CN118271306A - Aromatic heterocycle substituted arylsulfonyl pyrrole derivative and application thereof - Google Patents

Aromatic heterocycle substituted arylsulfonyl pyrrole derivative and application thereof Download PDF

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CN118271306A
CN118271306A CN202211715354.5A CN202211715354A CN118271306A CN 118271306 A CN118271306 A CN 118271306A CN 202211715354 A CN202211715354 A CN 202211715354A CN 118271306 A CN118271306 A CN 118271306A
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sulfonyl
pyrrol
fluorophenyl
pharmaceutically acceptable
mixture
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王显连
徐永梅
陈春麟
蔡金娜
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Shanghai Medicilon Inc
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Shanghai Medicilon Inc
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Abstract

The invention discloses an aryl sulfonyl pyrrole derivative substituted by aromatic heterocycle and application thereof, and discloses a compound shown in a general formula (I) or a tautomer, an enantiomer, a diastereomer, a mixture and pharmaceutically acceptable salts thereof,Wherein: x 1 and X 2 are independently selected from C or N; x 1 and X 2 may be the same or different; r 1 is selected from one of H, F, cl and CH 3; y 1 is selected from one of O and S; y 2 is selected from one of C and N.

Description

Aromatic heterocycle substituted arylsulfonyl pyrrole derivative and application thereof
Technical Field
The invention relates to a novel aromatic heterocyclic substituted arylsulfonyl pyrrole derivative and application thereof.
Background
Peptic ulcers are mainly chronic ulcers that occur in the stomach and duodenum. Although there are regional differences, peptic ulcers usually account for 10% to 20% of the general population, and are a frequently occurring and common disease. Ulcer formation has various factors, and the digestive effect of acidic gastric juice on mucous membrane is a basic factor for ulcer formation. Therefore, inhibition of gastric acid secretion is increasingly the first method of treatment for peptic ulcer diseases.
Since the first proton pump inhibitor (Proton Pump Inhibitors, PPIs) omeprazole was marketed in 1988, several PPIs products have been marketed worldwide to date, including lansoprazole, pantoprazole, rabeprazole, esomeprazole, and the like. PPIs have become the drug of choice for treating gastric acid related diseases including peptic ulcer, reflux esophagitis, and zepine-el syndrome. The Proton Pump (Proton Pump) is essentially H+/K+ -ATPase (H +/K+ -ATPase), which specifically pumps protons (H +) into the gastric cavity to form strong acidity in the stomach. Proton pump inhibitors can inhibit the activity of proton pumps and thereby modulate proton pump mediated gastric acid secretion.
Potassium ion competitive acid blockers (Potasium-Competitive Acid Blockers, P-CABs) are a novel class of gastric acid blockers which act to inhibit H +/K+ -ATPase enzymatic activity by reversibly, competitively binding to Potassium ions (K +) to H +/K+ -ATPase. Compared with PPIs, P-CABs has the characteristics of lipophilicity, alkalescence, stability under acidic (low pH) conditions and the like. Meanwhile, the P-CABs has the advantages of quick response, easy achievement of acid inhibition effect and the like.
The first P-CABs new drug voronoi was marketed in japan in 2014 for the treatment of gastric acid related diseases such as peptic ulcer. A series of potassium ion competitive acid blocker structures have also been disclosed. There remains a need to develop new compounds with better patentability in a variety of structural types to meet clinical needs.
Disclosure of Invention
In view of the above problems, it is a technical object of the present invention to provide a compound for treating gastric acid related diseases such as peptic ulcer, which is of a novel structural type and has excellent effects and actions. The compounds represented by the general formula or tautomers, enantiomers, diastereomers, mixtures and pharmaceutically acceptable salts thereof have been found to have excellent effects and actions as therapeutic agents, particularly as gastric acid secretion inhibitors, H +/K+ -ATPase inhibitors, potassium ion competitive acid blockers (P-CABs).
In a first aspect, the present invention provides compounds of formula (I) or a tautomer, enantiomer, diastereomer, mixture, and pharmaceutically acceptable salt thereof,
X 1 and X 2 are independently selected from C or N; x 1 and X 2 may be the same or different;
R 1 is selected from one of H, F, cl and CH 3;
Y 1 is selected from one of O and S;
y 2 is selected from one of C and N.
In a second aspect, the present invention provides compounds of formula (II) or a tautomer, enantiomer, diastereomer, mixture, and pharmaceutically acceptable salt thereof,
X 1 and X 2 are independently selected from C or N; x 1 and X 2 may be the same or different;
R 1 is selected from one of H, F, cl and CH 3;
Y 1 is selected from one of C and N;
Y 2 and Y 3 are selected from one of C, O and S.
In a third aspect, the present invention provides compounds of formula (III) or a tautomer, enantiomer, diastereomer, mixture, and pharmaceutically acceptable salt thereof,
X 1 and X 2 are independently selected from C or N; x 1 and X 2 may be the same or different;
R 1 is selected from one of H, F, cl and CH 3;
y 4 is selected from one of O and S.
In a fourth aspect, the present invention provides compounds of formula (IV) or a tautomer, enantiomer, diastereomer, mixture, and pharmaceutically acceptable salt thereof,
X 1 and X 2 are independently selected from C or N; x 1 and X 2 may be the same or different;
R 1 is selected from one of H, F, cl and CH 3;
Y 5 is selected from one of O and S.
