WO2015096771A1 - 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide compound and composition and use thereof - Google Patents
2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide compound and composition and use thereof Download PDFInfo
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- WO2015096771A1 WO2015096771A1 PCT/CN2014/094942 CN2014094942W WO2015096771A1 WO 2015096771 A1 WO2015096771 A1 WO 2015096771A1 CN 2014094942 W CN2014094942 W CN 2014094942W WO 2015096771 A1 WO2015096771 A1 WO 2015096771A1
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- ethyl
- oxo
- indole
- dihydrobenzo
- sulfonamide
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- 0 *N(C(c1cccc2cccc3c12)=O)C3=O Chemical compound *N(C(c1cccc2cccc3c12)=O)C3=O 0.000 description 1
- TWOOVCPUMKWXNA-UHFFFAOYSA-N CCN(c(c1c2cccc11)ccc1S(Nc(cc1)ccc1C(C)=O)(=O)=O)C2=O Chemical compound CCN(c(c1c2cccc11)ccc1S(Nc(cc1)ccc1C(C)=O)(=O)=O)C2=O TWOOVCPUMKWXNA-UHFFFAOYSA-N 0.000 description 1
- FBJRRYCFCNCYHU-UHFFFAOYSA-N CCN(c(c1c2cccc11)ccc1S(Nc1cccc(C(C)(C)C)c1)(=O)=O)C2=O Chemical compound CCN(c(c1c2cccc11)ccc1S(Nc1cccc(C(C)(C)C)c1)(=O)=O)C2=O FBJRRYCFCNCYHU-UHFFFAOYSA-N 0.000 description 1
- LLUXHQYYAQRGKI-UHFFFAOYSA-N CCN(c(cc1)c(c2ccc3)c3c1S(NCc(c(F)ccc1)c1Cl)(=O)=O)C2=O Chemical compound CCN(c(cc1)c(c2ccc3)c3c1S(NCc(c(F)ccc1)c1Cl)(=O)=O)C2=O LLUXHQYYAQRGKI-UHFFFAOYSA-N 0.000 description 1
- BCFMZQAGHBFDET-UHFFFAOYSA-N CCN(c(cc1)c(c2ccc3)c3c1S(NCc(cc1F)cc(F)c1F)(=O)=O)C2=O Chemical compound CCN(c(cc1)c(c2ccc3)c3c1S(NCc(cc1F)cc(F)c1F)(=O)=O)C2=O BCFMZQAGHBFDET-UHFFFAOYSA-N 0.000 description 1
- SCLDISKZJONBTM-UHFFFAOYSA-N CCN(c(cc1)c(c2ccc3)c3c1S(NCc1cc(cc(cc3)F)c3[nH]1)(=O)=O)C2=O Chemical compound CCN(c(cc1)c(c2ccc3)c3c1S(NCc1cc(cc(cc3)F)c3[nH]1)(=O)=O)C2=O SCLDISKZJONBTM-UHFFFAOYSA-N 0.000 description 1
- XZLRBEJBFPODQF-UHFFFAOYSA-N CCN(c(cc1)c(c2ccc3)c3c1S(NCc1cc3cc(OC)ccc3[nH]1)(=O)=O)C2=O Chemical compound CCN(c(cc1)c(c2ccc3)c3c1S(NCc1cc3cc(OC)ccc3[nH]1)(=O)=O)C2=O XZLRBEJBFPODQF-UHFFFAOYSA-N 0.000 description 1
- IIKQWKDJPZHRJE-UHFFFAOYSA-N CCN(c(cc1)c(c2ccc3)c3c1S(NCc1ccccn1)(=O)=O)C2=O Chemical compound CCN(c(cc1)c(c2ccc3)c3c1S(NCc1ccccn1)(=O)=O)C2=O IIKQWKDJPZHRJE-UHFFFAOYSA-N 0.000 description 1
- CSCNKXNQAPIIDE-UHFFFAOYSA-N CCN(c(cc1)c(c2ccc3)c3c1S(Nc(cc1OC)ccc1OC)(=O)=O)C2=O Chemical compound CCN(c(cc1)c(c2ccc3)c3c1S(Nc(cc1OC)ccc1OC)(=O)=O)C2=O CSCNKXNQAPIIDE-UHFFFAOYSA-N 0.000 description 1
- GPYLCFQEKPUWLD-UHFFFAOYSA-N O=C1Nc2cccc3c2c1ccc3 Chemical compound O=C1Nc2cccc3c2c1ccc3 GPYLCFQEKPUWLD-UHFFFAOYSA-N 0.000 description 1
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Definitions
- the invention belongs to the technical field of chemical medicine, in particular to a kind of 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide derivatives and pharmaceutically acceptable salts or stereoisoties thereof
- RORs Retinoic acid-related orphan nuclear receptors
- the ROR family includes three types of ROR ⁇ , ROR ⁇ , and ROR ⁇ .
- Three different RORs can express and regulate different physiological processes in different tissues.
- ROR ⁇ is mainly distributed in the liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus and brain.
- ROR ⁇ has a small range of action, mainly in the central nervous system.
- ROR ⁇ can be expressed in many tissues, including liver, animal fat and bone. muscle. The lack of ROR ⁇ in mammals shows a decrease in blood glucose.
- ROR ⁇ 1 is expressed in many tissues such as thymus, muscle, kidney and liver, while ROR ⁇ t is expressed only in immune cells.
- ROR ⁇ t is thought to regulate the differentiation of T cell helper T cell 17 (Th17).
- Th17 is a class of cells that help T cells that produce interleukin-17 (IL-17) and other cytokines. Th17 has been found to play a key role in the development of immune diseases in mice, such as encephalomyelitis and collagen-induced arthritis.
- Th17 has been found to be associated with human inflammatory diseases and immune disorders such as multiple sclerosis, rheumatoid arthritis, psoriasis, clonal diseases and asthma. It has been reported in the literature that ROR ⁇ may be involved in the development and progression of prostate cancer.
- ROR is also able to regulate gene transcription in the absence of endogenous ligand ligation, and it has been found in the crystal structure test of the ligand binding domain of ROR that cholesterol and cholesterol sulfonate can enter the ligand pocket. Soon, it was found that some hydroxycholesterol derivatives can regulate the transcriptional activity of ROR, however, it is unclear whether these cholesterol derivatives are endogenous ligands of ROR. Subsequent studies have shown that a synthetic small molecule, T1317, binds to ROR ⁇ and ROR ⁇ and regulates their activity, but this compound also interacts with at least four other nuclear receptors (LXR ⁇ / ⁇ , FXR, PXR). Thereby limiting its development as a drug for the treatment of immune diseases.
- LXR ⁇ / ⁇ , FXR, PXR nuclear receptors
- a selective inverse agonist SR3335 of ROR ⁇ , a reverse agonist SR1001 with dual effects on ROR ⁇ and ROR ⁇ , and selective inverse agonists SR2211 and SR1555 of ROR ⁇ , which can inhibit interleukin-17 cells, are currently found.
- GlaxoSmithKline has published a series of patents that mention a class of aromatic amines that inhibit ROR receptors. It has also been reported that the natural products digoxin and ursolic acid can be used as selective regulators of ROR ⁇ and can inhibit the differentiation of interleukin-17 cells. However, further studies have shown that digoxin has strong side effects, and ursolic acid also has a role in the glucocorticoid receptor. These studies have shown that selective inhibitors of the synthesis of ROR ⁇ have great potential as drugs for inhibiting the expression of interleukin-17.
- One of the technical problems to be solved by the present invention is to provide a novel class of 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide compounds.
- R 1 is selected from:
- R 2 , R 3 are selected from:
- R 4 is any one selected from the group consisting of -OR 6 , -COR 6 , -COOR 6 , -S(O) m R 6 , -S(O) m R 6 , wherein m is 0 or 2, and R 6 is selected from C 1 -C 3 alkyl;
- R 5 is selected from -COR 7 , -COOR 7 , wherein R 7 is selected from C 1 -C 3 alkylene;
- the cycloalkyl group is optionally selected from the group consisting of phenyl, naphthyl, and the cycloalkyl group is selected from 0, 1, 2 or 3, optionally selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, tert-butyl.
- the heterocyclic group is optionally selected from the group consisting of imidazolyl, triazolyl, pyrazolyl, indolyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrole , piperazinyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, 1,3-dioxolanyl, isoquinolinyl, porphyrinyl, 1H-carbazolyl, 1H-benzo[ d] imidazolyl, 1H-indenyl, benzo[d][1,3]dioxolyl, benzo[d]thiazolyl,H-pyrazole-3(2H)-one, And the heterocyclic group may be selected from 0, 1, 2 or 3, selected from halogen, methyl, ethyl, propy
- R 2 and R 3 are not H at the same time.
- the R 1 is selected from the group consisting of
- the R 2 , R 3 are selected from:
- C 1 -C 3 alkylene-R 4 , R 4 is selected from -OR 6 , -COR 6 , -COOR 6 , -S(O) 2 R 6 , -S(O) 2 R 6 ,R 6 is selected from hydrogen, C 1 -C 3 alkyl;
- R 5 is selected from -COR 7 , -COOR 7 , wherein R 7 is selected from C 1 -C 3 alkylene; cycloalkyl Selected from phenyl, naphthyl, wherein the above cycloalkyl group can be selected from 0, 1, 2 or 3, optionally selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, carboxyl, phenyldiazenyl, -CONH 2 , -COOR 8 , -COR 8 , -OR 8 , -NHCOR 8 , -NHCOOR 8 , -C 6 H 5 R 9 , morpholinyl, piperidinyl, tetrahydrofuranyl, pyridyl group substituted, wherein R 8 optionally from C1 ⁇ C4 alkyl, phenyl, R 9 optionally from methyl, eth
- R 5 is selected from -COR 7 , -COOR 7 , wherein R 7 is selected from C 1 -C 3 alkylene; heterocyclic Selected from imidazolyl, pyrazolyl, indolyl, thienyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrrolyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, 1,3 -dioxolanyl, isoquinolyl, porphyrinyl, 1H-carbazolyl, 1H-benzo[d]imidazolyl, 1H-indenyl, benzo[d][1,3] An oxolyl group, a benzo[d]thiazolyl group, an H-pyrazole-3(2H)-one group, wherein the above heterocyclic Selected from imidazolyl, pyrazolyl, indolyl,
- R 1 is selected from the group consisting of:
- R 2 , R 3 are selected from:
- a phenyl group which may be 1 or 2 or 3 methoxy, ethoxy, formyl, tert-butyl, morpholinyl, phenyldiazenyl, phenoxy, carboxamide, Substituted with t-butyl carbamate;
- Another object of the invention is to provide the use of the above compounds.
- Another object of the invention is to provide a pharmaceutical composition.
- a pharmaceutical composition as a ROR gamma receptor inhibitor comprising the above compound or a pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal complex, hydrate, solvent Compound.
- the present invention provides 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide compounds having the structural features of Formula I. Studies have found that these compounds can effectively inhibit the ROR ⁇ receptor, thereby regulating the differentiation of Th17, and can be used as a treatment for encephalomyelitis, collagen-induced arthritis, multiple sclerosis, rheumatoid arthritis, psoriasis, clonal diseases, asthma and A therapeutic drug for inflammation-related diseases such as prostate cancer.
- Figure 1 illustrates the inhibitory activity of the compounds of Examples 1-91 on the RORy protein.
- Figure 2 illustrates the inhibitory activity of the compounds of Examples 1-91 on ROR gamma cell levels.
- any variable e.g. R 1, R 2, etc.
- any variable e.g. R 1, R 2, etc.
- combinations of substituents and variables are allowed as long as such combinations stabilize the compound.
- a line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that the bond is only attached to any suitable carbon atom adjacent to the ring. It will be understood that one of ordinary skill in the art can select the substituents and substitution patterns of the compounds of the invention to provide chemical stability. Compounds which are readily synthesized from readily available starting materials by the techniques of the art and the methods set forth below.
- substituent itself is substituted by more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.
- the phrase "optionally substituted with one or more substituents" is considered to be a phrase "Alternatively substituted with at least one substituent” is equivalent and in this case the preferred embodiment will have from 0 to 3 substituents.
- alkyl and “alkylene” as used herein are meant to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
- the definition of "C1-C4" in the "C1-C4" alkyl group includes a group having 1, 2, 3, 4, carbon atoms arranged in a straight chain or a branched chain.
- “C1-C4" alkyl” specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl.
- cycloalkyl refers to the number of specific carbon atoms.
- Monocyclic saturated aliphatic hydrocarbon groups For example, “cycloalkyl” includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl and the like.
- alkyl, cycloalkyl and heterocyclyl substituents may be unsubstituted or substituted.
- a (C1-C4)alkyl group may be substituted by one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclic groups such as morpholinyl, piperidinyl and the like. .
- the invention includes the free forms of the compounds of formula I, as well as the pharmaceutically acceptable salts and stereoisomers thereof.
- Some specific exemplary compounds herein are protonated salts of amine compounds.
- the term "free form" refers to an amine compound in a non-salt form.
- the pharmaceutically acceptable salts included include not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula I.
- the free form of the particular salt of the compound can be isolated using techniques known in the art. For example, it can be dissolved by using a suitable alkaline dilute aqueous solution such as a dilute aqueous solution of NaOH or potassium carbonate.
- the salt is treated with a dilute aqueous solution of dilute aqueous ammonia and sodium bicarbonate to regenerate the free form.
- the free form differs somewhat from its respective salt form in solubility in certain physical properties, such as in polar solvents, but for purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
- the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods.
- the salt of the basic compound is prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric or excess amount of the desired salt or mixture of the inorganic or organic acid in a suitable solvent or combination of solvents.
- a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.
- pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid.
- conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard.
- Fatty acid lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.
- a suitable "pharmaceutically acceptable salt” refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
- Salts derived from inorganic bases include aluminum salts, ammonium salts. Salt, calcium salt, copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganese salt, potassium salt, sodium salt, zinc salt and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred.
- a salt derived from a pharmaceutically acceptable organic non-toxic base comprising a salt of a primary, secondary and tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin such as a fine Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, B Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine , piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, t
- the acidic moiety such as a carboxyl group
- a cationic moiety such as tetravalent
- the compounds of the invention are potential internal salts or zwitterions.
- the compounds of the invention can be prepared using the reactions as shown in the scheme below. Accordingly, the following illustrative schemes are for illustrative purposes and are not limited to the listed compounds or any particular substituents. The number of substituents shown in the schemes does not necessarily have to correspond to the number used in the claims, and for the sake of clarity, it is shown that the mono-substituents are attached to a compound which allows multiple substituents under the definition of formula I above.
- the compound as shown in the scheme can be synthesized from 1,8-naphthalic anhydride as a starting material by a 5-step reaction.
- the compounds and pharmaceutically acceptable salts thereof of the present application can be used according to the following methods for the treatment of the following diseases and other diseases not listed below: 1) encephalomyelitis; 2) collagen-induced arthritis; 3) multiple Sclerosing disease; 4) rheumatoid arthritis; 5) psoriasis; 6) clonal disease; 7) asthma; 8) prostate cancer.
- a further aspect of the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) according to the invention and one or more pharmaceutically acceptable excipients.
- the compositions of the present invention may be in liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration employed. .
- the compounds of the present invention can be applied to various routes of administration when used, including but not limited to the following routes, oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal, through lumbar puncture, menstrual Urethral, transdermal or parenteral (including intravenous, intramuscular, subcutaneous, intradermal, intra-abdominal, intrathecal, surgical implantation).
- Oral compositions can be solid, gel or liquid.
- solid preparations include, but are not limited to, tablets, capsules, granules, and bulk powders. These preparations may optionally contain a binder, a diluent, a disintegrant, a lubricant, a glidant, a sweetener, a flavoring agent and the like.
- binders include, but are not limited to, microcrystalline cellulose, dextrose solution, gum arabic, gelatin solution, sucrose, and starch paste;
- examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate And stearic acid;
- examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, dicalcium phosphate;
- examples of glidants include, but are not limited to, silica;
- examples of disintegrants include, but are not limited to, Sodium carboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar and carboxymethyl cellulose.
- compositions of the invention are administered parenterally, generally by injection, including subcutaneous, intramuscular or intravenous injection.
- the injection can be formulated into any conventional form, such as a liquid solution or suspension, a solid form or emulsion suitable for dissolution or suspension in a liquid prior to injection.
- pharmaceutically acceptable carriers which can be used in the injection of the present invention include, but are not limited to, aqueous carriers, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifiers, chelating agents And other pharmaceutically acceptable substances.
- aqueous carriers include sodium chloride injection, forest format injection, isotonic glucose injection Injection, sterile water injection, glucose and lactated Ringer's injection;
- non-aqueous carrier include plant-derived fixed oil, cottonseed oil, corn oil, sesame oil and peanut oil;
- antimicrobial agents include m-cresol , benzyl alcohol, chlorobutanol, benzalkonium chloride, etc.;
- isotonic agents include sodium chloride and glucose; buffers include phosphates and citrates.
- compositions of the invention may also be prepared as sterile lyophilized powders in which the compound is dissolved in a sodium phosphate buffer solution containing glucose or other suitable excipients, followed by standard solutions under standard conditions known to those skilled in the art. The bacteria are filtered, followed by lyophilization to give the desired preparation.
- 1,8-Naphthalic anhydride (1-1) (11.9 g, 0.06 mol), hydroxylamine hydrochloride (4.18 g, 0.06 mol) and pyridine (70 mL) were added to a round bottom flask, and the mixture was heated to reflux for 1 hour. After cooling to 80 ° C, 4-toluenesulfonyl chloride (22.88 g, 0.12 mol) was quickly added, and the mixture was warmed to reflux for 1.5 hours. After cooling to room temperature, the mixture was poured into 200 g of ice water, and a yellow precipitate was precipitated by stirring.
- the present invention uses the AlphaScreen detection technique to verify the ability of the compounds of the invention to inhibit RORy protein.
- the inhibitory activity of the compound of the present invention against the ROR ⁇ protein was determined.
- the target protein ROR ⁇ 100nM; assay buffer (10 ⁇ ) MOPS (500 mM), CHAPS (0.5 mM), NaF (500 mM), BSA (1 mg/mL), pH 7.4; donor microbeads 50 ⁇ g/mL in the kit, subject to Body microbead 50 ⁇ g/mL; ROR ⁇ co-agonistic factor, short peptide SRC1-4 (QKPTSGPQTPQAQQKSLLQQLLTE) 20nM; 150 ⁇ L reaction system: ROR ⁇ : 15 ⁇ L, experimental buffer: 15 ⁇ L, deionized water: 15 ⁇ L, small molecule compound: 15 ⁇ L, for Microbeads: 15 ⁇ L, acceptor beads: 15 ⁇ L; positive inhibitors: T1317, SR2211, UA, Digoxin.
