the preferably compound to the inhibitory activity of ROR γ albumen50Numerical value is as shown in following table one：
Table one：Active IC of the preferably compound to the inhibitory activity of ROR γ albumen50
Test result indicates that：The compounds of this invention has extraordinary inhibitory action, particularly compound to ROR γ albumen E10, E63 are suitable with comparison medicine to the inhibitory activity of ROR γ albumen.
Embodiment 93
External activity is tested：The present invention verifies the rejection ability of the compounds of this invention using Luciferase detection techniques.
1st, experiment purpose
Determine the compounds of this invention inhibitory activity horizontal to nuclear receptor ROR gamma cellses.
2nd, experiment material
People's renal epithelial cell system 293T cells；DMEM culture mediums containing 10% hyclone；96 orifice plate transparent panels；Double reports Accuse gene detecting kit；Opti-MEM reagents；The transfection reagents of Lipo-fectamine 2000；Recombinant plasmid：Gal4-RORγ LBD：25ng, Full-length-ROR γ：25ng, pG5-luc, Renilla；Positive inhibitor：T1317,SR2211,UA.
3rd, experimental method
People's renal epithelial cell system 293T cells, with the DMEM medium cultures containing 10% hyclone.The day before transfection By cell prepare with 96 orifice plates in, cell density 1x104Individual/hole.Adherent growth is transiently transfected after 24 hours, using double The method of reporter gene cotransfection, transfection reagent Lipo-fectamine2000, transfection is diluted respectively with Opti-MEM reagents Reagent and plasmid.Gal4-ROR γ LBD are per hole 25ng；PG5-luc genes are per hole 25ng；Renilla is per hole 5ng, cotransfection 24 The compound of various concentrations is added after hour, after being incubated 24 hours, using the double reporter gene detection kits of Luciferase, inspection Survey luminous signal, each 3 multiple holes of sample.
People's renal epithelial cell system 293T cells, with the DMEM medium cultures containing 10% hyclone.The day before transfection By cell prepare with 96 orifice plates in, cell density 1x104Individual/hole.Adherent growth is transiently transfected after 24 hours, using double The method of reporter gene cotransfection, transfection reagent Lipo-fectamine2000, transfection is diluted respectively with Opti-MEM reagents Reagent and plasmid.Full-length-ROR γ are per hole 25ng；PG5-luc genes are per hole 25ng；Renilla is per hole 5ng, corotation Dye adds the compound of various concentrations after 24 hours, after being incubated 24 hours, using the double reporter gene detection reagents of Luciferase Box, detect luminous signal, each 3 multiple holes of sample.
Inhibitory activity horizontal to ROR gamma cellses the compounds of this invention E1-E82 is illustrated in fig. 2 shown below.
The IC of the active preferably compound inhibitory activity horizontal to ROR gamma cellses50Numerical value is as shown in following table two：
NT：Do not test
Table two：The IC of the active preferably compound inhibitory activity horizontal to ROR gamma cellses50
Test result indicates that：The compounds of this invention finds that there is extraordinary suppression to make for it to the horizontal checkout of ROR gamma cellses With particularly compound E11, E17, E70 is more preferable than comparison medicine activity to the horizontal inhibitory activity of ROR gamma cellses.Chemical combination simultaneously Thing E19, E45, E63 are suitable with comparison medicine inhibitory activity.
2- oxos -1,2- dihydrobenzos [cd] indoles -6- sulfamide compounds of the present invention and its pharmaceutically may be used The salt of receiving, it can effectively suppress the protein active and cytoactive of vitamin A acid orphan's nuclear receptor γ hypotypes, particularly compound E10, E11, E17, E19, E45, E56, E63, E70 are suitable with positive compound, and contrast positive compound has Stability Analysis of Structures With easy the advantages of preparing.Simultaneously it can be seen that reactive compound is structurally characterized in that：1)R1For ethyl；2)R2,R3Mainly connect Have the phenyl ring compared with large-substituent, these substituents because on phenyl ring position it is changeable, and various structures, it can be seen that this kind of compound Mother nucleus structure to activity keep tool play a very important role.Fully showing that this kind of compound has herein turns into treatment inflammation disease Disease and the potentiality of immunologic derangement and treatment of cancer etc..
Embodiment described above only expresses the several embodiments of the present invention, and its description is more specific and detailed, but simultaneously Therefore the limitation to the scope of the claims of the present invention can not be interpreted as.It should be pointed out that for one of ordinary skill in the art For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the guarantor of the present invention Protect scope.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.