Preferably, the compound is selected from:
1- (5- (2-fluoropyridin-3-yl) -1- ((3- (oxazol-2-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl;
1- (5- (2-fluoropyridin-3-yl) -1- ((3- (furan-2-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide;
1- (5- (2-fluoropyridin-3-yl) -1- ((5- (furan-2-yl) pyridine-3-methyl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide;
1- (5- (2-fluorophenyl) -1- ((5- (thiophen-3-yl) pyridin-3-yl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide;
1- (1- ((3- (benzofuran-2-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methyl methylamine;
1- (1- ((3- (benzo [ b ] thiophen-2-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methylformamide;
1- (1- ((3- (benzo [ b ] thiophen-3-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methylformamide;
1- (1- ((5- (benzo [ b ] thiophen-2-yl) pyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl ] -N-methylformamide;
1- (1- ((5- (benzo [ b ] thiophen-3-yl) pyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl ] -N-methylformamide;
1- (1- ((3- (benzofuran-2-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methyl methylamine;
1- (1- ((3- (benzofuran-3-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methyl methylamine;
1- (1- ((5- (benzofuran-3-yl) pyridin-3-yl) (sulfonyl)) -5- (2-fluorophenyl) -1H-pyrrol-3-yl;
1- (5- (2-fluorophenyl) -1- ((3- (furan-2-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methyl methylamine;
1- (5- (2-fluorophenyl) -1- ((3- (furan-3-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl ] -N-methyl methylamine;
1- (5- (2-fluorophenyl) -1- ((5- (thiophen-2-yl) pyridin-3-yl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide;
1- (5- (2-fluorophenyl) -1- ((5- (furan-3-yl) pyridin-3-yl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide.
In a fifth aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of any one of the preceding claims, or a tautomer, enantiomer, diastereomer, mixture, and pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
In a sixth aspect, the invention provides the use of a compound according to any one of the preceding claims, or a tautomer, enantiomer, diastereomer, mixture thereof, and pharmaceutically acceptable salt thereof, or said pharmaceutical composition, for the preparation of a gastric acid secretion inhibitor.
In a seventh aspect, the invention provides the use of a compound according to any one of the preceding claims, or a tautomer, enantiomer, diastereomer, mixture, pharmaceutically acceptable salt thereof, or said pharmaceutical composition, in the preparation of an H +/K+ -atpase inhibitor.
In an eighth aspect, the invention provides the use of a compound according to any one of the preceding claims, or a tautomer, enantiomer, diastereomer, mixture, pharmaceutically acceptable salt thereof, or said pharmaceutical composition, in the preparation of a potassium ion competitive acid blocker.
In a ninth aspect, the present invention provides the use of a compound of any one of the preceding claims or a tautomer, enantiomer, diastereomer, mixture, pharmaceutically acceptable salt thereof or said pharmaceutical composition thereof, for the manufacture of a medicament for the prevention and/or treatment of peptic ulcer, jejunum-eimeria, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, barrett esophagitis, functional dyspepsia, helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, non-steroidal anti-inflammatory drug-induced ulcer or postoperative stress-induced gastric acid excess or ulcer; preferably, the symptomatic gastroesophageal reflux disease comprises a non-erosive reflux disease or a gastroesophageal reflux disease without esophagitis; or the invention provides the use of a compound of any one of the preceding claims, or a tautomer, enantiomer, diastereomer, mixture, pharmaceutically acceptable salt thereof, or said pharmaceutical composition thereof, in the manufacture of a medicament for inhibiting upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis, or invasive stress; preferably, the peptic ulcer comprises a gastric ulcer, a duodenal ulcer or a stoma ulcer.
Detailed Description
The invention is further illustrated by the following embodiments, which are to be understood as merely illustrative of the invention and not limiting thereof.
Unless stated to the contrary, the following terms have the following meanings.
"Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight or branched chain groups of 1 to 10 carbon atoms. Alkyl groups having 1 to 5 carbon atoms are preferred. More preferably an alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl.
The carbon atom content of the various carbon-hydrogen containing moieties is represented by the prefix of the moiety that is marked with the smallest and largest number of carbon atoms, i.e., the prefix Ci-j represents that the number of carbon atoms of the moiety is an integer from "i" to "j" (including i and j). Thus, for example, a C1-3 alkyl group refers to an alkyl group of 1 to 3 carbon atoms (including 1 and 3).
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
Unless otherwise indicated, all compounds appearing in the present invention are intended to include all possible isomers, such as tautomers, enantiomers, diastereomers, and mixtures thereof.
The term "compounds of the present invention" refers to compounds of the general formula. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (I).
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the invention with acids or bases that are suitable for use as medicaments. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is the salts of the compounds of the present invention with acids. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and the like; acidic amino acids such as aspartic acid and glutamic acid.
The term "pharmaceutically acceptable carrier" means a carrier that can be used to prepare pharmaceutical compositions, which are generally safe, nontoxic, not biologically or otherwise undesirable, and includes carriers that are pharmaceutically acceptable to animals and humans. As used in the specification and claims, a "pharmaceutically acceptable carrier" includes one or more such carriers.
The terms "comprising," "including," or "comprising" mean that the various ingredients can be used together in a mixture or composition of the invention. Thus, the terms "consisting essentially of and" consisting of are encompassed by the term "containing.
The term "preventing" refers, for example, to the prevention of progression of clinical symptoms of a disease in a mammal that may be exposed to or pre-treated for the disease but has not yet experienced or displayed symptoms of the disease.
The term "treating" may refer to inhibiting a disease, e.g., preventing or reducing the progression of a disease or a clinical symptom thereof, or alleviating a disease, e.g., degrading a disease or a clinical symptom thereof.
The invention provides a compound shown in a general formula (I) or tautomer, enantiomer, diastereomer, mixture and pharmaceutically acceptable salt thereof,
X 1 and X 2 are independently selected from C or N; x 1 and X 2 may be the same or different;
R 1 is selected from one of H, F, cl and CH 3;
Y 1 is selected from one of O and S;
y 2 is selected from one of C and N.
The invention also provides compounds of formula (II) or tautomers, enantiomers, diastereomers, mixtures, and pharmaceutically acceptable salts thereof,
X 1 and X 2 are independently selected from C or N; x 1 and X 2 may be the same or different;
R 1 is selected from one of H, F, cl and CH 3;
Y 1 is selected from one of C and N;
Y 2 and Y 3 are selected from one of C, O and S.