- the inhibitory activity data of the compounds E1-E82 of the present invention against ROR ⁇ protein is shown in Fig. 1.
- the experimental results show that the compound of the present invention has a very good inhibitory effect on the ROR ⁇ protein, and in particular, the inhibitory activities of the compounds E10 and E63 on the ROR ⁇ protein are comparable to those of the control drug.
- the present invention uses the Luciferase detection technique to verify the inhibitory ability of the compounds of the invention.
- the inhibitory activity of the compounds of the invention against nuclear receptor RORy cell levels was determined.
- Human renal epithelial cell line 293T cells Human renal epithelial cell line 293T cells; DMEM medium containing 10% fetal bovine serum; 96-well plate transparent plate; double reporter gene detection kit; Opti-MEM reagent; Lipo-fectamine 2000 transfection reagent; recombinant plasmid: Gal4- ROR ⁇ LBD: 25 ng, Full-length-ROR ⁇ : 25 ng, pG5-luc, Renilla; positive inhibitor: T1317, SR2211, UA.
- Human renal epithelial cell line 293T cells were cultured in DMEM medium containing 10% fetal calf serum. The cells were prepared in a 96-well plate one day prior to transfection with a cell density of 1 x 10 4 cells/well. Transient transfection was carried out 24 hours after adherent growth, using a double reporter gene co-transfection method, the transfection reagent was Lipo-fectamine2000, and the transfection reagent and plasmid were diluted with Opti-MEM reagent, respectively. Gal4-ROR ⁇ LBD was 25 ng per well; pG5-luc gene was 25 ng per well; Renilla was 5 ng per well. After transfection for 24 hours, different concentrations of compounds were added. After incubation for 24 hours, the Luciferase double reporter assay kit was used to detect the luminescent signal. 3 replicate wells per sample.
- Human renal epithelial cell line 293T cells were cultured in DMEM medium containing 10% fetal calf serum. The cells were prepared in a 96-well plate one day prior to transfection with a cell density of 1 x 10 4 cells/well. Transient transfection was carried out 24 hours after adherent growth, using a double reporter gene co-transfection method, the transfection reagent was Lipo-fectamine2000, and the transfection reagent and plasmid were diluted with Opti-MEM reagent, respectively. Full-length-ROR ⁇ was 25 ng per well; pG5-luc gene was 25 ng per well; Renilla was 5 ng per well. After transfection for 24 hours, different concentrations of compounds were added. After incubation for 24 hours, Luciferase double reporter assay kit was used to detect luminescence. Signal, 3 replicate wells per sample.
- the inhibitory activity of the compounds of the present invention E1-E82 on the level of ROR ⁇ cells is shown in Fig. 2 below.
- IC 50 values for the inhibitory activity of the more active compounds against ROR gamma cell levels are shown in Table 2 below:
- IC 50 of the inhibitory activity of the active compound is preferably on the cellular level ROR ⁇
- the experimental results show that the compounds of the present invention have a very good inhibitory effect on the ROR ⁇ cell level test, and in particular, the inhibitory activities of the compounds E11, E17 and E70 on the level of ROR ⁇ cells are better than those of the control drugs.
- the compounds E19, E45 and E63 were equivalent to the inhibitory activity of the reference drug.
- the 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide compound of the present invention and a pharmaceutically acceptable salt thereof can effectively inhibit the retinoic acid receptor ⁇ subunit
- the type of protein activity and cell activity, particularly the compounds E10, E11, E17, E19, E45, E56, E63, E70 are comparable to the positive compounds, and the comparative positive compounds have the advantages of structural stability and ease of preparation.
- R 1 is an ethyl group
- R 2 and R 3 are mainly benzene rings having a large substituent attached thereto, and these substitution genes are positionally variable on the benzene ring
- the structure is diverse, and it can be seen that the parent core structure of such compounds plays an important role in maintaining activity. It is well documented herein that such compounds have potential for the treatment of inflammatory diseases and immune disorders as well as for the treatment of cancer.
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Abstract
Description
本发明属于化学医药技术领域，具体地涉及一类2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺类衍生物及其药学上可接受的盐或立体异构体及其前药分子和制备方法，以及该类化合物在制备治疗由RORγ调控的免疫相关性疾病的药物中的应用。The invention belongs to the technical field of chemical medicine, in particular to a kind of 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide derivatives and pharmaceutically acceptable salts or stereoisoties thereof The construct and its prodrug molecule and preparation method, and the use of the compound in the preparation of a medicament for treating an immune-related disease regulated by RORγ.
维甲酸相关孤儿核受体(ROR)是核受体家族的成员之一，它能够调控多种生理和生化过程。ROR家族包括三种类型RORα,RORβ,以及RORγ。三种不同的ROR可以在不同的组织中表达并且调控不同的生理过程。RORα主要分布在肝脏，骨骼肌，皮肤，肺，脂肪组织，肾脏，胸腺和大脑.RORβ作用范围很小，主要作用于中枢神经系统.RORγ可以在许多组织中表达，包括肝脏，动物脂肪和骨骼肌。哺乳动物缺乏RORγ表现出血糖降低的现象。Retinoic acid-related orphan nuclear receptors (RORs) are members of the nuclear receptor family that regulate a variety of physiological and biochemical processes. The ROR family includes three types of RORα, RORβ, and RORγ. Three different RORs can express and regulate different physiological processes in different tissues. RORα is mainly distributed in the liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus and brain. RORβ has a small range of action, mainly in the central nervous system. RORγ can be expressed in many tissues, including liver, animal fat and bone. muscle. The lack of RORγ in mammals shows a decrease in blood glucose.
RORγ有两种亚型：RORγ1和RORγt(RORγ2)。RORγ1在许多组织，如：胸腺，肌肉，肾脏和肝脏中表达，而RORγt则只在免疫细胞内表达。RORγt被认为能够调控T细胞辅助T细胞17(Th17)的分化。Th17是一类辅助T细胞的细胞，这种细胞可以产生白介素17(IL-17)和其他细胞激素。已经发现Th17在小鼠的免疫疾病发面起着关键的作用，像脑脊髓炎和胶原诱导性关节炎。此外，Th17已经被发现与人类炎症疾病和免疫紊乱，如，多发性硬化症，风湿性关节炎，牛皮癣，克隆疾病和哮喘等疾病有关系。现已有文献报道RORγ可能与前列腺癌的发生与发展有关。There are two subtypes of RORγ: RORγ1 and RORγt (RORγ2). RORγ1 is expressed in many tissues such as thymus, muscle, kidney and liver, while RORγt is expressed only in immune cells. RORγt is thought to regulate the differentiation of T cell helper T cell 17 (Th17). Th17 is a class of cells that help T cells that produce interleukin-17 (IL-17) and other cytokines. Th17 has been found to play a key role in the development of immune diseases in mice, such as encephalomyelitis and collagen-induced arthritis. In addition, Th17 has been found to be associated with human inflammatory diseases and immune disorders such as multiple sclerosis, rheumatoid arthritis, psoriasis, clonal diseases and asthma. It has been reported in the literature that RORγ may be involved in the development and progression of prostate cancer.
ROR在没有内源配体连接时也能够调控基因转录，在对ROR的配体结合域的晶体结构测试中发现胆固醇以及胆固醇磺酸盐可以进入到配体口袋中。不久，发现一些列羟胆固醇衍生物可以调控ROR的转录活性，然而，这些胆固醇衍生物是否是ROR的内源配体还不清楚。紧接着有研究表明一种合成的小分子物质T1317可以与RORγ和RORα结合并调控它们的活性，但这一化合物还与至少四种其他核受体(LXRα/β,FXR,PXR)有作用,从而限制其作为治疗免疫性疾病药物的发展。目前发现一类RORα的选择性反向激动剂SR3335，对RORγ和RORα有双重作用的反向激动剂SR1001，RORγ的选择性反向激动剂SR2211和SR1555，它们都可以抑制白细胞介素17细胞的分化。目前葛兰素史克公司发表了一系列专利，提到一类芳香胺类化合物可以抑制ROR受体。也有文章报道天然产物地高辛和熊果酸可以作为RORγ的选择性调控物质并且都可以抑制白细胞介素17细胞的分化。然而进一步的研究表明地高辛有很强的副作用，熊果酸对糖皮质激素受体也有作用。这些研究都表明合成RORγ的选择性抑制剂作为抑制白细胞介素17表达的药物有很大的潜在价值。ROR is also able to regulate gene transcription in the absence of endogenous ligand ligation, and it has been found in the crystal structure test of the ligand binding domain of ROR that cholesterol and cholesterol sulfonate can enter the ligand pocket. Soon, it was found that some hydroxycholesterol derivatives can regulate the transcriptional activity of ROR, however, it is unclear whether these cholesterol derivatives are endogenous ligands of ROR. Subsequent studies have shown that a synthetic small molecule, T1317, binds to RORγ and RORα and regulates their activity, but this compound also interacts with at least four other nuclear receptors (LXRα/β, FXR, PXR). Thereby limiting its development as a drug for the treatment of immune diseases. A selective inverse agonist SR3335 of RORα, a reverse agonist SR1001 with dual effects on RORγ and RORα, and selective inverse agonists SR2211 and SR1555 of RORγ, which can inhibit interleukin-17 cells, are currently found. Differentiation. GlaxoSmithKline has published a series of patents that mention a class of aromatic amines that inhibit ROR receptors. It has also been reported that the natural products digoxin and ursolic acid can be used as selective regulators of RORγ and can inhibit the differentiation of interleukin-17 cells. However, further studies have shown that digoxin has strong side effects, and ursolic acid also has a role in the glucocorticoid receptor. These studies have shown that selective inhibitors of the synthesis of RORγ have great potential as drugs for inhibiting the expression of interleukin-17.
发明内容Summary of the invention
本发明需要解决的技术问题之一是提供一类新型2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺类化合物。 One of the technical problems to be solved by the present invention is to provide a novel class of 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide compounds.
解决上述技术问题的技术方案如下：The technical solution to solve the above technical problems is as follows:
本发明的一个目的在于提供一种式(Ⅰ)所示化合物，其或其各光学异构体、应用上可接受的共结晶复合物，水合物或溶剂合物：It is an object of the present invention to provide a compound of formula (I), or each of its optical isomers, an acceptable acceptable co-crystal complex, hydrate or solvate:
式中：In the formula:
R1任选自：R 1 is selected from:
1)H；1) H;
2)C1～C5烷基；2) C 1 - C 5 alkyl;
3)C3～C6环烷基；3) a C 3 -C 6 cycloalkyl group;
R2,R3任选自：R 2 , R 3 are selected from:
1)H；1) H;
2)C0～C4亚烷基-R4；2) C 0 - C 4 alkylene-R 4 ;
3)C0～C4亚烷基-R5-环烷基；3) C 0 -C 4 alkylene-R 5 -cycloalkyl;
4)C0～C4亚烷基-R5-杂环基；4) a C 0 -C 4 alkylene-R 5 -heterocyclic group;
以上所述R4任选自-OR6、-COR6、-COOR6、-S(O)mR6、-S(O)mR6，其中m为0或2，R6任选自C1～C3烷基；R 4 is any one selected from the group consisting of -OR 6 , -COR 6 , -COOR 6 , -S(O) m R 6 , -S(O) m R 6 , wherein m is 0 or 2, and R 6 is selected from C 1 -C 3 alkyl;
所述R5任选自-COR7、-COOR7，其中R7任选自C1～C3亚烷基；Wherein R 5 is selected from -COR 7 , -COOR 7 , wherein R 7 is selected from C 1 -C 3 alkylene;
所述环烷基任选自苯基、萘基，且所述环烷基被0、1、2或3个任选自卤素、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、氰基、羧基、硝基、氨基、苯基二氮烯基、-CONH2、-COOR8、-COR8、-OR8、-NHCOR8、-NHCOOR8、-C6H5R9、吗啉基、哌啶基、四氢呋喃基、吡啶基基团取代，其中R8任选自C1～C4烷基、苯基，R9任选自C1～C4烷基、卤素、乙酰基、甲氧基，乙氧基；The cycloalkyl group is optionally selected from the group consisting of phenyl, naphthyl, and the cycloalkyl group is selected from 0, 1, 2 or 3, optionally selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, tert-butyl. , trifluoromethyl, cyano, carboxyl, nitro, amino, phenyldiazenyl, -CONH 2 , -COOR 8 , -COR 8 , -OR 8 , -NHCOR 8 , -NHCOOR 8 , -C 6 H 5 R 9 , morpholinyl, piperidinyl, tetrahydrofuranyl, pyridyl group substituted, wherein R 8 is selected from C 1 -C 4 alkyl, phenyl, and R 9 is selected from C 1 -C 4 alkane Base, halogen, acetyl, methoxy, ethoxy;
所述杂环基任选自咪唑基、三唑基、吡唑基、吠喃基、噻吩基、噁唑基、异噁唑基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、哌嗪基、四氢吡咯基、哌啶基、吗啉基、1,3-二氧戊环基、异喹啉基、吲哚啉基、1H-吲唑基、1H-苯并[d]咪唑基、1H-吲哚基、苯并[d][1,3]二氧杂环戊烯基、苯并[d]噻唑基、H-吡唑-3(2H)-酮基，且所述杂环基可被0、1、2或3个任选自卤素、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、氰基、羧基、硝基、氨基、苯基二氮烯基、-CONH2、-COOR8、-COR8、-OR8、-NHCOR8、-NHCOOR8、-C6H5R9、吗啉基、哌啶基、四氢呋喃基、吡啶基基团取代，其中R8任选自C1～C4烷基、苯基，R9任选自C1～C4烷基、卤素、乙酰基、甲氧基，乙氧基；The heterocyclic group is optionally selected from the group consisting of imidazolyl, triazolyl, pyrazolyl, indolyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrole , piperazinyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, 1,3-dioxolanyl, isoquinolinyl, porphyrinyl, 1H-carbazolyl, 1H-benzo[ d] imidazolyl, 1H-indenyl, benzo[d][1,3]dioxolyl, benzo[d]thiazolyl,H-pyrazole-3(2H)-one, And the heterocyclic group may be selected from 0, 1, 2 or 3, selected from halogen, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, cyano, carboxyl, nitro , amino, phenyldiazenyl, -CONH 2 , -COOR 8 , -COR 8 , -OR 8 , -NHCOR 8 , -NHCOOR 8 , -C 6 H 5 R 9 , morpholinyl, piperidinyl, Substituted by tetrahydrofuranyl, pyridyl group, wherein R 8 is selected from C 1 -C 4 alkyl, phenyl, R 9 is selected from C 1 -C 4 alkyl, halogen, acetyl, methoxy, ethoxy base;
R2和R3不同时为H。 R 2 and R 3 are not H at the same time.
在其中一个实施例中，所述R1选自：In one embodiment, the R 1 is selected from the group consisting of
1)H；1) H;
2)甲基，乙基，丙基，异丙基，叔丁基；2) methyl, ethyl, propyl, isopropyl, tert-butyl;
3)环丙基，环丁基，环己基。3) Cyclopropyl, cyclobutyl, cyclohexyl.
在其中一个实施例中，所述R2，R3任选自：In one embodiment, the R 2 , R 3 are selected from:
1)C1-C3亚烷基-R4，R4任选自-OR6、-COR6、-COOR6、-S(O)2R6、-S(O)2R6，R6任选自氢、C1～C3烷基；1) C 1 -C 3 alkylene-R 4 , R 4 is selected from -OR 6 , -COR 6 , -COOR 6 , -S(O) 2 R 6 , -S(O) 2 R 6 ,R 6 is selected from hydrogen, C 1 -C 3 alkyl;
2)C0～C4亚烷基-R5-环烷基，R5任选自-COR7、-COOR7，其中R7任选自C1～C3亚烷基；环烷基任选自苯基、萘基，其中以上所述环烷基可被0、1、2或3个任选自氟、氯、溴、三氟甲基、羧基、苯基二氮烯基、-CONH2、-COOR8、-COR8、-OR8、-NHCOR8、-NHCOOR8、-C6H5R9、吗啉基、哌啶基、四氢呋喃基、吡啶基基团取代，其中R8任选自C1～C4烷基、苯基，R9任选自甲基、乙基、异丙基、叔丁基、氟、氯、溴、乙酰基、甲氧基，乙氧基；2) C 0 - C 4 alkylene-R 5 -cycloalkyl, R 5 is selected from -COR 7 , -COOR 7 , wherein R 7 is selected from C 1 -C 3 alkylene; cycloalkyl Selected from phenyl, naphthyl, wherein the above cycloalkyl group can be selected from 0, 1, 2 or 3, optionally selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, carboxyl, phenyldiazenyl, -CONH 2 , -COOR 8 , -COR 8 , -OR 8 , -NHCOR 8 , -NHCOOR 8 , -C 6 H 5 R 9 , morpholinyl, piperidinyl, tetrahydrofuranyl, pyridyl group substituted, wherein R 8 optionally from C1 ~ C4 alkyl, phenyl, R 9 optionally from methyl, ethyl, isopropyl, t-butyl, fluoro, chloro, bromo, acetyl, methoxy, ethoxy;
3)C0～C4亚烷基-R5-杂环基，R5任选自-COR7、-COOR7，其中R7任选自C1～C3亚烷基；杂环基任选自咪唑基、吡唑基、吠喃基、噻吩基、噁唑基、异噁唑基、吡啶基、嘧啶基、吡咯基、四氢吡咯基、哌啶基、吗啉基、1,3-二氧戊环基、异喹啉基、吲哚啉基、1H-吲唑基、1H-苯并[d]咪唑基、1H-吲哚基、苯并[d][1,3]二氧杂环戊烯基、苯并[d]噻唑基、H-吡唑-3(2H)-酮基，其中以上所述杂环基可被0、1、2或3个任选自氟、氯、溴、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、羧基、-CONH2、-COOR8、-COR8、-OR8、-NHCOR8、-NHCOOR8、-C6H5R9、吗啉基、哌啶基、四氢呋喃基、吡啶基基团取代，其中R8任选自C1～C4烷基、苯基，R9任选自甲基、乙基、异丙基、叔丁基、氟、氯、溴、乙酰基、甲氧基，乙氧基。3) C 0 - C 4 alkylene-R 5 -heterocyclyl, R 5 is selected from -COR 7 , -COOR 7 , wherein R 7 is selected from C 1 -C 3 alkylene; heterocyclic Selected from imidazolyl, pyrazolyl, indolyl, thienyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrrolyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, 1,3 -dioxolanyl, isoquinolyl, porphyrinyl, 1H-carbazolyl, 1H-benzo[d]imidazolyl, 1H-indenyl, benzo[d][1,3] An oxolyl group, a benzo[d]thiazolyl group, an H-pyrazole-3(2H)-one group, wherein the above heterocyclic group may be selected from 0, 1, 2 or 3, optionally selected from fluorine, Chlorine, bromine, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, carboxyl, -CONH 2 , -COOR 8 , -COR 8 , -OR 8 , -NHCOR 8 , -NHCOOR 8 , -C 6 H 5 R 9 , morpholinyl, piperidinyl, tetrahydrofuranyl, pyridyl group substituted, wherein R 8 is selected from C 1 -C 4 alkyl, phenyl, R 9 is selected from A Base, ethyl, isopropyl, tert-butyl, fluorine, chlorine, bromine, acetyl, methoxy, ethoxy.
