WO2015096771A1 - Composé 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide et composition et utilisation correspondantes - Google Patents

Composé 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide et composition et utilisation correspondantes Download PDF

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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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PCT/CN2014/094942
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Chinese (zh)
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许�永
薛晓纤
张岩
李静
金翔宇
罗小雨
宋宇
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中国科学院广州生物医药与健康研究院
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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

La présente invention concerne un composé présentant une caractéristique structurale de formule générale I comme nouvel inhibiteur du sous-type γ du récepteur nucléaire orphelin de l'acide rétinoïque (RORγ) et les utilisations du composé et d'un sel, d'un isomère, d'un racémate, d'un complexe de cocristallisation de promédicament, d'un hydrate et d'un solvate pharmaceutiquement acceptables dans le médicament pour le traitement ou la prévention d'une maladie associée à la régulation du RORγ et régie par celui-ci.
PCT/CN2014/094942 2013-12-25 2014-12-25 Composé 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide et composition et utilisation correspondantes WO2015096771A1 (fr)

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WO2016145298A1 (fr) 2015-03-12 2016-09-15 The Regents Of The University Of California Méthodes de traitement du cancer par des inhibiteurs de ror gamma

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CN105985282B (zh) * 2015-01-28 2020-12-08 中国科学院广州生物医药与健康研究院 一种2-氧代-1,2-二氢苯并[cd]吲哚类化合物及其应用
CN114790169A (zh) * 2016-01-29 2022-07-26 中国科学院广州生物医药与健康研究院 四氢喹啉相关二环类化合物及其应用
WO2021047406A1 (fr) * 2019-09-10 2021-03-18 四川科伦博泰生物医药股份有限公司 Composé tricyclique, composition pharmaceutique le contenant, procédé de préparation correspondant et utilisation associée
CN113912563A (zh) * 2020-07-10 2022-01-11 中国科学院广州生物医药与健康研究院 一种苯并五元氮杂环化合物及其应用
CN111995563A (zh) * 2020-08-04 2020-11-27 常州大学 磷酸二酯酶pde2活性抑制剂

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WO2016145298A1 (fr) 2015-03-12 2016-09-15 The Regents Of The University Of California Méthodes de traitement du cancer par des inhibiteurs de ror gamma
US10959984B2 (en) 2015-03-12 2021-03-30 The Regents Of The University Of California Methods for treating cancer with RORγ inhibitors

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