The invention also provides compounds of formula (III) or tautomers, enantiomers, diastereomers, mixtures, and pharmaceutically acceptable salts thereof,
X 1 and X 2 are independently selected from C or N; x 1 and X 2 may be the same or different;
R 1 is selected from one of H, F, cl and CH 3;
y 4 is selected from one of O and S.
The invention also provides compounds of formula (IV) or tautomers, enantiomers, diastereomers, mixtures, and pharmaceutically acceptable salts thereof,
X 1 and X 2 are independently selected from C or N; x 1 and X 2 may be the same or different;
R 1 is selected from one of H, F, cl and CH 3;
Y 5 is selected from one of O and S.
In some embodiments of the invention, the compound of formula (la) is selected from the compounds shown in table 1.
TABLE 1
The preparation method of the compound is specifically described in examples.
The invention also relates to a pharmaceutical composition containing an effective amount of a compound shown in a general formula or a tautomer, an enantiomer, a diastereomer, a mixture and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or excipient or diluent thereof.
By "effective amount" is meant a compound of the present invention: (i) treating a particular disease, condition, or disorder, (ii) reducing, ameliorating, or eliminating one or more symptoms of a particular disease, condition, or disorder, or (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition, or disorder described herein.
Examples of pharmaceutically acceptable carriers (pharmaceutically acceptable carriers) include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g.80，20 Wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
The invention also relates to application of the compound shown in the general formula or tautomer, enantiomer, diastereoisomer, mixture and pharmaceutically acceptable salt thereof or pharmaceutical composition thereof in preparing gastric acid secretion inhibitors. The gastric acid secretion can be inhibited by administering to a patient in need thereof an effective amount of a compound of the general formula or a tautomer, enantiomer, diastereomer, mixture, or pharmaceutically acceptable salt thereof or pharmaceutical composition thereof.
The invention also relates to application of the compound shown in the general formula or tautomer, enantiomer, diastereoisomer, mixture and pharmaceutically acceptable salt thereof or pharmaceutical composition thereof in preparing H +/K+ -ATPase (H +/K+ -ATPase) inhibitor. An effective amount of a compound of formula (I) or a tautomer, enantiomer, diastereomer, mixture, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, may be administered to a patient in need of such treatment to inhibit H +/K+ -ATPase (H +/K+ -ATPase).
The invention also relates to the use of the compounds shown in the general formula or tautomers, enantiomers, diastereomers, mixtures and pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof for preparing potassium ion competitive acid blockers (P-CABs).
The invention also relates to the use of a compound shown in the general formula or a tautomer, enantiomer, diastereomer, mixture, pharmaceutically acceptable salt or pharmaceutical composition thereof for treating and preventing peptic ulcer, zuo-Egypt syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, barrett esophagitis, functional dyspepsia, helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, ulcer caused by nonsteroidal anti-inflammatory agent or gastric hyperacidity or ulcer caused by postoperative stress; or in the preparation of a medicament for inhibiting upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress. The peptic ulcers referred to above include, but are not limited to, gastric ulcers, duodenal ulcers or stomal ulcers; symptomatic gastroesophageal reflux disease includes, but is not limited to, non-erosive reflux disease or gastroesophageal reflux disease without esophagitis.
The present invention will be described in more detail by way of examples. It is also to be understood that the following examples are given solely for the purpose of illustration and are not to be construed as limitations upon the scope of the invention, since numerous insubstantial modifications and variations will now occur to those skilled in the art in light of the foregoing disclosure. The specific process parameters and the like described below are also merely examples of suitable ranges, i.e., one skilled in the art can make a suitable selection from the description herein and are not intended to be limited to the specific values described below.
The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
The structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS), and the purity of the compound is determined by liquid phase high pressure chromatography (HPLC). NMR was measured using a Bruker AVANCE-400 NMR apparatus with chemical shifts in ppm. MS was determined using an agilent 6120 mass spectrometer. HPLC was determined using an agilent 1200DAD high pressure liquid chromatograph.
Example 1
1- (5- (2-Fluoropyridin-3-yl) -1- ((3- (oxazol-2-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl)
First step
5-Bromo-1H-pyrrole-3-carboxylic acid methyl ester
N-bromosuccinimide (2.85 g,16 mmol) was added to a solution of methyl 1H-pyrrole-3-carboxylate 1a (2.0 g,16 mmol) and tetrahydrofuran (60 mL) at-78deg.C under nitrogen, followed by 6 drops of pyridine as catalyst, and reacted at-78deg.C for 2H. N-bromosuccinimide (700 mg,3.95 mmol) was added and the reaction continued for 1h at-78 ℃. After the reaction was returned to room temperature, it was filtered. To the filtrate was added water (60 mL), followed by extraction with ethyl acetate (30 ml×2), and the organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate volume ratio=95:5) to give methyl 5-bromo-1H-pyrrole-3-carboxylate 1b (1.42 g, yield 43.5%).
1H NMR(400MHz,CDCl3):δ8.63(s,1H),7.37(dd,J＝2.9,1.7Hz,1H),6.59(dd,J＝2.5,1.8Hz,1H),3.81(s,3H).
Second step
1- (Tert-butyl) 3-methyl 5-bromo-1H-pyrrole-1, 3-dicarboxylic acid
Methyl 5-bromo-1H-pyrrole-3-carboxylate 1b (1.42 g,6.99 mmol), di-tert-butyl dicarbonate (1.6 g,7.34 mmol), 4-dimethylaminopyridine (426 mg, 3.495mmol), triethylamine (2.1 g,20.97 mmol) and dichloromethane (50 mL) were added to the reaction flask and reacted at room temperature for 1H. Di-tert-butyl dicarbonate (0.32 g,1.47 mmol) was added thereto and the mixture was reacted at room temperature overnight. After the reaction, water was added to wash, and the organic phase was collected, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate volume ratio=10:1) to give 1- (tert-butyl) 3-methyl-5-bromo-1H-pyrrole-1, 3-dicarboxylic acid 1c (2.0 g, white solid, yield 94.7%).