进一步地，在其中一个实施例中，R1选自：Further, in one embodiment, R 1 is selected from the group consisting of:
1)H；1) H;
2)乙基；2) ethyl;
R2，R3选自：R 2 , R 3 are selected from:
1)H；1) H;
2)苯基，其可被1个或2个或3个甲氧基、乙氧基、甲酰基、叔丁基、吗啉基、苯基二氮烯基、苯氧基、甲酰胺基、氨基甲酸叔丁酯取代；2) a phenyl group which may be 1 or 2 or 3 methoxy, ethoxy, formyl, tert-butyl, morpholinyl, phenyldiazenyl, phenoxy, carboxamide, Substituted with t-butyl carbamate;
3)喹啉、异喹啉、苯并噻唑、其可任选被0或1个乙氧基取代。3) Quinoline, isoquinoline, benzothiazole, which may be optionally substituted by 0 or 1 ethoxy group.
本发明的另一目的是提供上述化合物的应用。Another object of the invention is to provide the use of the above compounds.
具体技术方案如下：上述化合物或其药学上可接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物、溶剂合物在制备RORγ受体抑制剂中的应用。The specific technical scheme is as follows: the use of the above compound or a pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal complex, hydrate or solvate thereof for preparing a RORγ receptor inhibitor.
上述化合物或其药学上可接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物、溶剂合物作为RORγ受体抑制剂在制备治疗脑脊髓炎、胶原诱导性关节炎、多发性硬化症、风湿性关节炎、牛皮癣、克隆疾病、哮喘和前列腺癌的药物中的应用。 The above compound or a pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal complex, hydrate, solvate thereof as a RORγ receptor inhibitor in the preparation of therapeutic encephalomyelitis, collagen inducibility Use in medicines for arthritis, multiple sclerosis, rheumatoid arthritis, psoriasis, clonal diseases, asthma and prostate cancer.
本发明的另一目的是提供一种药物组合物。Another object of the invention is to provide a pharmaceutical composition.
具体技术方案如下。The specific technical solutions are as follows.
一种作为RORγ受体抑制剂的药物组合物，其活性成分包括有上述化合物或其药学上可接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物、溶剂合物。A pharmaceutical composition as a ROR gamma receptor inhibitor, the active ingredient comprising the above compound or a pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal complex, hydrate, solvent Compound.
本发明提供了具有式I结构特征的2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺类化合物。经研究发现，该类化合物可有效抑制RORγ受体，从而调控Th17的分化，可作为治疗脑脊髓炎、胶原诱导性关节炎、多发性硬化症、风湿性关节炎、牛皮癣、克隆疾病、哮喘和前列腺癌等炎症相关类疾病的治疗药物。The present invention provides 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide compounds having the structural features of Formula I. Studies have found that these compounds can effectively inhibit the RORγ receptor, thereby regulating the differentiation of Th17, and can be used as a treatment for encephalomyelitis, collagen-induced arthritis, multiple sclerosis, rheumatoid arthritis, psoriasis, clonal diseases, asthma and A therapeutic drug for inflammation-related diseases such as prostate cancer.
图1.说明实施例1-91化合物对RORγ蛋白的抑制活性。Figure 1. illustrates the inhibitory activity of the compounds of Examples 1-91 on the RORy protein.
图2.说明实施例1-91化合物对RORγ细胞水平的抑制活性。Figure 2. illustrates the inhibitory activity of the compounds of Examples 1-91 on ROR gamma cell levels.
本发明所述化学物中，当任何变量(例如R1、R2等)在任何组分中出现超过一次，则其每次出现的定义独立于其它每次出现的定义。同样，允许取代基及变量的组合，只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环，其意味着这种键仅连接到邻近环的任何适当的碳原子上.要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定.短语“任选被一个或多个取代基取代”被认为与短语“任选被至少一个取代基取代”相当且在此情况下优选的实施方案将具有0-3个取代基。The chemical composition of the present invention, when any variable (e.g. R 1, R 2, etc.) appear in any component more than once defined, it is at each occurrence independently each occurrence of other definitions. Also, combinations of substituents and variables are allowed as long as such combinations stabilize the compound. A line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that the bond is only attached to any suitable carbon atom adjacent to the ring. It will be understood that one of ordinary skill in the art can select the substituents and substitution patterns of the compounds of the invention to provide chemical stability. Compounds which are readily synthesized from readily available starting materials by the techniques of the art and the methods set forth below. If the substituent itself is substituted by more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized. The phrase "optionally substituted with one or more substituents" is considered to be a phrase "Alternatively substituted with at least one substituent" is equivalent and in this case the preferred embodiment will have from 0 to 3 substituents.
本文所用术语“烷基”和“亚烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如，“C1-C4”烷基中“C1-C4”的定义包括以直链或支链排列的具有1、2、3、4、碳原子的基团。例如，“C1-C4”烷基“具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、甲基-环丙基、2,2-二甲基-环丁基、2-乙基-环戊基、环己基等。The terms "alkyl" and "alkylene" as used herein are meant to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of "C1-C4" in the "C1-C4" alkyl group includes a group having 1, 2, 3, 4, carbon atoms arranged in a straight chain or a branched chain. For example, "C1-C4" alkyl " specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl. The term "cycloalkyl" refers to the number of specific carbon atoms. Monocyclic saturated aliphatic hydrocarbon groups. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl and the like.
除非另有定义，烷基、环烷基和杂环基取代基可为未被取代的或取代的。例如，(C1-C4)烷基可被一个、两个或三个选自OH、卤素、烷氧基、二烷基氨基或杂环基，例如吗啉基、哌啶基等的取代基取代。Unless otherwise defined, alkyl, cycloalkyl and heterocyclyl substituents may be unsubstituted or substituted. For example, a (C1-C4)alkyl group may be substituted by one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclic groups such as morpholinyl, piperidinyl and the like. .
本发明包括式Ⅰ化合物的游离形式，也包括其药学上可接受的盐及立体异构体。本文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐，也包括所有式Ⅰ化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如，可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶 液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别，但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。The invention includes the free forms of the compounds of formula I, as well as the pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine compounds. The term "free form" refers to an amine compound in a non-salt form. The pharmaceutically acceptable salts included include not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula I. The free form of the particular salt of the compound can be isolated using techniques known in the art. For example, it can be dissolved by using a suitable alkaline dilute aqueous solution such as a dilute aqueous solution of NaOH or potassium carbonate. The salt is treated with a dilute aqueous solution of dilute aqueous ammonia and sodium bicarbonate to regenerate the free form. The free form differs somewhat from its respective salt form in solubility in certain physical properties, such as in polar solvents, but for purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常，通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的，通过和适当的无机或有机碱反应形成酸性化合物的盐。The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Typically, the salt of the basic compound is prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric or excess amount of the desired salt or mixture of the inorganic or organic acid in a suitable solvent or combination of solvents. Similarly, a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.
因此，本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如，常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐，也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2一乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。Thus, pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard. Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.
如果本发明化合物为酸性的，则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐.得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐，所述碱包括伯胺、仲胺和叔胺的盐，取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪，哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。If the compound of the invention is acidic, a suitable "pharmaceutically acceptable salt" refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts. Salt, calcium salt, copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganese salt, potassium salt, sodium salt, zinc salt and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. A salt derived from a pharmaceutically acceptable organic non-toxic base, the base comprising a salt of a primary, secondary and tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin such as a fine Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, B Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine , piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
由于在生理条件下化合物中脱质子化的酸性部分例如羧基可为阴离子的，而这种带有的电荷然后可被内部带有阳离子的质子化了的或烷基化的碱性部分例如四价氮原子平衡抵消，所以应注意本发明化合物是潜在的内盐或两性离子。Since the acidic moiety, such as a carboxyl group, which is deprotonated in a compound under physiological conditions, can be anionic, such charged charge can then be protonated or alkylated in the interior with a cationic moiety such as tetravalent The balance of nitrogen atoms is counteracted, so it should be noted that the compounds of the invention are potential internal salts or zwitterions.
除在文献中已知的或在实验程序中例证的标准方法外，可采用如下列方案中显示的反应制备本发明化合物。因此，下列说明性方案是为说明的目的而不是局限于所列化合物或任何特定的取代基。方案中显示的取代基数目并不必需符合权利要求中所用的数目，且为清楚起见，显示单取代基连接到在上文中式I的定义下允许有多取代基的化合物上。In addition to the standard methods known in the literature or exemplified in the experimental procedures, the compounds of the invention can be prepared using the reactions as shown in the scheme below. Accordingly, the following illustrative schemes are for illustrative purposes and are not limited to the listed compounds or any particular substituents. The number of substituents shown in the schemes does not necessarily have to correspond to the number used in the claims, and for the sake of clarity, it is shown that the mono-substituents are attached to a compound which allows multiple substituents under the definition of formula I above.
方案Program
如方案所示化合物可以由1,8-萘二甲酸酐为起始原料通过5步反应合成。 The compound as shown in the scheme can be synthesized from 1,8-naphthalic anhydride as a starting material by a 5-step reaction.
本申请所涉及的化合物及其药学可接受的盐可根据下面的方法用于治疗下列的疾病以及下面没有列出的其它疾病：1)脑脊髓炎；2)胶原诱导性关节炎；3)多发性硬化症；4)风湿性关节炎；5)牛皮癣；6)克隆疾病；7)哮喘；8)前列腺癌。The compounds and pharmaceutically acceptable salts thereof of the present application can be used according to the following methods for the treatment of the following diseases and other diseases not listed below: 1) encephalomyelitis; 2) collagen-induced arthritis; 3) multiple Sclerosing disease; 4) rheumatoid arthritis; 5) psoriasis; 6) clonal disease; 7) asthma; 8) prostate cancer.
本发明再一方面提供一种药物组合物，包括本发明所述的式(Ⅰ)化合物和一种或几种药学上可接受的辅料。本发明所述的组合物可以是液体、半液体或固体形式，按照适合于所用的给药途径的方式配制。。本发明所述的化合物在使用时可适用于各种给药途径，包括但不限于以下途径，口服、颊、吸入、舌下、直肠、阴道、脑池内的或鞘内、通过腰椎穿刺、经尿道、经皮肤或肠外(包括静脉注射、肌肉注射、皮下、行皮内注射、腹腔内、鞘内、手术植入)等。A further aspect of the invention provides a pharmaceutical composition comprising a compound of formula (I) according to the invention and one or more pharmaceutically acceptable excipients. The compositions of the present invention may be in liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration employed. . The compounds of the present invention can be applied to various routes of administration when used, including but not limited to the following routes, oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal, through lumbar puncture, menstrual Urethral, transdermal or parenteral (including intravenous, intramuscular, subcutaneous, intradermal, intra-abdominal, intrathecal, surgical implantation).
口服组合物可以是固体、凝胶或液体。固体制剂的实例包括但不限于片剂、胶囊剂、颗粒剂和散装粉剂。这些制剂可以选择地含有粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂和矫味剂等。粘合剂的实例包括但不限于微晶纤维素、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；润滑剂的实例包括但不限于滑石、淀粉、硬脂酸镁、硬脂酸钙、硬脂酸；稀释剂的实例包括但不限于乳糖、蔗糖、淀粉、甘露糖醇、磷酸二钙；助流剂的实例包括但不限于二氧化硅；崩解剂的实例包括但不限于交联羧甲基纤维素钠、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂和羧甲基纤维素。Oral compositions can be solid, gel or liquid. Examples of solid preparations include, but are not limited to, tablets, capsules, granules, and bulk powders. These preparations may optionally contain a binder, a diluent, a disintegrant, a lubricant, a glidant, a sweetener, a flavoring agent and the like. Examples of binders include, but are not limited to, microcrystalline cellulose, dextrose solution, gum arabic, gelatin solution, sucrose, and starch paste; examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate And stearic acid; examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, dicalcium phosphate; examples of glidants include, but are not limited to, silica; examples of disintegrants include, but are not limited to, Sodium carboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar and carboxymethyl cellulose.
以肠胃外给予本发明组合物，一般以注射为主，包括皮下、肌内或静脉内注射。注射剂可以被制成任何常规形式，如液体溶液或悬液、适合于在注射之前溶解或悬浮在液体中的固体形式或者乳剂。可用于本发明注射剂的药学上可接收的载体的实例包括但不限于水性载体、非水性载体、抗微生物剂、等渗剂、缓冲剂、抗氧剂、悬浮与分散剂、乳化剂、螯合剂和其它药学上可接受的物质。水性载体的实例包括氯化钠注射液、林格式注射液、等渗葡萄糖注 射液、无菌水注射液、葡萄糖与乳酸化林格氏注射液；非水性载体的实例包括植物来源的固定油、棉籽油、玉米油、芝麻油和花生油；抗微生物剂的实例包括间甲酚、苄醇、氯丁醇、苯扎氯铵等；等渗剂的实例包括氯化钠和葡萄糖；缓冲剂包括磷酸盐和柠檬酸盐。The compositions of the invention are administered parenterally, generally by injection, including subcutaneous, intramuscular or intravenous injection. The injection can be formulated into any conventional form, such as a liquid solution or suspension, a solid form or emulsion suitable for dissolution or suspension in a liquid prior to injection. Examples of pharmaceutically acceptable carriers which can be used in the injection of the present invention include, but are not limited to, aqueous carriers, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifiers, chelating agents And other pharmaceutically acceptable substances. Examples of aqueous carriers include sodium chloride injection, forest format injection, isotonic glucose injection Injection, sterile water injection, glucose and lactated Ringer's injection; examples of non-aqueous carrier include plant-derived fixed oil, cottonseed oil, corn oil, sesame oil and peanut oil; examples of antimicrobial agents include m-cresol , benzyl alcohol, chlorobutanol, benzalkonium chloride, etc.; examples of isotonic agents include sodium chloride and glucose; buffers include phosphates and citrates.
发明组合物还可以制备成无菌的冻干粉针剂，将化合物溶于磷酸钠缓冲溶液，其中含有葡萄糖或其他适合的赋形剂，随后在本领域技术人员已知的标准条件下将溶液无菌过滤，继之以冷冻干燥，得到所需的制剂。The compositions of the invention may also be prepared as sterile lyophilized powders in which the compound is dissolved in a sodium phosphate buffer solution containing glucose or other suitable excipients, followed by standard solutions under standard conditions known to those skilled in the art. The bacteria are filtered, followed by lyophilization to give the desired preparation.
以下实施例对本发明做进一步的描述，但该实施例并非用于限制本发明的保护范围。The invention is further described in the following examples, but this example is not intended to limit the scope of the invention.
实施例1Example 1
1-乙基-2-氧代-N-(2-氧代-2-(吡咯烷-1-取代)乙基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E1)1-ethyl-2-oxo-N-(2-oxo-2-(pyrrolidin-1-substituted)ethyl)-1,2-dihydrobenzo[cd]indole-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-oxo-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E1)
步骤1.1,3-二氧代-2,3-二氢-1H-非那烯-2-基4-甲基苯磺酸酯Step 1. 1,3-dioxo-2,3-dihydro-1H-phenaphen-2-yl 4-methylbenzenesulfonate
(1,3-dioxo-2,3-dihydro-1H-phenalen-2-yl 4-methylbenzenesulfonate)(1,3-dioxo-2,3-dihydro-1H-phenalen-2-yl 4-methylbenzenesulfonate)
在圆底烧瓶中加入1,8-萘二甲酸酐(1-1)(11.9g，0.06mol)、盐酸羟胺(4.18g，0.06mol)和吡啶(70mL)，加热至回流1小时。冷却至80℃，快速加入4-甲苯磺酰氯(22.88g，0.12mol)，升温至回流反应1.5小时。冷却至室温，将混合物倾倒入200g冰水中，搅拌有黄色沉淀析出。静置，抽滤，水洗三次，碳酸氢钠饱和溶液搅拌洗涤，抽滤，水洗三次，得到17g中间体1-2(78％)。1,8-Naphthalic anhydride (1-1) (11.9 g, 0.06 mol), hydroxylamine hydrochloride (4.18 g, 0.06 mol) and pyridine (70 mL) were added to a round bottom flask, and the mixture was heated to reflux for 1 hour. After cooling to 80 ° C, 4-toluenesulfonyl chloride (22.88 g, 0.12 mol) was quickly added, and the mixture was warmed to reflux for 1.5 hours. After cooling to room temperature, the mixture was poured into 200 g of ice water, and a yellow precipitate was precipitated by stirring. The mixture was allowed to stand, suction-filtered, washed with water three times, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate, filtered, and washed three times with water to obtain 17 g of Intermediate 1-2 (78%).
步骤2.苯并[cd]吲哚-2(1H)-酮(benzo[cd]indol-2(1H)-one)Step 2. Benzo[cd]indole-2(1H)-one (benzo[cd]indol-2(1H)-one)
在圆底烧瓶中分别加入化合物1-2(17g，0.048mol)，50mL乙醇，40mL水以及2.7mol/L的氢氧化钠溶液60mL，加热回流3h，冷却并减压除去乙醇，在75℃时滴入盐酸，调节PH至3，有黄色沉淀析出，抽滤，柱层析得6.65g黄色固体1-3(82％)。In a round bottom flask, compound 1-2 (17 g, 0.048 mol), 50 mL ethanol, 40 mL water and 60 mL of 2.7 mol/L sodium hydroxide solution were added, and the mixture was heated under reflux for 3 h, cooled and evaporated under reduced pressure at 75 ° C. Hydrochloric acid was added dropwise, and the pH was adjusted to 3, and a yellow precipitate was precipitated, which was filtered, and then purified by column chromatography to yield 6.