Claims (5)

1. compound or its pharmaceutically acceptable salt, racemic modification with formula (I) architectural feature, it is characterised in that
R1It is selected from：
Ethyl；
R2, R3It is selected from：
1)H；
2) by 1 or 2 or 3 formoxyls, the tert-butyl group, morpholinyl, phenyl-diazenyl, phenoxy group, formamido, amino first The phenyl of tert-butyl acrylate substitution；
3) quinoline, isoquinolin, benzothiazole, it optionally can substitute by 0 or 1 ethyoxyl；
R2And R3It is asynchronously H；
Or R2, R3In one be selected from H, another is selected from phenyl of 3,4 methoxy substitutions.
2. compound or its pharmaceutically acceptable salt, racemic modification with formula (I) architectural feature, it is characterised in that described Compound selection is as follows：
1- ethyl-2-oxos-N- (2- oxos -2- (pyrrolidines -1- substitutions) ethyl) -1,2- dihydrobenzos [cd] indoles -6- sulphurs Acid amides,
N- ((1- Acetylpiperidins -4- substitutions) methyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulphonyl Amine,
1- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) cyclohexane carboxamide,
1- ethyls-N- (2- (ethylsulfonyl) ethyl) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- ((3,5- dimethyl -4,5- dihydro-isoxazoles -5- substitutions) methyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] Indoles -6- sulfonamide,
1- ethyls-N- ((3- isopropyl -4,5- dihydro-isoxazoles -5- substitutions) methyl) -2- oxo -1,2- dihydrobenzos [cd] Yin Diindyl -6- sulfonamide,
N- ((3,5- dimethyl -4,5- dihydro-isoxazole -5- bases) methyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] Yin Diindyl -6- sulfonamide,
1- ethyls-N- ((5- methyl isophthalic acid H- indazole -3- bases) methyl) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulphonyl Amine,
1- ethyls-N- ((4- methyl-6- (trifluoromethyl) pyrimidine-2-substitution) methyl)-2- oxo-1,2- dihydrobenzos [cd] Yin Diindyl -6- sulfonamide,
The tert-butyl group (3- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) phenyl) carbamic acid uncle Butyl ester,
N- (3,4- Dimethoxyphenyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide
1- ethyls-N- ((1- methyl -5- (trifluoromethyl) -1H- benzo [d] imidazoles -2- substitutions) methyl) -2- oxos -1,2- two Hydrogen benzo [cd] indoles -6- sulfonamide,
1- ethyls-N- ((the fluoro- 1H- indoles -2- substitutions of 5-) methyl) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulphonyl Amine,
1- ethyls-N- ((5- methoxyl group -1H- indoles -2- substitutions) methyl) -2- oxo base -1,2- dihydrobenzo [cd] indoles -6- Sulfonamide,
1- ethyls-N- (3- methyl isophthalic acids-(pyridine -3- substitutions) butyl) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulphonyl Amine,
1-N- (4- chloro- 3- (trifluoromethyl) phenyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- (4- acetylphenyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide
N- (benzo [d] [1,3] dioxole-5-substituent methyl)-1- ethyl-2-oxo-1,2- dihydrobenzos [cd] Indoles -6- sulfonamide,
1- ethyls-N- (4- morphlinophenyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
1- ethyls-N- (4- methyl-benzyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- (4- (tert-butyl group) benzyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
1- ethyls-N- (4- fluorobenzene ethyl) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] Yin Diindyl -6- sulfonamide,
1- ethyls-N- (2- morpholinoethyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
1- ethyls-N- (4- methoxy-benzyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
1- ethyls-N- (3- methyl-benzyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- ((6- chloropyridines-3-substitution) methyl)-1- ethyl-2-oxo-1,2- dihydrobenzos [cd] indoles-6- sulfonamide,
1- ethyls-N- (the fluoro- 4- methyl-benzyls of 3-) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- (the chloro- 6- luorobenzyls of 2-) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- (4- chlorobenzene ethyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
1- ethyls-N- (4- luorobenzyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- (2- chlorobenzyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
1- ethyls-N- (2- luorobenzyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- (1- acetyl group -4- substitutions) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
1- ethyls-N- (2- methyl-benzyls) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
1- ethyls-6- ((4- (pyridin-4-yl methyl) piperazine-1-substitution) sulfonyl) benzo [cd] indoles-2 (1H) -one,
N- (2- chlorobenzene ethyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
1- ethyl-2-oxos-N- (4- (trifluoromethyl) benzyl) -1,2- dihydrobenzos [cd] indoles -6- sulfonamide
N- (double (trifluoromethyl) benzyls of 3,5-) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