MS m/z(ESI)：304[M+H]。
Third step
5- (2-Fluoropyridin-3-yl) -1H-pyrrole-3-carboxylic acid methyl ester
1- (Tert-butyl) 3-methyl-5-bromo-1H-pyrrole-1, 3-dicarboxylic acid 1c (1.0 g,3.3 mmol), 2-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (883 mg,3.96 mmol), tetrakis (triphenylphosphine) palladium (190 mg,0.165 mmol), sodium carbonate (840 mg,7.92 mmol), 1, 4-dioxane (30 mL) and water (12 mL) were placed in a reaction flask, and the mixture was reacted three times with nitrogen, and the temperature of the oil bath was raised to 100℃for 16 hours. After the reaction was completed, the reaction was returned to room temperature, filtered, water was added to the filtrate, extracted with methylene chloride (15 ml×2), the organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate volume ratio=9:1-7:3) to give methyl 5- (2-fluoropyridin-3-yl) -1H-pyrrole-3-carboxylate 1d (500 mg, off-white solid, yield 68.87%).
MS m/z(ESI)：221.1[M+H]。
Fourth step
(5- (2-Fluoropyridin-3-yl) -1H-pyrrol-3-yl)
1.5M diisobutylaluminum hydride (4.5 mL, 6.812 mmol) was slowly added dropwise to a solution of 5- (2-fluoropyridin-3-yl) -1H-pyrrole-3-carboxylic acid methyl ester 1d (500 mg,2.273 mmol) in tetrahydrofuran (20 mL) at-78deg.C under nitrogen protection, and reacted for 1H at-78deg.C. 1.5M diisobutylaluminum hydride (4.5 mL,6.818 mmol) was added thereto, and the reaction was continued at-78℃for 1 hour. After the completion of the reaction, water quenching was added, extraction was performed with ethyl acetate (15 ml×2), and the organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (5- (2-fluoropyridin-3-yl) -1H-pyrrol-3-yl 1e (400 mg, gray solid, yield 91.74%).
1H NMR(400MHz,DMSO):δ11.29(s,1H),8.37-8.18(m,1H),8.06(s,1H),7.44(s,1H),6.95(s,1H),6.67(s,1H),4.75(s,1H),4.43(d,J＝4.3Hz,2H).
Fifth step
5- (2-Fluoropyridin-3-yl) -1H-pyrrole-3-carbaldehyde
Manganese dioxide (1.36 g,15.62 mmol) was added portionwise to a solution of (5- (2-fluoropyridin-3-yl) -1H-pyrrol-3-yl-1 e (300 mg,1.562 mmol) and acetonitrile (15 mL) and reacted at 75℃for 2.5H after completion of the reaction, the reaction solution was filtered and the filtrate concentrated under reduced pressure to give crude product which was purified by column chromatography (petroleum ether: ethyl acetate volume ratio = 9:1-7:3) to give 5- (2-fluoropyridin-3-yl) -1H-pyrrole-3-carbaldehyde 1f (140 mg, brown solid, yield 47.17%).
MS m/z(ESI)：191.1[M+H]。
Sixth step
1- ((3-Bromophenyl) sulfonyl) -5- (2-fluoropyridin-3-yl) -1H-pyrrole-3-carbaldehyde
In the reaction flask was added 5- (2-fluoropyridin-3-yl) -1H-pyrrole-3-carbaldehyde 1f (140 mg,0.737 mmol), 3-bromobenzenesulfonyl chloride (282 mg,1.105 mmol), 4-dimethylaminopyridine (27 mg,0.221 mmol), N-diisopropylethylamine (470 mg,3.684 mmol) and acetonitrile (7 mL), and the oil bath was warmed to 45℃for 2H. After the reaction was completed, the reaction mixture was concentrated, water was added, extracted with ethyl acetate (5 ml×2), and the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1g (200 mg, crude product, yield 68.88%) of 1- ((3-bromophenyl) sulfonyl) -5- (2-fluoropyridin-3-yl) -1H-pyrrole-3-carbaldehyde. The crude product is directly put into the next step.
MS m/z(ESI)：410.9[M+H]。
Seventh step
1- (1- ((3-Bromophenyl) sulfonyl) -5- (2-fluoropyridin-3-yl) -1H-pyrrol-3-yl ] -N-methyl methylamine
1- ((3-Bromophenyl) sulfonyl) -5- (2-fluoropyridin-3-yl) -1H-pyrrole-3-carbaldehyde 1g (180 mg,0.441 mmol), 2M solution of methylamine in tetrahydrofuran (1.1 mL,2.206 mmol), 1, 2-dichloroethane (4.5 mL) and a catalytic amount of acetic acid were added to the reaction flask, and the mixture was stirred at room temperature for 1H. Sodium triacetoxyborohydride (374 mg,1.764 mmol) was added thereto and reacted at room temperature for 1 hour. After the reaction was completed, water was added to quench, the organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (dichloromethane: methanol volume ratio=10:1) to give 1- (1- ((3-bromophenyl) sulfonyl) -5- (2-fluoropyridin-3-yl) -1H-pyrrol-3-yl ] -N-methyl methylamine for 1H (100 mg, off-white solid, yield 53.47%).
MS m/z(ESI)：425.9[M+H]。
Eighth step
1- (5- (2-Fluoropyridin-3-yl) -1- ((3- (oxazol-2-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl)
1- (1- ((3-Bromophenyl) sulfonyl) -5- (2-fluoropyridin-3-yl) -1H-pyrrol-3-yl ] -N-methylmethylamine 1H (30 mg,0.0707 mmol), 2- (tributyltin-yl) oxazole (33 mg,0.092 mmol), tetrakis (triphenylphosphine) palladium (8 mg, 0.007073 mmol) and 1, 4-dioxane (0.6 mL) were added to a glass tube, and replaced three times with nitrogen, the oil bath was warmed to 130℃for 5H after completion of the reaction, the reaction was returned to room temperature, filtered, and the liquid phase preparation (acetonitrile/water (containing 0.05% ammonia) was flushed) gradient to give 1- (5- (2-fluoropyridin-3-yl) -1- ((3- (oxazol-2-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl 1 (9.93 mg, yellow oil, yield 34.24%).