MS(ESI),m/z:M+170.0MS (ESI), m/z: M + 170.0
步骤3.1-乙基苯并[cd]吲哚-2(1H)-酮(1-ethylbenzo[cd]indol-2(1H)-one)Step 3.1-Ethylbenzo[cd]indole-2(1H)-one (1-ethylbenzo[cd]indol-2(1H)-one)
在圆底烧瓶中加入化合物1-3(6.65g，0.039mol)加入100mLN,N-二甲基甲酰胺作为溶剂，冰浴下加入氢化钠(2.81g,0.117mol)，搅拌5min，滴入碘丙烷(7.33g，0.047mol)，低温滴加10min，室温反应，TLC监测反应；待反应完全后，冰浴下滴入水淬灭反应；用乙酸乙酯萃取三次，合并有机层，饱和氯化钠水溶液洗一次，无水硫酸钠干燥过夜，旋干，得到6.46g黄色固体1-4(84％)。MS(ESI),m/z:M+198.0Compound 1-3 (6.65 g, 0.039 mol) was added to a round bottom flask, and 100 mL of N,N-dimethylformamide was added as a solvent. Sodium hydride (2.81 g, 0.117 mol) was added under ice-cooling, stirred for 5 min, and iodine was added dropwise. Propane (7.33g, 0.047mol), added dropwise at low temperature for 10min, reacted at room temperature, and monitored by TLC; after the reaction was completed, the reaction was quenched with water under ice bath; extracted three times with ethyl acetate. The sodium aqueous solution was washed once, dried over anhydrous sodium sulfate and dried overnight to yield 6.46 g (yel. MS (ESI), m/z: M + 198.0
步骤4.1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰氯Step 4.1-Ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonyl chloride
(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonyl chloride)(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonyl chloride)
将化合物1-4(6.46g，0.033mol)用100mL氯仿作为反应溶剂，冰浴下滴加氯磺酸(11.5g，0.099mol)，搅拌10min，升温至50℃，反应6h；将反应混合物倒入冰水中，搅拌至无气体逸出，用二氯甲烷萃取水层三次，合并有机层，饱和氯化钠水溶液洗一次，无水硫酸钠干燥，柱层析，得到5.75g黄绿色粉末状固体1-5(59％)。MS(ESI),m/z:M+297.1Compound 1-4 (6.46 g, 0.033 mol) was used as a reaction solvent with 100 mL of chloroform, and chlorosulfonic acid (11.5 g, 0.099 mol) was added dropwise under ice-cooling, stirred for 10 min, warmed to 50 ° C, and reacted for 6 h; The mixture was poured into ice water, stirred until no gas evolved, and the aqueous layer was extracted three times with dichloromethane. The organic layer was combined, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. 1-5 (59%). MS (ESI), m/z: M + 297.1
步骤5.1-乙基-2-氧代-N-(2-氧代-2-(吡咯烷-1–取代)乙基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E1)Step 5.1-Ethyl-2-oxo-N-(2-oxo-2-(pyrrolidin-1-substituted)ethyl)-1,2-dihydrobenzo[cd]indole-6-sulfonate Amide (E1)
(1-ethyl-2-oxo-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E1)(1-ethyl-2-oxo-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E1)
将1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰氯(100mg，0.34mmol)溶于10ml二氯甲烷中，加入2-氨基-1-(吡咯烷-1-基)乙酮(52mg，0.41mmol)滴加2mlDIPEA，室温反应5h，反应完全后，水洗，二氯甲烷萃取三次，合并有机层，饱和氯化钠水溶液洗一次，无水硫酸钠干燥，柱层析DCM:甲醇＝100:1-20:1，得到92mg黄绿色粉末状固体，收率70％。1-Ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonyl chloride (100 mg, 0.34 mmol) was dissolved in 10 ml of dichloromethane and 2-amino-1- (Pyrrolidin-1-yl)ethanone (52 mg, 0.41 mmol), 2 ml of DIPEA was added dropwise, and the mixture was reacted at room temperature for 5 h. After the reaction was completed, the mixture was washed with water and extracted with dichloromethane three times. Drying over sodium sulfate, column chromatography DCM:methanol = 100:1 - 20:1 to yield 92 mg of yellow green powdery solid, yield 70%.
1H-NMR(400MHz,d-DMSO)δ8.70(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.70 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 10.8 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.96 -7.89 (m, 2H), 7.28 (d, J = 7.2 Hz, 1H), 3.91 (q, J = 7.2 Hz, 2H)), 3.66 (d, J = 5.6 Hz, 1H), 3.25 (t, J = 6.5 Hz, 2H), 3.00 (t, J = 6.7 Hz, 2H), 1.75-1.72 (m, 2H), 1.62-1.58 (m, 2H), 1.25 (t, J = 6.9 Hz, 3H). (ESI), m/z: M + 388.0; M - 386.0.
实施例2Example 2
N-((1-乙酰基哌啶-4-取代)甲基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E2)N-((1-acetylpiperidin-4-substituted)methyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E2)
(N-((1-acetylpiperidin-4-yl)methyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E2)(N-((1-acetylpiperidin-4-yl)methyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E2)
合成方法如实施例1。 The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.69(d,J＝8.4Hz,1H),8.16(d,J＝6.8Hz,1H),8.07(d,J＝7.6Hz,1H),7.96(t,J＝7.2Hz,1H),7.86(t,J＝6.0Hz,1H),7.31(d,J＝7.6Hz,1H),4.24(d,J＝8.0Hz,1H),3.93(q,J＝6.8Hz,2H),3.69(d,J＝12.4Hz,1H),2.87(t,J＝13.2Hz,1H),2.64(t,J＝6.0Hz,2H),2.36(t,J＝12.0Hz,1H).1.92(s,3H),1.56-1.51(m,3H),1.28(t,J＝7.2Hz,3H). 1 H-NMR (400 MHz, d-DMSO) δ 8.69 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 6.8 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.96 (t, J = 7.2 Hz, 1H), 7.86 (t, J = 6.0 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 4.24 (d, J = 8.0 Hz, 1H), 3.93 (q) , J = 6.8 Hz, 2H), 3.69 (d, J = 12.4 Hz, 1H), 2.87 (t, J = 13.2 Hz, 1H), 2.64 (t, J = 6.0 Hz, 2H), 2.36 (t, J =12.0 Hz, 1H).1.92 (s, 3H), 1.56-1.51 (m, 3H), 1.28 (t, J = 7.2 Hz, 3H).
MS(ESI),m/z:M+417.0；M-415.0.MS (ESI), m/z: M + 417.0; M - 415.0.
实施例3Example 3
1-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)环己烷甲酰胺(E3)1-(1-Ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)cyclohexanecarboxamide (E3)
(N-(1-acetylcyclohexyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E3)(N-(1-acetylcyclohexyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E3)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.58(d,J＝8.4Hz,1H),8.15(d,J＝7.2Hz,1H),8.09(d,J＝7.6Hz,1H),7.96(t,J＝8.0Hz,1H),7.31(d,J＝7.6Hz,1H),3.92(q,J＝6.8Hz,2H),3.26-3.21(m,4H),1.25(t,J＝7.2Hz,3H),1.01-0.98(m,6H).MS(ESI),m/z:M-400.8. 1 H-NMR (400 MHz, d-DMSO) δ 8.58 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 7.2 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 3.92 (q, J = 6.8 Hz, 2H), 3.26 - 3.21 (m, 4H), 1.25 (t, J = 7.2 Hz, 3H), 1.01-0.98 (m, 6H). MS (ESI), m/z: M - 400.8.
实施例4Example 4
1-乙基-N-(2-(乙基磺酰基)乙基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E4)1-ethyl-N-(2-(ethylsulfonyl)ethyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E4)
(1-ethyl-N-(2-(ethylsulfonyl)ethyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E4)(1-ethyl-N-(2-(ethylsulfonyl)ethyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E4)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.67(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.67 (d, J = 8.4 Hz, 1H), 8.17-8.10 (m, 2H), 7.97 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 3.95 (q, J = 6.8 Hz, 2H), 3.18 - 3.04 (m, 6H), 1.26 (t, J = 6.8 Hz, 3H), 1.13 (t, J = 7.2 Hz, 2H).MS (ESI), m/z: M - 395.0.
实施例5Example 5
N-((3,5-二甲基-4,5-二氢异恶唑-5-取代)甲基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E5)N-((3,5-Dimethyl-4,5-dihydroisoxazole-5-substituted)methyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd ]吲哚-6-sulfonamide (E5)
(1-ethyl-N-((4-methylmorpholin-2-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E5)(1-ethyl-N-((4-methylmorpholin-2-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E5)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.68(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.68 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.99 (t, J = 6.0 Hz, 1H), 7.92 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 3.93 (q, J = 7.2 Hz, 1H), 3.54 (d) , J = 10.8 Hz, 2H), 3.18 (t, J = 10.4 Hz, 1H), 2.82 (t, J = 6.0 Hz, 2H), 2.49 - 2.39 (m, 2H), 1.98 (s, 3H). 1.75 (t, J = 8.4 Hz, 1H), 1.44 (t, J = 10.8 Hz, 1H), 1.27-1.23 (m, 4H). MS (ESI), m/z: M - 388.1.
实施例6Example 6
1-乙基-N-((3-异丙基-4,5-二氢异恶唑-5-取代)甲基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E6)1-ethyl-N-((3-isopropyl-4,5-dihydroisoxazole-5-substituted)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole哚-6-sulfonamide (E6)
(1-ethyl-N-((3-isopropyl-4,5-dihydroisoxazol-5-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E6)(1-ethyl-N-((3-isopropyl-4,5-dihydroisoxazol-5-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E6)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.70(d,J＝8.0Hz,1H),8.14-8.09(m,2H),8.06(d,J＝7.6Hz,1H),7.94(t,J＝7.6Hz,1H),7.29(d,J＝7.2Hz,1H),4.43-4.39(m,1H),3.93(q,J＝6.8Hz,2H),2.84-2.83(m,2H),2.48(s,3H),1.26(t,J＝6.8Hz,1H).0.98(s,6H).MS(ESI),m/z:M-400.0. 1 H-NMR (400 MHz, d-DMSO) δ 8.70 (d, J = 8.0 Hz, 1H), 8.14 - 8.09 (m, 2H), 8.06 (d, J = 7.6 Hz, 1H), 7.94 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 4.43-4.39 (m, 1H), 3.93 (q, J = 6.8 Hz, 2H), 2.84 - 2.83 (m, 2H), 2.48(s,3H), 1.26(t,J=6.8Hz,1H).0.98(s,6H).MS(ESI), m/z: M - 400.0.
实施例7Example 7
N-((3,5-二甲基-4,5-二氢异恶唑-5-基)甲基)-1-乙基-2-氧代-1,2-二氢苯并〔cd]吲哚-6-磺酰胺(E7)N-((3,5-Dimethyl-4,5-dihydroisoxazole-5-yl)methyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd ]吲哚-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)(N-((3,5-dimethyl-4,5-dihydroisoxazol-5-yl)methyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E7)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.72(d,J＝8.4Hz,1H),8.15-8.10(m,2H),8.07(d,J＝7.6Hz,1H),7.94(t,J＝7.2Hz,1H),7.30(d,J＝7.6Hz,1H),3.93(q,J＝7.2Hz,2H),2.85-2.82(m,3H),2.58(s,1H),1.75(s,3H).1.27-1.22(m,4H),1.17(s,2H).MS(ESI),m/z:M-386.0. 1 H-NMR (400 MHz, d-DMSO) δ 8.72 (d, J = 8.4 Hz, 1H), 8.15 - 8.10 (m, 2H), 8.07 (d, J = 7.6 Hz, 1H), 7.94 (t, J=7.2 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 3.93 (q, J=7.2 Hz, 2H), 2.85-2.82 (m, 3H), 2.58 (s, 1H), 1.75 ( s,3H).1.27-1.22(m,4H), 1.17(s,2H).MS(ESI), m/z: M - 386.0.
实施例8Example 8
1-乙基-N-((5-甲基-1H-吲唑-3-基)甲基)-2-氧代-1,2-二氢苯并〔cd]吲哚-6-磺酰胺(E8)1-ethyl-N-((5-methyl-1H-indazol-3-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E8)
(1-ethyl-N-((5-methyl-1H-indazol-3-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E8)(1-ethyl-N-((5-methyl-1H-indazol-3-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E8)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ12.49(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. 1 H-NMR (400 MHz, d-DMSO) δ 12.49 (s, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.39 (t, J = 5.6 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.83 (q, J = 7.2 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 7.6 Hz) , 1H), 6.87 (s, 1H), 6.81 (d, J = 8.4 Hz, 1H), 4.33 (d, J = 5.6 Hz, 2H), 3.85 (q, J = 7.2 Hz, 2H), 1.98 (s) , 3H), 1.27 (t, J = 7.2 Hz, 3H). MS (ESI), m/z: M + 421.0; M - 419.0.
实施例9Example 9
1-乙基-N-((4-甲基-6-(三氟甲基)嘧啶-2-取代)甲基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E9)1-ethyl-N-((4-methyl-6-(trifluoromethyl)pyrimidine-2-substituted)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole -6-sulfonamide (E9)
(1-ethyl-N-((4-methyl-6-(trifluoromethyl)pyrimidin-2-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E9)(1-ethyl-N-((4-methyl-6-(trifluoromethyl)pyrimidin-2-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E9)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.72(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.72 (t, J = 6.4 Hz, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 6.8 Hz, 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 = 7.2 Hz, 3H). MS (ESI), m/z: M - 449.0.
实施例10Example 10
叔丁基(3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)苯基)氨基甲酸叔丁酯(E10)tert-Butyl (3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)phenyl)carbamic acid tert-butyl ester (E10)
(tert-butyl(3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)phenyl)carbamate)(E10)(tert-butyl(3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)phenyl)carbamate)(E10)
1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰氯合成方法如实施例1.1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonyl chloride synthesis method as in Example 1.
取1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰氯(60mg,0.203mmol)，DAMP(5mg,0.041mmol)和叔丁基(3-氨基苯基)氨基甲酸叔丁酯(85mg，0.406mmol)溶于10mL DMF中，加入三乙胺2mL。室温反应过夜，反应完全后，水洗，乙酸乙酯萃取三次，合并有机层，10％盐酸50mL洗一次，饱和氯化钠水溶液洗一次，无水硫酸钠干燥，柱层析，得到54mg黄绿色粉末状固体，收率58％。1-Ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonyl chloride (60 mg, 0.203 mmol), DAMP (5 mg, 0.041 mmol) and tert-butyl (3- tert-Butyl aminophenyl)carbamate (85 mg, 0.406 mmol) was dissolved in 10 mL of DMF and 2 mL of triethylamine was added. After reacting at room temperature overnight, the reaction was completed, washed with water, and extracted with EtOAc EtOAc EtOAc EtOAc EtOAc. Solid, yield 58%.
1H-NMR(400MHz,d-DMSO)δ8.58(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.58 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.17 (s, 1H), 7.01 (t, J = 8.2 Hz, 2H), 6.83 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 7.2 Hz) , 1H), 6.63 (s, 1H), 3.91 (dd, J = 14.2 Hz, 7.0 Hz, 2H), 1.43 (s, 9H), 1.25 (t, J = 7.0 Hz, 3H). MS (ESI), m/z: M - 446.1.
实施例11Example 11
N-(3,4-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E11)N-(3,4-Dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E11)
(N-(3,4-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E11) (N-(3,4-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E11)
合成方法如实施例10。The synthesis method was as in Example 10.
1H-NMR(400MHz,d-DMSO)δ8.55(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.55 (d, J = 8.4 Hz, 1H), 8.04 (t, J = 3.6 Hz, 2H), 7.72 (t, J = 7.4 Hz, 1H), 7.36 -7.23 (m, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.64 (s, 1H), 6.55 (d, J = 8.8 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H) , 3.93 (dd, J = 14.0 Hz, 6.8 Hz, 2H), 3.73 (s, 3H), 3.65 (s, 3H), 1.24 (t, J = 7.0 Hz, 3H). MS (ESI), m/z :M + 413.1; M - 411.0.
实施例12Example 12
1-乙基-N-((1-甲基-5-(三氟甲基)-1H-苯并[d]咪唑-2-取代)甲基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E12)1-ethyl-N-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-substituted)methyl)-2-oxo-1,2-di Hydrogen benzo[cd]indole-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)(1-ethyl-N-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6- Sulfonamide)(E12)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.70(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). 1 H-NMR (400 MHz, d-DMSO) δ 8.70 (t, J = 6.0 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.35 (s, 1H), 6.95 (d, J = 7.6 Hz, 1H), 4.41 (d, J = 5.6 Hz, 2H), 3.73 (q, J = 7.2 Hz, 2H), 3.51 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H).
MS(ESI),m/z:M+489.0；M-487.0.MS (ESI), m/z: M + 489.0; M - 487.0.
实施例13Example 13
1-乙基-N-((5-氟-1H-吲哚-2-取代)甲基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E13)1-ethyl-N-((5-fluoro-1H-indol-2-substituted)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide ( E13)
(1-ethyl-N-((5-fluoro-1H-indol-2-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E13)(1-ethyl-N-((5-fluoro-1H-indol-2-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E13)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ10.78(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. 1 H-NMR (400 MHz, d-DMSO) δ 10.78 (s, 1H) 8.68 (d, J = 8.4 Hz, 1H), 8.33 (t, J = 5.6 Hz, 1H), 8.04-8.01 (m, 2H) ), 7.88 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.09 (t, J = 4.8 Hz, 1H), 6.94 (dd, J = 2.4 Hz, J = 2.0) Hz, 1H), 6.77-6.72 (m, 1H), 5.94 (s, 1H), 4.13 (d, J = 5.6 Hz, 2H), 3.87 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H). MS (ESI), m/z: M - 422.0.
实施例14 Example 14
1-乙基-N-((5-甲氧基-1H-吲哚-2–取代)甲基)-2-氧代基-1,2-二氢苯并[cd]吲哚-6-磺酰胺(14)1-ethyl-N-((5-methoxy-1H-indole-2-substituted)methyl)-2-oxoyl-1,2-dihydrobenzo[cd]indole-6- Sulfonamide (14)
(1-ethyl-N-((5-methoxy-1H-indol-2-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E14)(1-ethyl-N-((5-methoxy-1H-indol-2-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E14)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ10.51(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. 1 H-NMR (400MHz, d -DMSO) δ10.51 (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 = 7.6 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.68 (s, 1H), 6.56 (dd, J=1.6 Hz, J=1.6 Hz, 1H), 5.82 (s, 1H), 4.11 (d, J=6.0 Hz, 2H), 3.86 (q, J=7.2 Hz, 2H), 3.66 (s, 1H) .1.28(t, J=6.8Hz, 3H). MS (ESI), m/z: M + 436.0; M - 434.0.
实施例15Example 15
1-乙基-N-(3-甲基-1-(吡啶-3-取代)丁基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E15)1-ethyl-N-(3-methyl-1-(pyridin-3-substituted)butyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide ( E15)
(1-ethyl-N-(3-methyl-1-(pyridin-3-yl)butyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E15)(1-ethyl-N-(3-methyl-1-(pyridin-3-yl)butyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E15)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.53(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.53 (d, J = 8.4 Hz, 1H), 8.44 (d, J = 9.2 Hz, 1H), 8.05 (d, J = 7.2 Hz, 1H), 7.99 (s, 1H), 7.92-7.82 (m, 3H), 7.21 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.65 (dd, J = 4.8 Hz, J = 4.8 Hz, 2H), 4.17 (q, J = 9.2 Hz, 1H), 9.91-3.80 (m, 2H), 1.57-1.50 (m, 1H), 1.45-1.39 (m, 1H). 0.76 (d, J = 5.6 Hz, 3H), 0.69 (d, J = 6.4 Hz, 3H). MS (ESI), m/z: M - 442.1.