1- ethyls-N- (4- fluoro- 3- (trifluoromethyl) benzyl) -2- oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- (the bromo- 2- luorobenzyls of 4-) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
1- ethyl-2-oxos-N- (3,4,5- trifluoro-benzyls) -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- (2,5- dichloro benzyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- (2,4 difluorobenzene base) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
1- ethyls-N- ((1- ethyl-2-oxo-1-1,2- dihydrobenzos [cd] indoles-6-substitution) sulfonyl)-N- (fluoro- 2- of 5- Aminomethyl phenyl) -2- oxo 1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- (1- benzyl piepridines-4-substitution)-1- ethyl-2-oxo-1,2- dihydrobenzos [cd] indoles-6- sulfonamide,
6- ((4- (2- chlorphenyls) piperazine-1-substitution) sulfonyl)-1- ethyls benzo [cd] indoles-2 (1H) -one,
N- ([1,1'- biphenyl]-3-substitution)-1- ethyl-2-oxo-1,2- dihydrobenzos [cd] indoles-6- sulfonamide,
Tert-butyl group 4- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) tertiary fourth of piperidines -1- formic acid Ester,
N- (3- chlorobenzene ethyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- benzhydryl -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- (3- (tert-butyl group) phenyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- (2- (tert-butyl group) phenyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
2- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) methyl benzoate,
N- (2- benzoylphenyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- (2- acetylphenyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
1- ethyl-2-oxos-N- (pyridine-3-substitution)-1,2- dihydrobenzos [cd] indoles-6- sulfonamide,
N- (3- acetylphenyls) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
N- (3- bromo- 5- (trifluoromethyl) phenyl) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide, (E) -1- ethyl-2-oxos-N- (4- (phenyl-diazenyl) phenyl) -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
Ethyl 2- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) -3- (furans -2- bases) propionic acid Ethyl ester,
Ethyl -3- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide) -3- (5- methylfuran -2- bases) Ethyl propionate,
5- ((1- ethyl-2-oxos -1,2- dihydrobenzo [cd] indoles -6- sulfonamidos) methyl) tertiary fourth of thiophene -2-carboxylic acid Ester,
2- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) -3- (furans -2- substitutions) propionic acid,
3- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) -3- (5- methylfurans -2- substitutions) Propionic acid,
1- ((1- ethyl-2-oxo -1-1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) methyl) cyclopentane-carboxylic acid first Ester,
1- ethyls-N- (isoquinolin-8-substitution)-2- oxo-1,2- dihydrobenzos [cd] indoles-6- sulfonamide,
Ethyl 4- (3,5- 3,5-dimethylphenyls) -3- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfenyl ammonia Base) ethyl butyrate,
Ethyl 2- ((1- ethyl-2-oxo -1-1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) methyl) benzoic acid first Ester,
3- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide) ethyl butyrate,
2- ethyls -2- ((1- ethyl-2-oxos -1,2- dihydrobenzo [cd] indoles -6- sulfonamidos) methyl) butyric acid,
5- ((1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) methyl) thiophene-2-carboxylic acid,
1- ((1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) methyl) cyclopentane-carboxylic acid,
N- (the chloro- 4- luorobenzyls of 3-) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
4- (3,5- 3,5-dimethylphenyls) -3- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) fourth Acid,
2- ((1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) methyl) benzoic acid,
N- (1- acetylindole -5- bases) -1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamide,
3- (1- ethyl-2-oxo -1,2- dihydrobenzos [cd] indoles -6- sulfonamidos) enanthic acid,
1- ethyls -6- ((4- (pyridine -2- ylmethyls) piperazine -1- substitutions) sulfonyl) benzo [cd] indoles -2 (1H) -one.
3. compound described in claim 1-2 or its pharmaceutically acceptable salt, racemic modification are preparing ROR γ acceptor inhibitors In application.
4. compound described in claim 1-2 or its pharmaceutically acceptable salt, racemic modification exist as ROR γ acceptor inhibitors Prepare treatment encephalomyelitis, Collagen-induced Arthritis, multiple sclerosis, rheumatic arthritis, psoriasis, clone disease, Application in the medicine of asthma and prostate cancer.
5. a kind of pharmaceutical composition as ROR γ acceptor inhibitors, it is characterised in that its active ingredient includes having the right to seek 1- 2 compounds or its pharmaceutically acceptable salt, racemic modification.
CN201410821535.5A 2013-12-25 2014-12-24 Sulfamide compound of the dihydrobenzo of 2 oxo 1,2 [cd] indoles 6 and combinations thereof and application Active CN104530014B (en)

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