MS m/z(ESI)：413.2[M+H]。
1H NMR(400MHz,MeOD):δ8.31(d,J＝7.6Hz,1H),8.27(d,J＝4.7Hz,1H),8.06(s,1H),8.03(s,1H),7.84(s,1H),7.76-7.61(m,3H),7.36(d,J＝9.6Hz,2H),6.50(s,1H),4.10(s,2H),2.70(s,3H).
Example 2
1- (5- (2-Fluoropyridin-3-yl) -1- ((3- (furan-2-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide
1- (1- ((3-Bromophenyl) sulfonyl) -5- (2-fluoropyridin-3-yl) -1H-pyrrol-3-yl ] -N-methylmethylamine 1H (35 mg,0.0825 mmol), furan-2-ylboronic acid (14 mg,0.124 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (6 mg, 0.008235 mmol), sodium carbonate (26 mg,0.247 mmol), 1, 4-dioxane (2 mL) and water (0.5 mL) were added to a glass vial, the three times replaced with nitrogen, the oil bath was warmed to 80℃for 2H, after the reaction was completed, the reaction was returned to room temperature, filtered, and the liquid phase preparation (acetonitrile/water (containing 0.05% aqueous ammonia) was flushed) gradient to give 1- (5- (2-fluoropyridin-3-yl) -1- ((3- (furan-2-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide 2 (14.56 mg, yellow solid, 2.44% yield).
MS m/z(ESI)：412.5[M+H]。
1H NMR(400MHz,MeOD):δ8.27(d,J＝4.1Hz,1H),7.97(d,J＝7.8Hz,1H),7.81(d,J＝0.6Hz,1H),7.74-7.69(m,1H),7.64(s,2H),7.54(t,J＝7.9Hz,1H),7.40(d,J＝7.9Hz,1H),7.36(d,J＝5.5Hz,1H),6.87(d,J＝3.3Hz,1H),6.58(d,J＝1.4Hz,1H),6.49(d,J＝1.3Hz,1H),4.10(s,2H),2.69(s,3H).
Example 3
1- (5- (2-Fluoropyridin-3-yl) -1- ((5- (furan-2-yl) pyridine-3-methyl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide
First step
1- ((5-Bromopyridin-3-yl) sulfonyl) -5- (2-fluoropyridin-3-) -1H-pyrrole-3-carbaldehyde
In the reaction flask were added 5- (2-fluoropyridin-3-yl) -1H-pyrrole-3-carbaldehyde 1f (150 mg,0.789 mmol), 3-bromopyridine sulfonyl chloride (304 mg,1.184 mmol), 4-dimethylaminopyridine (29 mg,0.237 mmol), N-diisopropylethylamine (509 mg,3.945 mmol) and acetonitrile (6 mL), and the oil bath was warmed to 50℃for 2H. 3-bromopyridine sulfonyl chloride (100 mg,0.390 mmol) was added thereto, and the mixture was heated to 70℃and reacted for 2 hours. After the reaction, the reaction mixture was concentrated, water was added, the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by thin layer chromatography (petroleum ether: ethyl acetate volume ratio=2:1) to give 1- ((5-bromopyridin-3-yl) sulfonyl) -5- (2-fluoropyridin-3-) -1H-pyrrole-3-carbaldehyde 3a (130 mg, yellow semi-oil semi-solid, yield 40.2%).
MS m/z(ESI)：411.9[M+H]。
Second step
1- (1- ((5-Bromopyridin-3-yl) sulfonyl) -5- (2-fluoropyridin-3-) -1H-pyrrol-3-) -N-methyl methylamine
1- ((5-Bromopyridin-3-yl) sulfonyl) -5- (2-fluoropyridin-3-) -1H-pyrrole-3-carbaldehyde 3a (125 mg,0.305 mmol), 2M solution of methylamine in tetrahydrofuran (0.76 mL,1.528 mmol), 1, 2-dichloroethane (3 mL) and a catalytic amount of acetic acid were added to the reaction flask, and the mixture was stirred at room temperature for 1H. Sodium triacetoxyborohydride (319 mg,1.222 mmol) was added thereto and then reacted at room temperature for 1 hour, and sodium triacetoxyborohydride (323.3 mg,1.525 mmol) was added thereto and then reacted at room temperature for 1 hour. After the reaction, water quenching was added, extraction was performed with methylene chloride (10 ml×2), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a solid crude product. The crude solid was slurried with ethyl acetate and filtered to give the solid as crude (65 mg, white solid) which was then purified by thin layer chromatography (petroleum ether: ethyl acetate volume ratio = 3:1) to give 1- (1- ((5-bromopyridin-3-yl) sulfonyl) -5- (2-fluoropyridin-3-) -1H-pyrrol-3-) -N-methylmethylamine 3b (77 mg, yellow semi-oil semi-solid, overall yield 59.69%).
MS m/z(ESI)：424.9[M+H]。
Third step
1- (5- (2-Fluoropyridin-3-yl) -1- ((5- (furan-2-yl) pyridin-3-yl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide 1- (1- ((5-bromopyridin-3-yl) sulfonyl) -5- (2-fluoropyridin-3-) -1H-pyrrol-3-) -N-methylmethylamine 3b (25 mg,0.059 mmol), furan-2-ylboronic acid (10 mg,0.0885 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (4 mg,0.0059 mmol), sodium carbonate (19 mg,0.177 mmol), 1, 4-dioxane (0.4 mL) and water (0.1 mL) were added in a glass vial, the reaction was warmed to 80℃three times with nitrogen, after completion of the reaction, the reaction was returned to room temperature and filtered to prepare (acetonitrile/water (0.05% aqueous) gradient of 1- (2-phenylpyridin-3-yl) to give 1- (2-methylpyridin-3-yl) dichloromethane complex (4 mg,0.0059 mmol), sodium carbonate (19 mg,0.177 mmol), 1, 4-dioxane (0.4 mL) and water (0.1 mL) were reacted three times.