实施例16Example 16
1-N-(4-氯-3-(三氟甲基)苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E16)1-N-(4-chloro-3-(trifluoromethyl)phenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide ( E16)
(N-(4-chloro-3-(trifluoromethyl)phenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E16)(N-(4-chloro-3-(trifluoromethyl)phenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E16)
合成方法如实施例10。The synthesis method was as in Example 10.
1H-NMR(400MHz,d-DMSO)δ11.12(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). 1 H-NMR (400 MHz, d-DMSO) δ 11.12 (s, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 6.8 Hz, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.31 (dd, J = 14.2 Hz) , 8.2 Hz, 2H), 3.89 (dd, J = 14.2 Hz, 7.0 Hz, 2H), 1.23 (t, J = 7.0 Hz, 3H).
MS(ESI),m/z:M+457.0；M-453.0.MS (ESI), m/z: M + 457.0; M - 453.0.
实施例17Example 17
N-(4-乙酰基苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E17)N-(4-Acetylphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E17)
(N-(4-acetylphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E17)(N-(4-acetylphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E17)
合成方法如实施例10。The synthesis method was as in Example 10.
1H-NMR(400MHz,d-DMSO)δ10.82(s,1H),8.69(d,J＝8.4Hz,1H),8.19(d,J＝7.6Hz,1H),8.09(d,J＝7.2Hz,1H),7.94(t,J＝8.0Hz,1H),7.58-7.53(m,2H),7.31(d,J＝5.6Hz,2H),7.25(d,J＝7.6Hz,1H),3.86(q,J＝6.8Hz,2H),2.43(s,3H),1.22(t,J＝6.8Hz,3H).MS(ESI),m/z: 1 H-NMR (400 MHz, d-DMSO) δ 10.82 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.58-7.53 (m, 2H), 7.31 (d, J = 5.6 Hz, 2H), 7.25 (d, J = 7.6 Hz, 1H) , 3.86 (q, J = 6.8 Hz, 2H), 2.43 (s, 3H), 1.22 (t, J = 6.8 Hz, 3H). MS (ESI), m/z:
M+395.0；M-393.0.M + 395.0; M - 393.0.
实施例18Example 18
N-(苯并[d][1,3]间二氧杂环戊烯-5–取代甲基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E18)N-(Benzo[d][1,3]dioxol-5-substituted methyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole哚-6-sulfonamide (E18)
(N-(benzo[d][1,3]dioxol-5-ylmethyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E18)(N-(benzo[d][1,3]dioxol-5-ylmethyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E18)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.62(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.62 (d, J = 8.4 Hz, 1H), 8.31 (t, J = 6.4 Hz, 1H), 8.11 (d, J = 6.8 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.90 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 6.46 (d , J = 7.6 Hz, 2H), 5.80 (s, 2H), 3.91 (d, J = 6.8 Hz, 1H), 1.27 (t, J = 6.8 Hz, 3H). MS (ESI), m/z: M + 411.0; M - 409.1.
实施例19Example 19
1-乙基-N-(4-吗啉代苯基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E19)1-ethyl-N-(4-morpholinophenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E19)
(1-ethyl-N-(4-morpholinophenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E19)(1-ethyl-N-(4-morpholinophenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E19)
合成方法如实施例10。The synthesis method was as in Example 10.
1H-NMR(400MHz,d-DMSO)δ10.08(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. 1 H-NMR (400 MHz, d-DMSO) δ 10.08 (s, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 6.8 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.86 (t, J = 8.4 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 9.2 Hz) , 2H), 3.87 (q, J = 6.8 Hz, 2H), 3.62-3.60 (m, 4H), 2.91-2.89 (m, 4H), 1.22 (t, J = 7.2 Hz, 3H). MS (ESI) , m / z: M + 438.0; M - 436.0.
实施例20Example 20
1-乙基-2-氧代-N-(吡啶-2-基甲基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E20)1-ethyl-2-oxo-N-(pyridin-2-ylmethyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E20)
(1-ethyl-2-oxo-N-(pyridin-2-ylmethyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E20)(1-ethyl-2-oxo-N-(pyridin-2-ylmethyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E20)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.66(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.66 (d, J = 8.4 Hz, 1H), 8.49 (t, J = 6.0 Hz, 1H), 8.21. (d, J = 4.4 Hz, 1H), 8.11 (d, J = 6.8 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.91 (t, J = 8.0 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.20 - 7.15 (m, 2H), 7.05-7.02 (m, 1H), 4.11 (d, J = 6.4 Hz, 2H), 3.89 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 6.8 Hz, 3H). MS ( ESI), m/z: M + 368.0; M - 366.0.
实施例21Example 21
1-乙基-N-(4-甲基苄基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E21)1-ethyl-N-(4-methylbenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E21)
(1-ethyl-N-(4-methylbenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E21)(1-ethyl-N-(4-methylbenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide) (E21)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.64(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.64 (d, J = 8.4 Hz, 1H), 8.33 (t, J = 6.4 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 8.0 Hz, 2H), 6.81 (d , J=8.0 Hz, 2H), 3.94-3.87 (m, 4H), 2.10 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H). MS (ESI), m/z: M - 379.0.
实施例22Example 22
N-(4-(叔丁基)苄基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E22)N-(4-(tert-butyl)benzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E22)
(N-(4-(tert-butyl)benzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E22)(N-(4-(tert-butyl)benzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E22)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.62(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.62 (d, J = 8.8 Hz, 1H), 8.35 (t, J = 6.4 Hz, 1H), 8.09 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 3.97 (d , J = 6.4 Hz, 2H), 3.87 (q, J = 6.8 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H), 1.10 (s, 9H). MS (ESI), m/z: M - 421.2.
实施例23Example 23
1-乙基-N-(4-氟苯乙基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E23)1-ethyl-N-(4-fluorophenethyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E23)
(1-ethyl-N-(4-fluorophenethyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E23) (1-ethyl-N-(4-fluorophenethyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E23)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.55(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.55 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 6.8 Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.89 -7.85 (m, 2H), 7.20 (d, J = 7.6 Hz, 1H), 6.97-6.94 (m, 2H), 6.74 (t, J = 8.8 Hz, 2H), 3.90 (q, J = 6.8 Hz, 2H), 3.02 (q, J = 6.8 Hz, 2H), 2.57 (t, J = 6.8 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H). MS (ESI), m/z: M - 397.0.
实施例24Example 24
N-((2,2-二甲基-1,3-二氧戊环-4-基)甲基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E24)N-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]吲哚-6-sulfonamide (E24)
(N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E24)(N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E24)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.68(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.68 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 6.8 Hz, 1H), 8.09-8.03 (m, 2H), 7.95-9- 7.91 (m, 1H), 7.29 (d, J = 7.6 Hz, 1H), 3.98-9.90 (m, 2H), 3.84 (q, J = 6.0 Hz, 1H), 3.54 (q, J = 5.6 Hz, 1H) ), 2.84 (t, J = 6.0 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H), 1.14 (s, 3H), 1.11 (s, 3H). MS (ESI), m/z: M - 389.1.
实施例25Example 25
1-乙基-N-(2-吗啉代乙基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E25)1-ethyl-N-(2-morpholinoethyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E25)
(1-ethyl-N-(2-morpholinoethyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E25)(1-ethyl-N-(2-morpholinoethyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E25)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.68(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). 1 H-NMR (400 MHz, d-DMSO) δ 8.68 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 6.8 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.95 (q, J = 7.2 Hz, 1H), 7.71 (s, 1H), 7.29 (d, J = 7.6 Hz, 1H), 3.93 (q, J = 7.2 Hz, 2H), 3.25 (t, J = 4.4, 4H), 2.89 (s, 2H), 2.19 (t, J = 6.4 Hz, 2H), 2.07 (d, J = 4.0 Hz, 4H), 1.26 (t, J = 8.8 Hz, 3H).
MS(ESI),m/z:M+390.1；M-388.1.MS (ESI), m/z: M + 390.1; M - 388.1.
实施例26Example 26
1-乙基-N-(4-甲氧基苄基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E26)1-ethyl-N-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E26)
(1-ethyl-N-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E26) (1-ethyl-N-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E26)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.63(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.63 (d, J = 8.4 Hz, 1H), 8.28 (t, J = 6.4 Hz, 1H), 8.11 (d, J = 6.8 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.90 (q, J = 7.2 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.57 (d , J=8.8 Hz, 2H), 2.93-3.88 (m, 5H), 3.60 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H). MS (ESI), m/z: [M+H ]-,395.1.
实施例27Example 27
1-乙基-N-(3-甲基苄基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E27)1-ethyl-N-(3-methylbenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E27)
(1-ethyl-N-(3-methylbenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E27)(1-ethyl-N-(3-methylbenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide) (E27)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.65(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.65 (d, J = 8.4 Hz, 1H), 8.34 (t, J = 6.4 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.91 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 6.84 - 6.80 (m, 2H), 6.71 (s, 1H), 3.98 (d, J = 6.4 Hz, 2H), 3.90 (q, J = 6.8 Hz, 2H), 1.98 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H). MS (ESI), m/z: M - 379.1.
实施例28Example 28
N-((6-氯吡啶-3-取代)甲基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E28)N-((6-chloropyridin-3-substituted)methyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E28)
(N-((6-chloropyridin-3-yl)methyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E28)(N-((6-chloropyridin-3-yl)methyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E28)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.57(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 1 H-NMR (400 MHz, d-DMSO) δ 8.57 (d, J = 8.4 Hz, 1H), 8.48 (t, J = 6.4 Hz, 1H), 8.11 (d, J = 6.8 Hz, 1H), 7.98 -7.97 (m, 2H), 7.90 (q, J = 7.2 Hz, 1H), 7.44 - 7.41 (m, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 4.06 (d, J = 6.4 Hz, 1H), 3.91 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 8.8 Hz, 3H). MS (ESI), m/z: M - 400.0
实施例29Example 29
1-乙基-N-(3-氟-4-甲基苄基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E29)1-ethyl-N-(3-fluoro-4-methylbenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E29)
(1-ethyl-N-(3-fluoro-4-methylbenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E29)(1-ethyl-N-(3-fluoro-4-methylbenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E29)
合成方法如实施例1。 The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.64(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.64 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H), 8.13 (d, J = 6.8 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.86 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.86 (t, J = 8.8 Hz, 1H), 6.65 (t, J = 6.4 Hz) , 1H), 3.97 (s, 2H), 3.90 (q, J = 7.2 Hz, 2H), 1.96 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H). MS (ESI), m/z :M - 397.1.
实施例30Example 30
N-(2-氯-6-氟苄基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E30)N-(2-chloro-6-fluorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E30)
(N-(2-chloro-6-fluorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E30)(N-(2-chloro-6-fluorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E30)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.63(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). 1 H-NMR (400 MHz, d-DMSO) δ 8.63 (d, J = 8.4 Hz, 1H), 8.37 (t, J = 6.0 Hz, 1H), 8.10 (d, J = 6.8 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.86 (q, J = 6.8 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.13 - 7.07 (m, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.13 (d, J = 4.8 Hz, 1H), 3.92 (q, J = 6.8 Hz, 1H), 1.27 (t, J = 6.8 Hz) , 3H).
MS(ESI),m/z:M-417.0.MS (ESI), m/z: M - 417.0.
实施例31Example 31
N-(4-氯苯乙基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E31)N-(4-chlorophenethyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E31)
(N-(4-chlorophenethyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E31)(N-(4-chlorophenethyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E31)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.55(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.55 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.89 -7.85 (m, 2H), 7.21 (d, J = 7.6 Hz, 1H), 6.95 (s, 4H), 3.94 (q, J = 7.2 Hz, 2H), 3.08 (q, J = 6.8 Hz, 2H) , 2.59 (t, J = 6.8 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H). MS (ESI), m/z: M - 413.0.
实施例32Example 32
1-乙基-N-(4-氟苄基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E32)1-ethyl-N-(4-fluorobenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E32)
(1-ethyl-N-(4-fluorobenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E32)(1-ethyl-N-(4-fluorobenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide) (E32)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.64(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.64 (d, J = 8.4 Hz, 1H), 8.40 (t, J = 6.4 Hz, 1H), 8.13 (d, J = 6.8 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.89 (q, J = 7.2 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.10-7.07 (m, 2H), 6.89 - 6.83 (m, 2H), 4.01 (d, J = 6.4 Hz, 2H), 3.88 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H). MS (ESI), m/z: M - 383.0.
实施例33Example 33
N-(2-氯苄基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E33)N-(2-chlorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E33)
(N-(2-chlorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E33)(N-(2-chlorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E33)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.68(d,J＝8.0Hz,1H),8.13(d,J＝7.2Hz,1H),8.04(d,J＝7.6Hz,1H),7.92(t,J＝7.2Hz,1H),7.27-7.29(m,3H),7.12-7.02(m,2H),4.12(s,2H),3.93(q,J＝7.2Hz,1H),1.27(t,J＝7.2Hz,3H).MS(ESI),m/z:M-399.0. 1 H-NMR (400 MHz, d-DMSO) δ 8.68 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 7.2 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.92 (t, J = 7.2 Hz, 1H), 7.27-7.29 (m, 3H), 7.12-7.02 (m, 2H), 4.12 (s, 2H), 3.93 (q, J = 7.2 Hz, 1H), 1.27 ( t, J = 7.2 Hz, 3H). MS (ESI), m/z: M - 399.0.
实施例34Example 34
1-乙基-N-(3-吗啉代丙基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E34)1-ethyl-N-(3-morpholinopropyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E34)
(1-ethyl-N-(3-morpholinopropyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E34)(1-ethyl-N-(3-morpholinopropyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E34)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.69(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.69 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 6.8 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.31 (d, J = 7.6 Hz, 1H), 3.95 (q, J = 7.2 Hz, 2H), 3.37 (s, 4H), 2.82 (d, J = 5.2 Hz, 2H), 2.06-2.02 (m, 6H), 1.42 (t, J = 6.8 Hz, 2H), 1.28 (t, J = 6.8 Hz, 3H). MS (ESI), m /z: M + 403.5; M - 402.1.
实施例35Example 35
1-乙基-N-(2-氟苄基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E35)1-ethyl-N-(2-fluorobenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E35)
(1-ethyl-N-(2-fluorobenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E35)(1-ethyl-N-(2-fluorobenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E35)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.64(d,J＝8.4Hz,1H),8.41(s,1H),8.12(d,J＝6.8Hz,1H),8.03(d,J＝8.0Hz,1H),7.91(t,J＝7.2Hz,1H),7.21(d,J＝7.6Hz,1H),7.15(t,J＝8.0Hz,1H),7.07-7.05(m,1H),7.91-7.83(m,2H),4.06(s,2H),3.92(q,J＝7.2Hz,2H),1.29(t,J＝7.2Hz,3H).MS(ESI),m/z:M-383.0. 1 H-NMR (400 MHz, d-DMSO) δ 8.64 (d, J = 8.4 Hz, 1H), 8.41 (s, 1H), 8.12 (d, J = 6.8 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.91 (t, J = 7.2 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.07-7.05 (m, 1H) , 7.91-7.83 (m, 2H), 4.06 (s, 2H), 3.92 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H). MS (ESI), m/z: M - 383.0.
实施例36Example 36
N-(1-乙酰基-4–取代)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6–磺酰胺(E36)N-(1-acetyl-4-substituted)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E36)
(N-(1-acetylpiperidin-4-yl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E36) (N-(1-acetylpiperidin-4-yl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E36)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.70(d,J＝8.4Hz,1H),8.16-8.11(m,2H),8.02(d,J＝7.6Hz,1H),7.94(q,J＝7.2Hz,1H),7.30(d,J＝8.0Hz,1H),4.01(q,J＝6.8Hz,1H),3.93(q,J＝7.2Hz,2H),3.58(d,J＝14.0Hz,1H),3.33-3.19(m,1H),2.97-2.90(m,1H),2.62-2.55(m,1H),1.88(s,3H),1.49(d,J＝10.0Hz,2H),1.28(t,J＝7.2Hz,3H),1.27-1.22(m,2H).MS(ESI),m/z:M+402.1；M-400.1. 1 H-NMR (400 MHz, d-DMSO) δ 8.70 (d, J = 8.4 Hz, 1H), 8.16 - 8.11 (m, 2H), 8.02 (d, J = 7.6 Hz, 1H), 7.94 (q, J = 7.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.01 (q, J = 6.8 Hz, 1H), 3.93 (q, J = 7.2 Hz, 2H), 3.58 (d, J = 14.0 Hz, 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 = 10.0 Hz, 2H) ), 1.28 (t, J = 7.2 Hz, 3H), 1.27-1.22 (m, 2H). MS (ESI), m/z: M + 402.1; M - 400.1.
实施例37Example 37
1-乙基-N-(2-甲基苄基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E37)1-ethyl-N-(2-methylbenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E37)
(1-ethyl-N-(2-methylbenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E37)(1-ethyl-N-(2-methylbenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide) (E37)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.70(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.70 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H), 8.13 (d, J = 6.8 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.94-7.90 (m, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 6.99-6.92 (m, 3H), 3.98- 3.90 (m, 4H), 2.09 (s, 3H), 1.28 (t, J = 6.8 Hz, 3H). MS (ESI), m/z: M - 379.1.
实施例38Example 38
1-乙基-6-((4-(吡啶-4-基甲基)哌嗪-1–取代)磺酰基)苯并[cd]吲哚-2(1H)-酮(E38)1-ethyl-6-((4-(pyridin-4-ylmethyl)piperazine-1 -substituted)sulfonyl)benzo[cd]indole-2(1H)-one (E38)
(1-ethyl-6-((4-(pyridin-4-ylmethyl)piperazin-1-yl)sulfonyl)benzo[cd]indol-2(1H)-one)(E38)(1-ethyl-6-((4-(pyridin-4-ylmethyl)piperazin-1-yl)sulfonyl)benzo[cd]indol-2(1H)-one)(E38)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.64(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.64 (d, J = 8.4 Hz, 1H), 8.40 - 8.38 (m, 2H), 8.16 (d, J = 7.2 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.94 (dd, J = 7.2 Hz; J = 7.2 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 6.8 Hz, 2H), 3.94 (q, J = 6.8 Hz, 2H), 3.44 (s, 2H), 3.00 (s, 4H), 2.40-2.38 (m, 4H), 1.29 (t, J = 7.2 Hz, 3H). MS (ESI) , m/z: M + 437.5; M - 436.1.
实施例39Example 39
N-(2-氯苯乙基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E39)N-(2-chlorophenethyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E39)
(N-(2-chlorophenethyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E39) (N-(2-chlorophenethyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E39)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.60(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.60 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 8.00 (t, J = 5.6 Hz, 1H), 7.91 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.11 (d) , J = 6.8 Hz, 1H), 7.05-6.97 (m, 2H), 3.93 (q, J = 7.2 Hz, 2H), 3.06 (q, J = 6.4 Hz, 2H), 2.69 (t, J = 7.2 Hz) , 2H), 1.29 (t, J = 7.2 Hz, 3H) MS (ESI), m/z: M - 413.1.
实施例40Example 40
1-乙基-2-氧代-N-(4-(三氟甲基)苄基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E40)1-ethyl-2-oxo-N-(4-(trifluoromethyl)benzyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E40)
(1-ethyl-2-oxo-N-(4-(trifluoromethyl)benzyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E40)(1-ethyl-2-oxo-N-(4-(trifluoromethyl)benzyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E40)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.60(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.60 (d, J = 8.4 Hz, 1H), 8.52 (s, 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.99 (d, J = 7.2 Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 7.6 Hz) , 1H), 4.15 (s, 2H), 3.89 (d, J = 7.2 Hz, 2H), 1.25 (t, J = 6.8 Hz, 3H). MS (ESI), m/z: M - 433.0.
实施例41Example 41
N-(3,5-双(三氟甲基)苄基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E41)N-(3,5-bis(trifluoromethyl)benzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E41)
(N-(3,5-bis(trifluoromethyl)benzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E41)(N-(3,5-bis(trifluoromethyl)benzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E41)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.66(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.66 (t, J = 6.0 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 7.2 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.62 (s, 3H), 7.10 (d, J = 7.6 Hz, 1H), 4.34 (d, J = 6.0 Hz) , 2H), 3.87 (q, J = 7.2 Hz, 2H), 1.22 (t, J = 6.8 Hz, 3H). MS (ESI), m/z: M - 501.0.
实施例42Example 42
1-乙基-N-(4-氟-3-(三氟甲基)苄基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E42)1-ethyl-N-(4-fluoro-3-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E42)
(1-ethyl-N-(4-fluoro-3-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E42) (1-ethyl-N-(4-fluoro-3-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E42)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.59(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.59 (d, J = 8.4 Hz, 1H), 8.51 (t, J = 6.0 Hz, 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.94 -7.87 (m, 2H), 7.39 (s, 1H), 7.17-7.10 (m, 3H), 4.15 (d, J = 6.4 Hz, 2H), 3.89 (q, J = 6.8 Hz, 2H), 1.23 ( t, J = 7.2 Hz, 3H). MS (ESI), m / z: M - 451.0.
实施例43Example 43
N-(4-溴-2-氟苄基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E43)N-(4-bromo-2-fluorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E43)
(N-(4-bromo-2-fluorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E43)(N-(4-bromo-2-fluorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E43)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.66(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.66 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 5.6 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.95 (t, J = 7.6 Hz, 1H), 7.38 (q, J = 5.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.96 (t, J = 7.2 Hz, 1H), 6.87-8 - 6.83 (m, 1H), 4.11 (s, 2H), 3.92 (q, J = 6.8 Hz, 2H), 1.25 (t, J = 6.8 Hz, 3H). MS (ESI), m/z: M - 460.9.
实施例44Example 44
1-乙基-2-氧代-N-(3,4,5-三氟苄基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E44)1-ethyl-2-oxo-N-(3,4,5-trifluorobenzyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E44)
(1-ethyl-2-oxo-N-(3,4,5-trifluorobenzyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E44)(1-ethyl-2-oxo-N-(3,4,5-trifluorobenzyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E44)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.60(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.60 (d, J = 8.0 Hz, 1H), 8.50 (s, 1H), 8.12 (d, J = 6.8 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.91 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.85 (t, J = 8.0 Hz, 1H), 4.06 (s, 2H), 3.91 (q, J = 6.8 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H). MS (ESI), m/z: M - 419.0.
实施例45Example 45
N-(2,5-二氯苄基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E45)N-(2,5-Dichlorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E45)
(N-(2,5-dichlorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E45)(N-(2,5-dichlorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E45)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.68(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.68 (d, J = 8.4 Hz, 1H), 8.28 (t, J = 5.2 Hz, 1H), 8.12-8.09 (m, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 7.2 Hz, 2H), 7.18-7.11 (m, 1H), 4.25 (d, J = 5.2 Hz, 2H), 3.93 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H). MS (ESI), m/z: M - 433.0.
实施例46Example 46
N-(2,4-二氟苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E46)N-(2,4-difluorophenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E46)
(N-(2,4-difluorophenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E46)(N-(2,4-difluorophenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E46)
合成方法如实施例10。The synthesis method was as in Example 10.
1H-NMR(400MHz,d-DMSO)δ8.22(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.22 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.41 - 7.34 (m, 1H), 7.32 - 7.28 (m, 1H), 7.26 - 7.22 (m, 1H), 3.95 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 6.8 Hz, 3H). MS (ESI), m/z: M - 387.0.
实施例47Example 47
1-乙基-N-((1-乙基-2-氧代-1-1,2-二氢苯并[cd]吲哚-6–取代)磺酰基)-N-(5-氟-2-甲基苯基)-2-氧代1,2-二氢苯并[cd]吲哚-6-磺酰胺(E47)1-ethyl-N-((1-ethyl-2-oxo-1-1,2-dihydrobenzo[cd]indole-6-substituted)sulfonyl)-N-(5-fluoro- 2-methylphenyl)-2-oxo 1,2-dihydrobenzo[cd]indole-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)(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)
合成方法如实施例10。The synthesis method was as in Example 10.
1H-NMR(400MHz,d-DMSO)δ8.23(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.23 (d, J = 8.0 Hz, 2H), 8.12 (d, J = 6.8 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.74 (t, J = 7.6 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 5.6 Hz, 2H), 6.64 (d, J = 8.8 Hz, 1H), 3.98 (d) , J = 7.2 Hz, 4H), 1.77 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). MS (ESI), m/z: M - 643.70.
实施例48Example 48
N-(1-苄基哌啶-4–取代)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E48)N-(1-benzylpiperidin-4-substituted)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E48)
(N-(1-benzylpiperidin-4-yl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E48)(N-(1-benzylpiperidin-4-yl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E48)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.70(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.70 (d, J = 8.0 Hz, 1H), 8.13 - 8.08 (m, 2H), 7.95 - 7.91 (m, 2H), 7.27 - 7.22 (m, 3H) ), 7.14 (d, J = 6.8 Hz, 3H), 3.91 (d, J = 6.8 Hz, 2H), 3.30 (s, 2H), 2.95 (s, 1H), 2.57-2.50 (m, 2H) 1.78 ( t, J = 6.8 Hz, 3H), 1.45-1.42 (m, 2H), 1.33-1.24 (m, 5H). MS (ESI), m/z: M + 450.2; M - 448.2.
实施例49Example 49
6-((4-(2-氯苯基)哌嗪-1-取代)磺酰基)-1-乙基苯并[cd]吲哚-2(1H)-酮(E49)6-((4-(2-Chlorophenyl)piperazine-1-substituted)sulfonyl)-1-ethylbenzo[cd]indole-2(1H)-one (E49)
(6-((4-(2-chlorophenyl)piperazin-1-yl)sulfonyl)-1-ethylbenzo[cd]indol-2(1H)-one)(E49)(6-((4-chlorophenyl)piperazin-1-yl)sulfonyl)-1-ethylbenzo[cd]indol-2(1H)-one)(E49)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.69(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.69 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 6.8 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.98 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.88 (s, 1H), 6.81 (d, J = 8.4 Hz) , 1H), 6.75 (d, J = 7.6 Hz, 1H), 3.95 (q, J = 6.8 Hz, 2H), 3.20 (s, 4H), 3.09 (s, 4H), 1.28 (t, J = 7.2 Hz) , 3H). MS (ESI), m / z: M - 445.0.
实施例50Example 50
N-([1,1'-联苯]-3–取代)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E50)N-([1,1'-biphenyl]-3-substituted)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E50)
(N-([1,1'-biphenyl]-3-yl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E50)(N-([1,1'-biphenyl]-3-yl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E50)
合成方法如实施例10。The synthesis method was as in Example 10.
1H-NMR(400MHz,d-DMSO)δ10.7(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. 1 H-NMR (400 MHz, d-DMSO) δ 10.7 (s, 1H), 8.74 (d, J = 8.4 Hz, 1H), 8.21. (d, J = 7.6 Hz, 1H), 8.08 (d, J = 6.8 Hz, 1H), 7.92 (t, J = 7.6 Hz, 1H), 7.41 (s, 4H), 7.26-7.22 (m, 5H), 7.05 (d, J = 6.8 Hz, 1H), 3.86 (d, J = 6.8 Hz, 2H), 1.22 (t, J = 6.8 Hz, 3H). MS (ESI), m/z: M - 427.0.
实施例51Example 51
叔丁基4-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)哌啶-1-甲酸叔丁酯(E51)tert-Butyl 4-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)piperidine-1-carboxylic acid tert-butyl ester (E51)
(tert-butyl4-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)piperidine-1-carboxylate)(E51)(tert-butyl4-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)piperidine-1-carboxylate)(E51)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.68(d,J＝8.4Hz,1H),8.15-8.10(m,2H),7.98-7.92(m,2H),7.29(d,J＝7.6Hz,1H),3.93(d,J＝7.2Hz,2H),3.67-3.64(m,2H),3.18(s,1H),2.69(s,2H),1.47-1.44(m,2H),1.32(s,9H),1.32-1.25(m,3H),1.17-1.51(m,2H).MS(ESI),m/z:M-458.0. 1 H-NMR (400 MHz, d-DMSO) δ 8.68 (d, J = 8.4 Hz, 1H), 8.15 - 8.10 (m, 2H), 7.98 - 7.92 (m, 2H), 7.29 (d, J = 7.6 Hz, 1H), 3.93 (d, J = 7.2 Hz, 2H), 3.67-3.64 (m, 2H), 3.18 (s, 1H), 2.69 (s, 2H), 1.47-1.44 (m, 2H), 1.32 (s, 9H), 1.32-1.25 (m, 3H), 1.17-1.51 (m, 2H). MS (ESI), m/z: M - 458.0.
实施例52 Example 52
N-(3-氯苯乙基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(52)N-(3-Chlorophenethyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (52)
(N-(3-chlorophenethyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E52)(N-(3-chlorophenethyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E52)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.55(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.55 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 6.8 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.88 -7.85 (m, 2H), 7.25 (d, J = 7.6 Hz, 1H), 7.03-6.99 (m, 3H), 6.92 (d, J = 6.8 Hz, 1H), 3.95 (q, J = 7.2 Hz, 2H), 3.08 (q, J = 6.0 Hz, 3H), 2.62 (t, J = 6.4 Hz, 2H), 1.30 (t, J = 6.8 Hz, 3H). MS (ESI), m/z: M - 413.0.
实施例53Example 53
N-二苯甲基-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E53)N-Diphenylmethyl-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E53)
(N-benzhydryl-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E53)(N-benzhydryl-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E53)
合成方法如实施例10。The synthesis method was as in Example 10.
1H-NMR(400MHz,d-DMSO)δ8.63(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.63 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.82 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.08-7.3 -03 (m, 4H), 6.97-6.66 (m, 5H), 5.48 (s, 1H), 3.88 (q, J = 6.8 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H). MS ( ESI), m/z: M - 441.0.
实施例54Example 54
N-环戊基-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E54)N-cyclopentyl-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E54)
(N-cyclopentyl-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E54)(N-cyclopentyl-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide) (E54)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.72(d,J＝8.4Hz,1H),8.14(d,J＝6.8Hz,1H),8.09(d,J＝7.6Hz,1H),7.95(t,J＝7.6Hz,1H),7.80(d,J＝7.2Hz,1H),7.26(d,J＝7.6Hz,1H),3.95(q,J＝7.2Hz,2H),3.44(q,J＝6.4Hz,1H),1.51-1.46(m,4H),1.28-1.22(m,7H).MS(ESI),m/z:M-343.0. 1 H-NMR (400 MHz, d-DMSO) δ 8.72 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 6.8 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.95 (t, J = 7.6 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 3.95 (q, J = 7.2 Hz, 2H), 3.44 (q) , J = 6.4 Hz, 1H), 1.51-1.46 (m, 4H), 1.28-1.22 (m, 7H). MS (ESI), m/z: M - 343.0.
实施例55Example 55
N-(3-(叔丁基)苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E55)N-(3-(tert-butyl)phenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E55)
(N-(3-(tert-butyl)phenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E55) (N-(3-(tert-butyl)phenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E55)
合成方法如实施例10。The synthesis method was as in Example 10.
1H-NMR(400MHz,d-DMSO)δ8.49(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 1 H-NMR (400 MHz, d-DMSO) δ 8.49 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 6.8 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 5.6 Hz, 2H), 6.98 (s, 1H), 6.90 (s, 1H), 6.84 (d, J = 7.2 Hz, 2H), 3.94 (dd, J = 14.2 Hz, 7.4 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H), 1.09 (s, 9H). MS (ESI), m/z: M - 407.1
实施例56Example 56
N-(2-(叔丁基)苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E56)N-(2-(tert-butyl)phenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E56)
(N-(2-(tert-butyl)phenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E56)(N-(2-(tert-butyl)phenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E56)
1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰氯合成方法如实施例1.1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonyl chloride synthesis method as in Example 1.
取1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰氯(100mg,0.338mmol)，和2-(叔丁基)苯胺(92mg，0.617mmol)溶于3mL吡啶中。室温反应过夜，反应完全后，水洗，乙酸乙酯萃取三次，合并有机层，10％盐酸50mL洗一次，饱和氯化钠水溶液洗一次，无水硫酸钠干燥，柱层析，得到50mg黄绿色粉末状固体，收率36％。1-Ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonyl chloride (100 mg, 0.338 mmol), and 2-(tert-butyl)aniline (92 mg, 0.617 mmol) ) dissolved in 3 mL of pyridine. After reacting at room temperature overnight, after completion of the reaction, the mixture was washed with water and extracted with EtOAc EtOAc EtOAc EtOAc. Solid, yield 36%.
1H-NMR(400MHz,d-DMSO)δ9.37(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 1 H-NMR (400 MHz, d-DMSO) δ 9.37 (s, 1H), 8.76 (d, J = 8.4 Hz, 1H), 8.21. (d, J = 7.2 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz) , 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.36 (d, J = 7.6 Hz, 1H), 3.97 (q, J = 7.2 Hz, 2H), 1.45 (s, 9H), 1.29 (t) , J = 7.2 Hz, 3H). MS (ESI), m / z: M - 407.1
实施例57Example 57
2-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)苯甲酸甲酯(E57)Methyl 2-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)benzoate (E57)
(2-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)benzoate)(E57)(2-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)benzoate)(E57)
合成方法如实施例56。The synthesis method was as in Example 56.
1H-NMR(400MHz,d-DMSO)δ10.67(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 1 H-NMR (400 MHz, d-DMSO) δ 10.67 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.96 (t, J = 7.6 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.55-7.48 (m, 2H), 7.27 (d, J = 7.6 Hz, 1H) , 7.10 (t, J = 7.2 Hz, 1H), 3.88 (q, J = 7.2 Hz, 2H), 3.69 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H). MS (ESI), m /z:M - 409.1
实施例58Example 58
N-(2-苯甲酰基苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E58) N-(2-benzoylphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E58)
(N-(2-benzoylphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E58)(N-(2-benzoylphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E58)
合成方法如实施例56。The synthesis method was as in Example 56.
1H-NMR(400MHz,d-DMSO)δ9.88(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 1 H-NMR (400 MHz, d-DMSO) δ 9.88 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 6.8 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.47-7.42 (m, 2H), 7.28 (t, J = 7.6 Hz, 1H) , 7.19-7.17 (m, 3H), 7.06 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 3.81 (q, J = 6.8 Hz, 2H), 1.21 (t, J=6.8 Hz, 3H). MS (ESI), m/z: M - 455.0
实施例59Example 59
N-(2-乙酰基苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E59)N-(2-Acetylphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E59)
(N-(2-acetylphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E59)(N-(2-acetylphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E59)
合成方法如实施例56。The synthesis method was as in Example 56.
1H-NMR(400MHz,d-DMSO)δ11.67(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 1 H-NMR (400MHz, d -DMSO) δ11.67 (s, 1H), 8.44 (d, J = 8.0Hz, 1H), 8.25 (d, J = 7.6Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 8.4 Hz) , 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 3.89 (q, J = 7.2 Hz, 2H), 2.48 (s, 3H), 1.23 (t , J=7.2 Hz, 3H). MS (ESI), m/z: M - 393.0
实施例60Example 60
1-乙基-2-氧代-N-(吡啶-3-取代)-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E60)1-ethyl-2-oxo-N-(pyridine-3-substituted)-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E60)
1-ethyl-2-oxo-N-(pyridin-3-yl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide(E60)1-ethyl-2-oxo-N-(pyridin-3-yl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide(E60)
合成方法如实施例56。The synthesis method was as in Example 56.
1H-NMR(400MHz,d-DMSO)δ10.83(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 1 H-NMR (400MHz, d -DMSO) δ10.83 (s, 1H), 8.66 (d, J = 8.4Hz, 1H), 8.26 (s, 1H), 8.18-8.16 (m, 2H), 8.13 ( d, J = 6.8 Hz, 1H), 7.94 (t, J = 7.6 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.23-7.20 ( m, 1H), 3.89 (q, J = 6.8 Hz, 2H), 1.23 (t, J = 6.8 Hz, 3H). MS (ESI), m/z: M - 352.0
实施例61Example 61
N-(3-乙酰基苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E61)N-(3-Acetylphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E61)
(N-(3-acetylphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E61) (N-(3-acetylphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E61)
合成方法如实施例56。The synthesis method was as in Example 56.
1H-NMR(400MHz,d-DMSO)δ10.80(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). 1 H-NMR (400 MHz, d-DMSO) δ 10.80 (s, 1H), 8.69 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 7.6 Hz, 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.93 (t, J = 7.6 Hz, 1H), 7.59 (s, 1H), 7.54 (d, J = 3.6 Hz, 1H), 7.34 - 7.31 (m, 2H), 7.25 (d, J = 7.6 Hz, 1H), 3.86 (dd, J = 13.8 Hz, 7.0 Hz, 2H), 2.43 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H).
实施例62Example 62
N-(3-溴-5-(三氟甲基)苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E62)N-(3-Bromo-5-(trifluoromethyl)phenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E62)
(N-(3-bromo-5-(trifluoromethyl)phenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E62)(N-(3-bromo-5-(trifluoromethyl)phenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E62)
合成方法如实施例56。The synthesis method was as in Example 56.
1H-NMR(400MHz,d-DMSO)δ11.28(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). 1 H-NMR (400 MHz, d-DMSO) δ 11.28 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 7.2 Hz, 1H), 7.97 (t, J = 7.6 Hz, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.32 (t, J = 7.6 Hz, 2H), 3.89 (dd, J = 14.0 Hz, 6.8 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H).