MS m/z(ESI)：413.3[M+H]。
1H NMR(400MHz,MeOD):δ9.15(s,1H),8.51(s,1H),8.31(d,J＝4.0Hz,1H),7.95(s,1H),7.87(s,1H),7.81-7.76(m,1H),7.74(d,J＝1.1Hz,1H),7.42–7.36(m,1H),7.08(d,J＝3.4Hz,1H),6.64(dd,J＝3.4,1.7Hz,1H),6.55(d,J＝1.6Hz,1H),4.11(s,2H),2.70(s,3H).
Example 4
1- (5- (2-Fluorophenyl) -1- ((5- (thiophen-3-yl) pyridin-3-yl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide
First step
1- ((5-Bromopyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde
In a 100mL eggplant-shaped bottle were successively added 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde 4a (200 mg,1.06 mmol), 4-dimethylaminopyridine (38.8 mg,0.318 mmol), acetonitrile (1 mL) and 5-bromopyridine-3-sulfonyl chloride (407 mg,1.59 mmol), heated to 45℃and reacted at a constant temperature for 5H. After the reaction was completed, the organic phase was collected by extraction with ethyl acetate (25 ml×3), washed with saturated aqueous sodium chloride (25 ml×2), then dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (petroleum ether: volume ratio of ethyl acetate=4.7:1) to give 1- ((5-bromopyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde 4b (221 mg, reddish brown solid, yield 51.2%).
MS m/z(ESI)：408.9[M+H]。
Second step
1- (1- ((5-Bromopyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl ] -N-methyl methylamine
To a 50mL eggplant-shaped bottle was added a tetrahydrofuran solution (2M, 1.1 mL) of 1- ((5-bromopyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde 4b (180 mg,0.44 mmol), methylene chloride (20 mL) and methylamine in this order, and sodium borohydride acetate (373 mg,1.76 mmol) and glacial acetic acid (1 mL) were added while stirring at room temperature for 4 hours. After the reaction was completed, extracted with dichloromethane (25 ml×2), the organic phases were combined, washed with saturated aqueous sodium chloride (25 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1- (1- ((5-bromopyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl ] -N-methylmethylamine 4c (212 mg, pale yellow solid, yield 100%).
MS m/z(ESI)：425.9[M+H]。
Third step
1- (5- (2-Fluorophenyl) -1- ((5- (thiophen-3-yl) pyridin-3-yl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide
To a glass tube was added successively 1- (1- ((5-bromopyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl ] -N-methylmethylamine 4c (70 mg,0.165 mmol), thiophen-3-ylboronic acid (25.5 mg, 0.199mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (12.08 mg,0.0165 mmol), sodium carbonate (52.5 mg, 0.495mmol), dioxane (1.2 mL) and water (0.3 mL), after three times of air exchange (argon), the oil bath was warmed to 80℃and incubated for 1 hour, after the reaction was completed, it was cooled to room temperature, filtered, extracted with ethyl acetate (10 mL. Times.3), the organic phase was combined, washed with saturated aqueous sodium chloride solution (5 mL. Times 2), and then dried, filtered and the crude product was concentrated by column chromatography (volume ratio of methylene chloride: methanol=30: l) to give 1- (5-fluorophenyl) -1- (5-pyrrol-3-yl) -1-methyl-3-sulfonyl-1-3-methyl-amide as a yellow solid (1-3-pyridyl) -1-3-methyl-ethyl-3-methyl-4-methyl-4-ethyl-4-methyl-4-L-ethyl-4-ethyl-thiophene (5-ethyl) sulfate).
MS m/z(ESI)：428.3[M+H]。
1H NMR(400MHz,MeOD):δ8.98(s,1H),8.53(d,J＝7.6Hz,1H),7.79-6.97(m,8H),6.53(s,J＝7.6Hz,1H),3.91(s,2H),2.54(m,3H).
Example 5
1- (1- ((3- (Benzofuran-2-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methyl methylamine
First step
1- ((3-Chlorophenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde
Sodium hydride (22.5 mg,9.4 mmol) and anhydrous tetrahydrofuran (1 mL) were sequentially added to a 100mL eggplant-shaped bottle, the mixture was purged with water (argon) four times, and 15-crown ether-5 (1.7 g,7.8 mmol) was added. 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde 5a (500 mg,2.6 mmol) was dissolved in N, N-dimethylformamide (5 mL), and then slowly dropped into the above-mentioned reaction solution under ice bath, 3-chlorobenzenesulfonyl chloride (844 mg,4.0 mmol) was further added thereto, and the mixture was stirred at room temperature for 2 hours. After the completion of the reaction, water (5 mL) was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (5 mL. Times.3), and the organic phases were combined, washed with saturated aqueous sodium chloride solution (5 mL. Times.2), then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate vol=10:1) to give 1- ((3-chlorophenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde 5b (509 mg, red oil, yield: 53.8%).
MS m/z(ESI)：364.0[M+H]。
Second step
1- (1- ((3-Chlorophenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methyl methylamine
A50 mL eggplant-shaped bottle was successively charged with 1- ((3-chlorophenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde 5b (356 mg,0.98 mmol), methylene chloride (2 mL) and a tetrahydrofuran solution of methylamine (2M, 2.45 mL), and sodium borohydride acetate (831 mg,3.92 mmol) and glacial acetic acid (1 mL) were added under ice bath, followed by stirring at room temperature for 4 hours. After the completion of the reaction, the organic phases were combined by extraction with methylene chloride (5 mL. Times.2), washed with saturated aqueous sodium chloride (5 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1- (1- ((3-chlorophenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methylmethylamine 5c (454 mg, reddish brown solid, yield: 100%).