实施例63Example 63
(E)-1-乙基-2-氧代-N-(4-(苯基二氮烯基)苯基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E63)(E)-1-ethyl-2-oxo-N-(4-(phenyldiazenyl)phenyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide ( E63)
((E)-1-ethyl-2-oxo-N-(4-(phenyldiazenyl)phenyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E63)((E)-1-ethyl-2-oxo-N-(4-(phenyldiazenyl)phenyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E63)
合成方法如实施例56。The synthesis method was as in Example 56.
1H-NMR(400MHz,d-DMSO)δ11.10(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). 1 H-NMR (400 MHz, d-DMSO) δ 11.10 (s, 1H), 8.74 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.95 (t, J = 7.8 Hz, 1H), 7.73 (t, J = 9.0 Hz, 4H), 7.50 (dd, J = 14.6 Hz, 7.0 Hz, 3H), 7.27 (dd, J = 8.0 Hz, 4.0 Hz, 3H), 3.86 (dd, J = 14.0 Hz, 6.8 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H).
实施例64 Example 64
乙基2-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)-3-(呋喃-2-基)丙酸乙酯(E64)Ethyl 2-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3-(furan-2-yl)propanoate (E64)
(ethyl2-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3-(furan-2-yl)propanoate)(E64)(ethyl2-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3-(furan-2-yl)propanoate)(E64)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.58(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.58 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 7.6 Hz, 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.09 (s, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.09 (s, 1H), 5.91 (s, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.24 - 4.19 (m, 1H), 3.98 (q, J = 7.2 Hz, 2H), 3.85 (q, J = 7.2 Hz, 2H), 3.04 - 3.00 (m, 1H), 1.57 ( s, 1H), 1.38 (t, J = 7.2 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H). MS (ESI), m/z: M + 443.1; M - 441.1.
实施例65Example 65
乙基-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺)-3-(5-甲基呋喃-2-基)丙酸乙酯(E65)Ethyl-3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)-3-(5-methylfuran-2-yl)propane Ethyl acetate (E65)
(ethyl3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3-(5-methylfuran-2-yl)propano ate)(E65)(ethyl3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3-(5-methylfuran-2-yl)propanoate) (E65)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.61(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.61 (d, J = 8.4 Hz, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 6.8 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 5.75 (s, 1H), 5.50 (s, 1H), 4.62 (q, J = 7.6 Hz, 1H), 3.95-3.85 (m, 4H), 2.70 (d, J = 7.2 Hz, 2H), 1.62 (s, 3H), 1.27 (t, J = 6.8 Hz, 3H) , 1.06 (t, J = 6.8 Hz, 3H). MS (ESI), m/z: M - 455.1.
实施例66Example 66
5-((1-乙基-2-氧代-1，2-二氢苯并[cd]吲哚-6-亚磺酰氨基)甲基)噻吩-2-甲酸叔丁酯(E66)5-((1-Ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)thiophene-2-carboxylic acid tert-butyl ester (E66)
(ethyl5-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)thiophene-2-carboxylate)(E66)(ethyl5-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)thiophene-2-carboxylate)(E66)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.64(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.64 (d, J = 8.4 Hz, 2H), 8.14 (d, J = 6.8 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.93 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 4.28 (d) , J = 6.0 Hz, 2H), 4.17 (q, J = 6.8 Hz, 2H), 3.92 (q, J = 6.8 Hz, 2H), 1.27-1.20 (m, 6H). MS (ESI), m/z :M - 443.0.
实施例67Example 67
2-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)-3-(呋喃-2–取代)丙酸(E67)2-(1-Ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3-(furan-2-substituted)propionic acid (E67)
(2-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3-(furan-2-yl)propanoic acid)(E67)(2-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3-(furan-2-yl)propanoic acid)(E67)
乙基2-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)-3-(呋喃-2-基)丙酸乙酯合成方法如实施例64.Ethyl 2-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3-(furan-2-yl)propanoate The synthesis method is as in Example 64.
将乙基2-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)-3-(呋喃-2-基)丙酸乙酯(130mg，0.29mmol)用THF溶解，室温滴加2N氢氧化钠溶液0.5mL，室温反应过夜。旋去四氢呋喃。在冰浴下滴加浓盐酸，直至无沉淀析出，抽滤，得到106mg产物，收率88％。Ethyl 2-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3-(furan-2-yl)propanoic acid The ester (130 mg, 0.29 mmol) was dissolved in THF, and 0.5 mL of a 2N sodium hydroxide solution was added dropwise at room temperature overnight. Rotate the tetrahydrofuran. Concentrated hydrochloric acid was added dropwise to an ice bath until no precipitate formed, and suction filtered to give a product (yield: 88%).
1H-NMR(400MHz,d-DMSO)δ8.48(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.48 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.68 (t, J = 7.6 Hz, 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 = 7.6 Hz, 3H). MS (ESI), m/z: M - 413.0.
实施例68Example 68
3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)-3-(5-甲基呋喃-2–取代)丙酸(E68)3-(1-Ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3-(5-methylfuran-2-substituted) propionic acid (E68)
(3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3-(5-methylfuran-2-yl)propanoic acid)(E68)(3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)-3-(5-methylfuran-2-yl)propanoic acid)(E68)
合成方法如实施例67。The synthesis method was as in Example 67.
1H-NMR(400MHz,d-DMSO)δ8.59(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. 1 H-NMR (400 MHz, d-DMSO) δ 8.59 (d, J = 8.4 Hz, 1H), 8.11 - 8.03 (m, 2H), 7.82 (t, J = 8.0 Hz, 1H), 6.84 (d, J=7.6 Hz, 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 = 7.2 Hz, 3H). MS (ESI), m/z: M - 427.0.
实施例69Example 69
1-((1-乙基-2-氧代-1-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)甲基)环戊烷羧酸甲酯(E68) Methyl 1-((1-ethyl-2-oxo-1-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)cyclopentanecarboxylate (E68)
(ethyl1-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)cyclopentane carboxylate)(E68)(ethyl1-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)cyclopentane carboxylate)(E68)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.63(d,J＝8.4Hz,1H),8.17(d,J＝7.6Hz,1H),8.11(d,J＝7.2Hz,1H),7.86(t,J＝8.0Hz,1H),6.93(d,J＝7.6Hz,1H),5.36(t,J＝6.8Hz,1H),4.04-3.96(m,4H),2.92(d,J＝7.2Hz,2H),1.93-1.89(m,2H),1.71(s,2H),1.58-1.54(m,6H),1.39(t,J＝7.2Hz,3H),1.16(t,J＝7.2Hz,3H).MS(ESI),m/z:M-429.0. 1 H-NMR (400 MHz, d-DMSO) δ 8.63 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.86 (t, J = 8.0 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 5.36 (t, J = 6.8 Hz, 1H), 4.04-3.96 (m, 4H), 2.92 (d, J = 7.2 Hz, 2H), 1.93-1.89 (m, 2H), 1.71 (s, 2H), 1.58-1.54 (m, 6H), 1.39 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.2) Hz, 3H). MS (ESI), m/z: M - 429.0.
实施例70Example 70
1-乙基-N-(异喹啉-8–取代)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E70)1-ethyl-N-(isoquinoline-8-substituted)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E70)
(1-ethyl-N-(isoquinolin-7-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E70)(1-ethyl-N-(isoquinolin-7-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E70)
合成方法如实施例56。The synthesis method was as in Example 56.
1H-NMR(400MHz,d-DMSO)δ11.04(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). 1 H-NMR (400 MHz, d-DMSO) δ 11.04 (s, 1H), 9.15 (s, 1H), 8.74 (d, J = 8.4 Hz, 1H), 8.32 (d, J = 5.6 Hz, 1H) , 8.29 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.93 (t, J = 7.6 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H), 7.62 (d, J = 6.0 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 3.84 (dd, J = 14.0 Hz) , J = 7.2 Hz, 2H), 1.18 (t, J = 7.20 Hz, 3H).
实施例71Example 71
乙基4-(3,5-二甲基苯基)-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)丁酸乙酯(E71)Ethyl 4-(3,5-dimethylphenyl)-3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido) Ethyl butyrate (E71)
(ethyl 4-(3,5-dimethylphenyl)-3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)butanoate)(E71)(ethyl 4-(3,5-dimethylphenyl)-3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido) butanoate) (E71)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.54(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). 1 H-NMR (400 MHz, d-DMSO) δ 8.54 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 6.66 (t, J = 8.0 Hz, 1H), 6.59 (s, 1H), 6.34 (d, J = 7.6 Hz, 1H), 5.80 (d, J = 7.2 Hz) , 1H), 4.96 (q, J = 6.4 Hz, 1H), 4.01-3.89 (m, 4H), 2.69 (dd, J = 6.4 Hz, 2H), 2.06 (d, J = 9.6 Hz, 6H), 1.56 (s, 2H), 1.35 (t, J = 7.2 Hz, 3H), 1.13 (t, J = 7.2 Hz, 3H).
实施例72 Example 72
乙基2-((1-乙基-2-氧代-1-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)甲基)苯甲酸甲酯(E72)Methyl 2-((1-ethyl-2-oxo-1-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)benzoate (E72)
(ethyl 2-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)benzoate)(E72)(ethyl 2-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)benzoate)(E72)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.46(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). 1 H-NMR (400 MHz, d-DMSO) δ 8.46 (d, J = 8.4 Hz, 1H), 8.02 (t, J = 7.2 Hz, 2H), 7.72 (t, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.10-7.07 (m, 2H), 6.74 (d, J = 7.6 Hz, 1H), 6.27 (t, J = 6.8 Hz, 1H), 4.39 (d, J = 7.2 Hz, 2H), 4.19 (q, J = 7.6 Hz, 2H), 3.95 (q, J = 7.6 Hz, 2H), 1.39 (t, J = 7.2 Hz) , 3H), 1.30 (t, J = 7.2 Hz, 3H).
实施例73Example 73
3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺)丁酸乙酯(E73)3-(1-Ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide) ethyl butyrate (E73)
(ethyl 3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)heptanoate)(E73)(ethyl 3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)heptanoate)(E73)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.62(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). 1 H-NMR (400 MHz, d-DMSO) δ 8.62 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 7.6 Hz, 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 5.40 (d, J = 9.2 Hz, 1H), 4.01-3.90 (m, 4H), 3.50 (d, J = 4.4 Hz, 1H), 2.36 (s, 2H), 1.49-1.43 (m, 1H), 1.39 (t, J = 7.2 Hz, 4H), 1.14 (t, J = 5.6 Hz, 3H), 1.15.14. m, 3H), 1.12-0.93 (m, 1H), 0.58 (t, J = 7.2 Hz, 3H).
实施例74Example 74
2-乙基-2-((1-乙基-2-氧代-1，2-二氢苯并[cd]吲哚-6-亚磺酰氨基)甲基)丁酸(E74)2-ethyl-2-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)butyric acid (E74)
(2-ethyl-2-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)butanoic acid)(E74)(2-ethyl-2-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)butanoic acid)(E74)
合成方法如实施例67。The synthesis method was as in Example 67.
1H-NMR(400MHz,d-DMSO)δ8.78(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). 1 H-NMR (400 MHz, d-DMSO) δ 8.78 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 7.2 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.65 (s, 1H), 7.34 (d, J = 7.6 Hz, 1H), 3.95 (q, J = 7.2 Hz, 2H), 2.85 (s, 2H), 1.50-1.38 (m, 4H), 1.27 (t, J = 6.8 Hz, 3H), 1.21 (s, 1H), 0.58 (t, J = 7.2 Hz, 4H).
实施例75Example 75
5-((1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)甲基)噻吩-2-羧酸(E75) 5-((1-Ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)thiophene-2-carboxylic acid (E75)
(5-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)thiophene-2-carboxylic acid)(E75)(5-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)thiophene-2-carboxylic acid)(E75)
合成方法如实施例67。The synthesis method was as in Example 67.
1H-NMR(400MHz,d-DMSO)δ8.64-8.608.64(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). 1 H-NMR (400 MHz, d-DMSO) δ 8.64-8.608.64 (m, 2H), 8.11 (d, J = 6.8 Hz, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.93 ( t, J = 7.6 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.22 (d, J = 7.6 Hz, 2H), 6.81 (s, 1H), 4.26 (d, J = 5.6 Hz, 2H), 3.92 (t, J = 6.0 Hz, 3H), 1.28-0.22 (m, 5H).
实施例76Example 76
1-((1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)甲基)环戊烷羧酸(E76)(1-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)cyclopentanecarboxylic acid)(E76)1-((1-Ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)cyclopentanecarboxylic acid (E76) (1-( (1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)cyclopentanecarboxylic acid)(E76)
合成方法如实施例67。The synthesis method was as in Example 67.
1H-NMR(400MHz,d-DMSO)δ8.63(d,J＝8.4Hz,1H),8.17(d,J＝7.6Hz,1H),8.11(d,J＝7.2Hz,1H),7.86(t,J＝8.0Hz,1H),6.93(d,J＝7.6Hz,1H),5.36(t,J＝6.8Hz,1H),3.92(m,3H),2.83(s,2H),1.81(m,2H),1.45(m,6H),1.25(m,4H). 1 H-NMR (400 MHz, d-DMSO) δ 8.63 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.86 (t, J = 8.0 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 5.36 (t, J = 6.8 Hz, 1H), 3.92 (m, 3H), 2.83 (s, 2H), 1.81 (m, 2H), 1.45 (m, 6H), 1.25 (m, 4H).
实施例77Example 77
N-(3-氯-4-氟苄基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E77)N-(3-chloro-4-fluorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E77)
(N-(3-chloro-4-fluorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E77)(N-(3-chloro-4-fluorobenzyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E77)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,CDCl3)δ8.60(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). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.60 (d, J = 8.4 Hz, 1H), 8.09 (t, J = 7.2 Hz, 2H), 7.82 (t, J = 7.8 Hz, 1H), 6.98 ( d, J = 7.2 Hz, 1H), 6.94 (d, J = 4.4 Hz, 1H), 6.88-6.83 (m, 2H), 4.10 (d, J = 6.0 Hz, 2H), 3.97 (dd, J = 14.4) Hz, 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H).
实施例78Example 78
4-(3,5-二甲基苯基)-3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)丁酸(E78)4-(3,5-Dimethylphenyl)-3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)butyric acid (E78)
(4-(3,5-dimethylphenyl)-3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)butanoic acid)(E78) (4-(3,5-dimethylphenyl)-3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)butanoic acid)(E78)
合成方法如实施例67。The synthesis method was as in Example 67.
1H-NMR(400MHz,d-DMSO)δ8.53(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). 1 H-NMR (400 MHz, d-DMSO) δ 8.53 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 6.8 Hz, 1H), 7.85-7.79 (m, 2H), 6.98 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.35 (s, 1H), 6.35 (d, J = 7.6 Hz, 1H), 6.02 (d, J = 7.6 Hz, 1H) , 4.80 (t, J = 7.2 Hz, 2H), 3.85 (s, 3H), 1.83 (s, 3H), 1.28-1.22 (m, 7H).
实施例79Example 79
2-((1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)甲基)苯甲酸(E79)2-((1-Ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)benzoic acid (E79)
(2-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)benzoic acid)(E79)(2-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)methyl)benzoic acid)(E79)
合成方法如实施例67。The synthesis method was as in Example 67.
1H-NMR(400MHz,d-DMSO)δ8.65(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). 1 H-NMR (400 MHz, d-DMSO) δ 8.65 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 8.15 (d, J = 6.8 Hz, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.91 (t, J = 8.0 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 7.2 Hz) , 1H), 7.23-7.18 (m, 2H), 4.40 (d, J = 5.6 Hz, 2H), 3.92 (d, J = 7.2 Hz, 2H), 1.29 (t, J = 6.8 Hz, 3H).
实施例80Example 80
N-(1-乙酰基吲哚-5-基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E80)N-(1-acetylindol-5-yl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E80)
(N-(1-acetylindolin-5-yl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E80)(N-(1-acetylindolin-5-yl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide)(E80)
合成方法如实施例56。The synthesis method was as in Example 56.
1H-NMR(400MHz,d-DMSO)δ10.31(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). 1 H-NMR (400 MHz, d-DMSO) δ 10.31 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 7.2 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.91 (t, J = 8.4 Hz, 1H), 7.25 (d, J = 7.6 Hz) , 1H), 6.91 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H), 3.96 (t, J = 8.4 Hz, 2H), 3.88 (q, J = 6.8 Hz, 2H), 2.97 (t , J = 8.4 Hz, 2H), 2.05 (s, 1H), 1.24 (t, J = 7.2 Hz, 3H).
实施例81Example 81
3-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)庚酸(E81)3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)heptanoic acid (E81)
(3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)heptanoic acid)(E81)(3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)heptanoic acid)(E81)
合成方法如实施例67。The synthesis method was as in Example 67.
1H-NMR(400MHz,d-DMSO)δ8.69(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). 1 H-NMR (400 MHz, d-DMSO) δ 8.69 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 6.8 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.93 (t, J = 7.2 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 3.95 (d, J = 6.8 Hz, 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 = 6.0 Hz, 3H).
实施例82Example 82
1-乙基-6-((4-(吡啶-2-基甲基)哌嗪-1-取代)磺酰基)苯并[cd]吲哚-2(1H)-酮(E82)1-ethyl-6-((4-(pyridin-2-ylmethyl)piperazine-1-substituted)sulfonyl)benzo[cd]indole-2(1H)-one (E82)
(1-ethyl-6-((4-(pyridin-2-ylmethyl)piperazin-1-yl)sulfonyl)benzo[cd]indol-2(1H)-one)(E82)(1-ethyl-6-((4-(pyridin-2-ylmethyl)piperazin-1-yl)sulfonyl)benzo[cd]indol-2(1H)-one)(E82)
合成方法如实施例1。The synthesis method was as in Example 1.
1H-NMR(400MHz,d-DMSO)δ8.65(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). 1 H-NMR (400 MHz, d-DMSO) δ 8.65 (d, J = 8.4 Hz, 1H), 8.41 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 7.2 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 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 = 6.8 Hz, 3H).
实施例83Example 83
1-乙基-2-氧代-N-(3,4,5-三甲氧基苯基)-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E83)1-ethyl-2-oxo-N-(3,4,5-trimethoxyphenyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E83)
1-ethyl-2-oxo-N-(3,4,5-trimethoxyphenyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide(E83)1-ethyl-2-oxo-N-(3,4,5-trimethoxyphenyl)-1,2-dihydrobenzo[cd]indole-6-sulfonamide(E83)
合成方法如实施例67。The synthesis method was as in Example 67.