MS m/z(ESI)：379.0[M+H]。
Third step
1- (1- ((3- (Benzofuran-2-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methyl methylamine
To the glass tube was added, in order, 1- (1- ((3-chlorophenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methylmethylamine 5c (38 mg,0.10 mmol), benzofuran-2-ylboronic acid (49 mg,0.20 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (7 mg,0.01 mmol), potassium carbonate (48 mg,0.20 mmol), dioxane (1 mL) and water (0.2 mL). After three times of ventilation (argon), the temperature of the oil bath is raised to 85 ℃, and the oil bath is kept warm and stirred for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated aqueous sodium chloride solution (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by thin layer chromatography (dichloromethane: methanol volume ratio = 10:1) to give 35mg of crude product, which was then prepared by liquid phase (acetonitrile/water (0.05% aqueous ammonia) gradient washed) to give 1- (1- ((3- (benzofuran-2-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methyl methylamine 5 (3.37 mg, white powder, yield 7.30%).
MS m/z(ESI)：461.3[M+H]。
1H NMR(400MHz,CD3OD):δ8.17(d,J＝8.0Hz,1H),7.81(s,2H),7.66(d,J＝8.0Hz,1H),7.60-7.56(m,2H),7.52-7.45(m,2H),7.36(t,J＝8.0Hz,1H),7.33-7.26(m,2H),7.15(d,J＝8.0Hz,2H),7.04(t,J＝8.0Hz,1H),6.39(s,1H),4.10(s,2H),2.69(s,3H).
Example 6
1- (1- ((3- (Benzo [ b ] thiophen-2-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methylformamide
To the glass tube was added, in order, 1- (1- ((3-chlorophenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methylmethylamine 5c (23 mg,0.059 mmol), benzo [ b ] thiophen-2-ylboronic acid (21 mg,0.118 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (4 mg,0.0059 mmol), potassium carbonate (16 mg,0.118 mmol), dioxane (1 mL) and water (0.2 mL). After three times of ventilation (argon), the temperature of the oil bath is raised to 85 ℃, and the oil bath is kept warm and stirred for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated aqueous sodium chloride solution (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by thin layer chromatography (dichloromethane: methanol volume ratio = 10:1) to give 1- (1- ((3- (benzo [ b ] thiophen-2-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methylformamide 6 (7.20 mg, white solid, 25.7% yield).
MS m/z(ESI)：477.2[M+H]。
1H NMR(400MHz,CD3OD):δ8.03(d,J＝8.0Hz,1H),7.90-7.84(m,2H),7.72(s,1H),7.67(s,1H),7.64(s,1H),7.55(t,J＝8.0Hz,1H),7.51(s,J＝8.0Hz,1H),7.43-7.37(m,3H),7.14(d,J＝4.0Hz,2H),7.05(t,J＝10.0Hz,1H),6.38(s,1H),3.93(s,2H),2.57(s,3H).
Example 7
1- (1- ((3- (Benzo [ b ] thiophen-3-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methylformamide
To the glass tube was added, in order, 1- (1- ((3-chlorophenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methylmethylamine 5c (27 mg,0.0709 mmol), benzo [ b ] thiophen-3-ylboronic acid (25 mg,0.142 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (5.2 mg, 0.0075 mmol), sodium carbonate (23 mg,0.213 mmol), dioxane (0.8 mL) and water (0.2 mL). After three air changes (argon), the oil bath was warmed to 80 ℃ and stirred for 2 hours with heat preservation. After the completion of the reaction, it was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate (10 ml×3), and the organic phases were combined, washed with saturated aqueous sodium chloride solution (5 ml×2), then dried over anhydrous sodium sulfate, filtered, and concentrated. After purification by column chromatography (dichloromethane: methanol volume ratio=10:l), the crude product was separated by liquid phase preparation (acetonitrile/water (0.05% aqueous ammonia) gradient rinse) to give 1- (1- ((3- (benzo [ b ] thiophen-3-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methylformamide 7 (17.75 mg, light yellow solid, 52.60% yield).
MS m/z(ESI)：477.3[M+H]。
1H NMR(400MHz,MeOD):δ8.02-7.96(m,1H),7.88(d,J＝8.0Hz,1H),7.69-7.65(m,1H),7.64-7.57(m,3H),7.54-7.48(m,2H),7.47-7.40(m,2H),7.32-7.28(m,1H),7.09(t,J＝8.0Hz,1H),7.00(t,J＝8.0Hz,1H),6.94(t,J＝8.0Hz,1H),6.34(s,1H),3.75(s,2H),2.43(s,3H).
Example 8
1- (1- ((5- (Benzo [ b ] thiophen-2-yl) pyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl ] -N-methylformamide
1- (1- ((5-Bromopyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl ] -N-methylmethylamine 4c (37 mg,0.087 mmol), benzo [ b ] thiophen-2-ylboronic acid (31 mg,0.174 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (6 mg,0.0087 mmol), potassium carbonate (24 mg,0.174 mmol), dioxane (1.0 mL) and water (0.2 mL) were added sequentially in a glass tube, after three passes through an oil bath to 90℃and stirring at1 hour at the end of the reaction, it was cooled to room temperature, filtered, the filtrate was extracted with ethyl acetate (10 mL. Times.3), the organic phase was combined, washed with saturated aqueous sodium chloride solution (5 mL. Times.2), then dried with sodium sulfate, filtered and concentrated, the crude product was purified by column chromatography (volume ratio of methylene chloride: 10: l) to give 1- (1- (5-benzopyridin-2-yl) -pyrrol-3-yl) sulfonyl-2-methyl-3-yl-methyl-2-methyl-amine (20 mg, 5-phenyl) -8-sulfonyl-8-phenyl-2-methyl-2-methyl-butan-2-yl) amide as a pale yellow solid.