1HNMR(400MHz,CDCl3)δ8.52(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). 1 H NMR (400 MHz, CDCl 3 ) δ 8.52 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 7.2 Hz, 2H), 7.79 (d, J = 7.6 Hz, 1H), 6.87-6.85 ( m, 1H), 6.61 (d, J = 8.4 Hz, 3H), 6.68 (d, J = 8.8 Hz, 2H), 3.95 (q, J = 7.2 Hz, 2H), 3.72 (s, 3H), 3.62 ( s, 6H), 1.31 (t, J = 7.2 Hz, 3H).
实施例84Example 84
1-乙基-N-(4-甲氧基苯基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E84)1-ethyl-N-(4-methoxyphenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E84)
1-ethyl-N-(4-methoxyphenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide(E84)1-ethyl-N-(4-methoxyphenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide(E84)
合成方法如实施例67。The synthesis method was as in Example 67.
1H NMR(400MHz,CDCl3)δ8.48(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). 1 H NMR (400MHz, CDCl 3 ) δ8.48 (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 = 8.8 Hz, 2H), 6.47 (s, 1H), 3.95 (q, J = 7.2 Hz, 2H), 3.71 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H).
实施例85Example 85
N-(3,4-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E85)N-(3,4-Dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E85)
N-(3,4-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide(E85)N-(3,4-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide(E85)
合成方法如实施例1。The synthesis method was as in Example 1.
1HNMR(400MHz,CDCl3)δ8.52(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). 1 H NMR (400 MHz, CDCl 3 ) δ 8.52 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.68 (s, 1H), 6.43 (d, J = 8.8 Hz, 1H) , 6.08 (d, J = 6.8 Hz, 1H), 3.94 (q, J = 7.2 Hz, 2H), 3.72 (s, 3H), 3.04 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H) .
实施例86Example 86
1-乙基-N-(3-甲氧基苯基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E86)1-ethyl-N-(3-methoxyphenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E86)
1-ethyl-N-(3-methoxyphenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide(E86)1-ethyl-N-(3-methoxyphenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide(E86)
合成方法如实施例67。The synthesis method was as in Example 67.
1HNMR(400MHz,CDCl3)δ8.57(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). 1 H NMR (400 MHz, CDCl 3 ) δ 8.57 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 7.6 Hz, 1H), 8.07 (d, J = 7.2 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 6.97 (s, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.74 - 6.58 (m, 2H), 6.54 ( d, J = 8.0 Hz, 1H), 3.94 (q, J = 7.2 Hz, 2H), 3.68 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H).
实施例87Example 87
N-(3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E87)N-(3,5-Dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E87)
N-(3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide(E87)N-(3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide(E87)
合成方法如实施例67。The synthesis method was as in Example 67.
1HNMR(400MHz,CDCl3)δ8.59(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). 1 H NMR (400 MHz, CDCl 3 ) δ 8.59 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 8.07 (d, J = 7.2 Hz, 1H), 7.90-7.70 ( m, 1H), 6.92 (s, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.19 (s, 2H), 6.14 (s, 1H), 3.95 (q, J = 7.2 Hz, 2H), 3.64 (s, 6H), 1.36 (t, J = 7.2 Hz, 3H).
实施例88Example 88
N-(4-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)苯基)乙酰胺(E88)N-(4-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)phenyl)acetamide (E88)
N-(4-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)phenyl)acetamide(E88)N-(4-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)phenyl)acetamide(E88)
合成方法如实施例67。The synthesis method was as in Example 67.
1H NMR(400MHz,d-DMSO)δ10.33(s,1H),9.79(s,1H),8.68(d,J＝8.0Hz,1H),8.10(dd,J＝14.4,6.8Hz,2H),7.92(t,J＝7.2Hz,1H),7.34(d,J＝7.6Hz,2H),7.23(d,J＝7.6Hz,1H), 6.94(d,J＝7.6Hz,2H),3.88(d,J＝6.8Hz,2H),1.95(s,3H),1.23(t,J＝7.2Hz,3H). 1 H NMR (400 MHz, d-DMSO) δ 10.33 (s, 1H), 9.79 (s, 1H), 8.68 (d, J = 8.0 Hz, 1H), 8.10 (dd, J = 14.4, 6.8 Hz, 2H) ), 7.92 (t, J = 7.2 Hz, 1H), 7.34 (d, J = 7.6 Hz, 2H), 7.23 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 7.6 Hz, 2H), 3.88 (d, J = 6.8 Hz, 2H), 1.95 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H).
实施例89Example 89
2-(1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-亚磺酰氨基)苯甲酸(E89)2-(1-Ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)benzoic acid (E89)
2-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)benzoic acid(E89)2-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)benzoic acid(E89)
合成方法如实施例67。The synthesis method was as in Example 67.
1H NMR(400MHz,d-DMSO)δ11.96(s,1H),8.52(d,J＝8.4Hz,1H),8.26(d,J＝7.6Hz,1H),8.13(d,J＝7.2Hz,1H),8.02-7.84(m,1H),7.80(d,J＝7.2Hz,1H),7.63-7.41(m,2H),7.28(d,J＝7.6Hz,1H),7.02(t,J＝7.6Hz,1H),3.89(q,J＝7.2Hz,2H),1.23(t,J＝7.2Hz,3H). 1 H NMR (400MHz, d- DMSO) δ11.96 (s, 1H), 8.52 (d, J = 8.4Hz, 1H), 8.26 (d, J = 7.6Hz, 1H), 8.13 (d, J = 7.2 Hz, 1H), 8.02-7.84 (m, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.63-7.41 (m, 2H), 7.28 (d, J = 7.6 Hz, 1H), 7.02 (t , J = 7.6 Hz, 1H), 3.89 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H).
实施例90Example 90
1-乙基-N-(4-氟苯基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(E90)1-ethyl-N-(4-fluorophenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (E90)
1-ethyl-N-(4-fluorophenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide(E90)1-ethyl-N-(4-fluorophenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide(E90)
合成方法如实施例67。The synthesis method was as in Example 67.
1H NMR(400MHz,d-DMSO)δ10.48(s,1H),8.64(d,J＝8.4Hz,1H),8.13-8.07(m,2H),8.00-7.79(m,1H),7.25(d,J＝7.6Hz,1H),7.17-6.83(m,4H),3.89(q,J＝7.2Hz,2H),1.25(t,J＝7.2Hz,3H). 1 H NMR (400MHz, d- DMSO) δ10.48 (s, 1H), 8.64 (d, J = 8.4Hz, 1H), 8.13-8.07 (m, 2H), 8.00-7.79 (m, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.17 - 6.83 (m, 4H), 3.89 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H).
实施例91Example 91
N-((1-乙基-2-氧代-1,2-二氢苯并[cd]吲哚-6-基)磺酰基)-N-(4-甲氧基苯基)异烟酰胺(E91)N-((1-Ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)sulfonyl)-N-(4-methoxyphenyl)isonicotinamide (E91)
N-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)sulfonyl)-N-(4-methoxyphenyl)isonicotina mide(E91)N-((1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)sulfonyl)-N-(4-methoxyphenyl)isonicotina mide(E91)
1-乙基-N-(4-甲氧基苯基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺的合成方法参见实施例83。For the synthesis of 1-ethyl-N-(4-methoxyphenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide, see Example 83.
将1-乙基-N-(4-甲氧基苯基)-2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺(100mg，0.26mmol)用二氯甲烷溶解，室温加入异烟酸(34mg，0.28mmol)，HATU(148mg，380mmol)以及DIPEA(0.5mL)，室温反应过夜。水洗，乙酸乙酯萃取三次，合并有几层，饱和食盐水洗一遍，无水硫酸钠干燥。柱层析：石油醚：乙酸乙酯＝1:1，得产物23mg，收率18％。1H NMR(400MHz,CDCl3)δ8.53(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).1-ethyl-N-(4-methoxyphenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide (100 mg, 0.26 mmol) with dichloro The methane was dissolved, and isonicotinic acid (34 mg, 0.28 mmol), HATU (148 mg, 380 mmol) and DIPEA (0.5 mL) were added at room temperature overnight. The mixture was washed with water and extracted three times with ethyl acetate. Column chromatography: petroleum ether: ethyl acetate = 1:1 afforded product 23 mg, yield 18%. 1 H NMR (400MHz, CDCl 3 ) δ8.53 (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 = 7.6 Hz, 1H), 7.16 (d, J = 4.4 Hz, 2H), 7.04 (t, J = 7.6 Hz, 3H), 6.77 (d, J = 8.4 Hz, 2H) ), 4.03 (q, J = 7.2 Hz, 2H), 3.78 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H).
实施例92Example 92
体外活性实验：本发明采用AlphaScreen检测技术验证本发明化合物的对RORγ蛋白抑制能力。 In vitro activity assay: The present invention uses the AlphaScreen detection technique to verify the ability of the compounds of the invention to inhibit RORy protein.
1、实验目的1. Experimental purpose
测定本发明化合物对RORγ蛋白的抑制活性。The inhibitory activity of the compound of the present invention against the RORγ protein was determined.
2、实验材料2, experimental materials
目的蛋白RORγ100nM；实验缓冲液(10×)MOPS(500mM)，CHAPS(0.5mM)，NaF(500mM)，BSA(1mg/mL)，PH7.4；试剂盒中供体微珠50μg/mL,受体微珠50μg/mL；RORγ共激动因子，短肽SRC1-4(QKPTSGPQTPQAQQKSLLQQLLTE)20nM；150μL反应体系中：RORγ:15μL，实验缓冲液：15μL，去离子水：15μL，小分子化合物：15μL，供体微珠：15μL，受体微珠：15μL；阳性抑制剂：T1317,SR2211,UA,Digoxin。The target protein RORγ100nM; assay buffer (10×) MOPS (500 mM), CHAPS (0.5 mM), NaF (500 mM), BSA (1 mg/mL), pH 7.4;
3、实验方法3. Experimental methods
避光孵育2小时，转移至384孔板，每孔转移40μL液体，通过多功能检测酶标仪，激发波长：680nM，发射波长520-620nM检测读数。Incubate for 2 hours in the dark, transfer to a 384-well plate, transfer 40 μL of liquid per well, and pass the multi-function detection microplate reader, excitation wavelength: 680 nM, emission wavelength 520-620 nM detection reading.
4、实验结果4. Experimental results
本发明化合物E1-E82对RORγ蛋白的抑制活性数据如图1所示。The inhibitory activity data of the compounds E1-E82 of the present invention against RORγ protein is shown in Fig. 1.
活性较好化合物对RORγ蛋白的抑制活性的IC50数值如下表一所示：The IC 50 values for the inhibitory activity of the more active compounds against RORγ protein are shown in Table 1 below:
表一：活性较好化合物对RORγ蛋白的抑制活性的IC50 Table 1: IC 50 of inhibitory activity of the more active compound against RORγ protein
实验结果表明：本发明化合物对RORγ蛋白具有非常好的抑制作用，特别是化合物E10、E63对RORγ蛋白的抑制活性与对照药相当。The experimental results show that the compound of the present invention has a very good inhibitory effect on the RORγ protein, and in particular, the inhibitory activities of the compounds E10 and E63 on the RORγ protein are comparable to those of the control drug.
实施例93Example 93
体外活性实验：本发明采用Luciferase检测技术验证本发明化合物的抑制能力。 In vitro activity assay: The present invention uses the Luciferase detection technique to verify the inhibitory ability of the compounds of the invention.
1、实验目的1. Experimental purpose
测定本发明化合物对核受体RORγ细胞水平的抑制活性。The inhibitory activity of the compounds of the invention against nuclear receptor RORy cell levels was determined.
2、实验材料2, experimental materials
人肾上皮细胞系293T细胞；含有10％胎牛血清的DMEM培养基；96孔板透明板；双报告基因检测试剂盒；Opti-MEM试剂；Lipo-fectamine 2000转染试剂；重组质粒：Gal4-RORγLBD：25ng，Full-length-RORγ：25ng，pG5-luc、Renilla；阳性抑制剂：T1317,SR2211,UA。Human renal epithelial cell line 293T cells; DMEM medium containing 10% fetal bovine serum; 96-well plate transparent plate; double reporter gene detection kit; Opti-MEM reagent; Lipo-
3、实验方法3. Experimental methods
人肾上皮细胞系293T细胞，用含有10％胎牛血清的DMEM培养基培养。转染前一天将细胞制备与96孔板中，细胞密度为1x104个/孔。贴壁生长24小时后进行瞬时转染，采用双报告基因共转染的方法，转染试剂为Lipo-fectamine2000，用Opti-MEM试剂分别稀释转染试剂和质粒。Gal4-RORγLBD每孔25ng；pG5-luc基因每孔25ng；Renilla每孔5ng，共转染24小时后加入不同浓度的化合物，孵育24小时后，采用Luciferase双报告基因检测试剂盒，检测发光信号，每个样品3个复孔。Human renal epithelial cell line 293T cells were cultured in DMEM medium containing 10% fetal calf serum. The cells were prepared in a 96-well plate one day prior to transfection with a cell density of 1 x 10 4 cells/well. Transient transfection was carried out 24 hours after adherent growth, using a double reporter gene co-transfection method, the transfection reagent was Lipo-fectamine2000, and the transfection reagent and plasmid were diluted with Opti-MEM reagent, respectively. Gal4-RORγLBD was 25 ng per well; pG5-luc gene was 25 ng per well; Renilla was 5 ng per well. After transfection for 24 hours, different concentrations of compounds were added. After incubation for 24 hours, the Luciferase double reporter assay kit was used to detect the luminescent signal. 3 replicate wells per sample.
人肾上皮细胞系293T细胞，用含有10％胎牛血清的DMEM培养基培养。转染前一天将细胞制备与96孔板中，细胞密度为1x104个/孔。贴壁生长24小时后进行瞬时转染，采用双报告基因共转染的方法，转染试剂为Lipo-fectamine2000，用Opti-MEM试剂分别稀释转染试剂和质粒。Full-length-RORγ每孔25ng；pG5-luc基因每孔25ng；Renilla每孔5ng，共转染24小时后加入不同浓度的化合物，孵育24小时后，采用Luciferase双报告基因检测试剂盒，检测发光信号，每个样品3个复孔。Human renal epithelial cell line 293T cells were cultured in DMEM medium containing 10% fetal calf serum. The cells were prepared in a 96-well plate one day prior to transfection with a cell density of 1 x 10 4 cells/well. Transient transfection was carried out 24 hours after adherent growth, using a double reporter gene co-transfection method, the transfection reagent was Lipo-fectamine2000, and the transfection reagent and plasmid were diluted with Opti-MEM reagent, respectively. Full-length-RORγ was 25 ng per well; pG5-luc gene was 25 ng per well; Renilla was 5 ng per well. After transfection for 24 hours, different concentrations of compounds were added. After incubation for 24 hours, Luciferase double reporter assay kit was used to detect luminescence. Signal, 3 replicate wells per sample.
本发明化合物E1-E82对RORγ细胞水平的抑制活性如下图2所示。The inhibitory activity of the compounds of the present invention E1-E82 on the level of RORγ cells is shown in Fig. 2 below.
活性较好化合物对RORγ细胞水平的抑制活性的IC50数值如下表二所示：The IC 50 values for the inhibitory activity of the more active compounds against ROR gamma cell levels are shown in Table 2 below:
NT：没有测试NT: no test
表二：活性较好化合物对RORγ细胞水平的抑制活性的IC50 Table II: IC 50 of the inhibitory activity of the active compound is preferably on the cellular level RORγ
实验结果表明：本发明化合物对RORγ细胞水平测试发现，其具有非常好的抑制作用，特别是化合物E11、E17、E70对RORγ细胞水平的抑制活性比对照药活性更好。同时化合物E19、E45、E63与对照药抑制活性相当。The experimental results show that the compounds of the present invention have a very good inhibitory effect on the RORγ cell level test, and in particular, the inhibitory activities of the compounds E11, E17 and E70 on the level of RORγ cells are better than those of the control drugs. At the same time, the compounds E19, E45 and E63 were equivalent to the inhibitory activity of the reference drug.
本发明所述的2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺类化合物及其药学上可接受的盐，可以有效抑制维甲酸孤核受体γ亚型的蛋白活性及细胞活性，特别是化合物E10、E11、E17、E19、E45、E56、E63、E70与阳性化合物相当，且对比阳性化合物具有结构稳定和容易制备的优点。同时可以看到活性化合物的结构特点是：1)R1为乙基；2)R2,R3主要是连有较大取代基的苯环，这些取代基因在苯环上位置多变，且结构多样，可以看出这类化合物的母核结构对活性保持具有很重要的作用。在此充分表明这类化合物具有成为治疗炎症疾病和免疫紊乱以及癌症治疗等方面的潜力。The 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide compound of the present invention and a pharmaceutically acceptable salt thereof can effectively inhibit the retinoic acid receptor γ subunit The type of protein activity and cell activity, particularly the compounds E10, E11, E17, E19, E45, E56, E63, E70 are comparable to the positive compounds, and the comparative positive compounds have the advantages of structural stability and ease of preparation. At the same time, it can be seen that the structural characteristics of the active compound are: 1) R 1 is an ethyl group; 2) R 2 and R 3 are mainly benzene rings having a large substituent attached thereto, and these substitution genes are positionally variable on the benzene ring, and The structure is diverse, and it can be seen that the parent core structure of such compounds plays an important role in maintaining activity. It is well documented herein that such compounds have potential for the treatment of inflammatory diseases and immune disorders as well as for the treatment of cancer.
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。 The above-mentioned embodiments are merely illustrative of several embodiments of the present invention, and the description thereof is more specific and detailed, but is not to be construed as limiting the scope of the invention. It should be noted that a number of variations and modifications may be made by those skilled in the art without departing from the spirit and scope of the invention. Therefore, the scope of the invention should be determined by the appended claims.
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| CN114790169A (en) * | 2016-01-29 | 2022-07-26 | 中国科学院广州生物医药与健康研究院 | Tetrahydroquinoline related bicyclic compound and application thereof |
| WO2021047406A1 (en) * | 2019-09-10 | 2021-03-18 | 四川科伦博泰生物医药股份有限公司 | Tricyclic compound, pharmaceutical composition containing same, preparation method therefor and use thereof |
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| WO2013160418A1 (en) * | 2012-04-27 | 2013-10-31 | Glaxo Group Limited | Novel compounds |
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- 2014-12-24 CN CN201410821535.5A patent/CN104530014B/en active Active
- 2014-12-25 WO PCT/CN2014/094942 patent/WO2015096771A1/en not_active Ceased
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016145298A1 (en) | 2015-03-12 | 2016-09-15 | The Regents Of The University Of California | METHODS FOR TREATING CANCER WITH RORgamma INHIBITORS |
| US10959984B2 (en) | 2015-03-12 | 2021-03-30 | The Regents Of The University Of California | Methods for treating cancer with RORγ inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104530014B (en) | 2018-03-20 |
| CN104530014A (en) | 2015-04-22 |
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