MS m/z(ESI)：478.5[M+H]。
1H NMR(400MHz,MeOD):δ9.18(s,1H),8.57(s,1H),7.94-7.90(m,3H),7.85(s,1H),7.67(s,1H),7.49-7.2(m,3H),7.19(d,J＝8.0Hz,2H),7.08(t,J＝8.0Hz,1H),6.40(s,1H),3.76(s,2H),2.45(s,3H).
Example 9
1- (1- ((5- (Benzo [ b ] thiophen-3-yl) pyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl ] -N-methylformamide
1- (1- ((5-Bromopyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl ] -N-methyl methylamine 4c (36 mg,0.0849 mmol), benzo [ b ] thiophen-2-ylboronic acid (30.2 mg,0.169 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (6.2 mg,0.00849 mmol), sodium carbonate (27 mg,0.255 mmol), dioxane (0.8 mL) and water (0.2 mL) were added in this order in a glass tube, after three passes of air exchange (argon), the oil bath was warmed to 90℃and stirred for 2 hours at the end of the reaction, it was cooled to room temperature, filtered, the filtrate was extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium chloride (5 mL. Times.2 mmol), filtered and concentrated, and the crude product was purified by column chromatography (volume ratio of dichloromethane: methanol: 10 l) to give 1- (5-pyrrol-3-yl) -1- (3-methylphenyl) -pyrrol-3-yl) amide (yellow solid (33.9 mg, 33.9%).
MS m/z(ESI)：478.5[M+H]。
1H NMR(400MHz,MeOD):δ9.04(s,1H),8.61(s,1H),8.04-8.00(m,1H),7.91(s,1H),7.82(s,1H),7.70(s,1H),7.68-7.63(m,1H),7.49-7.45(m,2H),7.34(q,J＝4.0Hz,1H),7.17(t,J＝6.0Hz,1H),7.08-7.04(m,1H),6.98(t,J＝8.0Hz,1H),6.42(s,1H),3.81(s,2H),2.48(s,3H).
Example 10
1- (1- ((3- (Benzofuran-2-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methyl methylamine
1- (1- ((3-Chlorophenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methylmethylamine 5c (27 mg,0.08 mmol), benzofuran-2-boronic acid (23 mg,0.14 mmol), potassium carbonate (30 mg,0.21 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (5.2 mg,0.01 mmol), 1, 4-dioxane (1.0 mL) and water (0.2 mL) were sequentially added to the eggplant-shaped bottle. After the oil pump ventilates (argon) four times, the mixture is put into an oil bath which is heated to 80 ℃ in advance for reaction for 2 hours. After the completion of the reaction, the reaction was allowed to return to room temperature, and water (10 mL) was added thereto, followed by extraction with ethyl acetate (30 mL. Times.3), washing with a saturated aqueous sodium chloride solution (20 mL. Times.2), drying over anhydrous sodium sulfate, filtration and concentration. The crude product was purified by liquid phase preparation (acetonitrile/water (0.05% aqueous ammonia) gradient rinse) to give 1- (1- ((3- (benzofuran-2-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methyl methylamine 10 (3.44 mg, colorless oil, 10.4% yield).
MS m/z(ESI)：462.3[M+H]。
1H NMR(400MHz,MeOD):δ9.32(d,J＝4.0Hz,1H),8.57(d,J＝4.0Hz,1H),8.08(t,J＝4.0Hz,1H),7.86(d,J＝4.0Hz,1H),7.70(d,J＝8.0Hz,1H),7.61(d,J＝8.0Hz,1H),7.50-7.48(m,2H),7.42-7.40(m,1H),7.34-7.32(m,1H),7.22-7.19(m,2H),7.09-7.04(m,1H),6.45(d,J＝4.0Hz,1H),4.11(s,2H),2.71(s,3H).
Example 11
1- (1- ((3- (Benzofuran-3-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methyl methylamine
1- (1- ((3-Chlorophenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methylmethylamine 5c (25 mg,0.064 mmol), benzofuran-2-boronic acid (21 mg,0.128 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (5 mg,0.0064 mmol), potassium carbonate (18 mg,0.128 mmol), dioxane (1 mL) and water (0.2 mL) were sequentially added to a microwave tube. After three times of ventilation (argon), the temperature of the oil bath is raised to 85 ℃, and the oil bath is kept warm and stirred for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated aqueous sodium chloride solution (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by thin plate chromatography (dichloromethane: methanol volume ratio = 10:1) to give 1- (1- ((3- (benzofuran-3-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methyl methylamine 11 (11.73 mg, white solid, 39.8% yield).
MS m/z(ESI)：461.3[M+H]。
1H NMR(400MHz,CD3OD)δ8.05(s,1H),7.99(d,J＝8.0Hz,1H),7.72(s,1H),7.65(s,1H),7.63(d,J＝4.0Hz,1H),7.59(d,J＝8.0Hz,2H),7.51(d,J＝8.0Hz,1H),7.41(t,J＝6.0Hz,1H),7.38–7.29(m,2H),7.12–6.95(m,3H),6.38(s,1H),3.91(s,2H),2.55(s,3H).
Example 12
1- (1- ((5- (Benzofuran-3-yl) pyridin-3-yl) (sulfonyl)) -5- (2-fluorophenyl) -1H-pyrrol-3-yl)
1- (1- ((5-Bromopyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl ] -N-methylmethylamine 4c (30 mg,0.07 mmol), benzofuran-3-boronic acid (23 mg,0.14 mmol), potassium carbonate (30 mg,0.21 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (5.2 mg,0.01 mmol), 1, 4-dioxane (1.0 mL) and water (0.2 mL) were sequentially added to a eggplant-shaped bottle and placed in an oil bath heated to 80℃in advance after four times of oil pump ventilation (argon) to react for 1 hour.
MS m/z(ESI)：462.3[M+H]。
1H NMR(400MHz,MeOD):δ9.18(s,1H),8.61(s,1H),8.23(s,1H),7.99(s,1H),7.88(s,1H),7.68-7.61(m,2H),7.47-7.44(m,1H),7.41-7.37(m,2H),7.19-7.10(m,2H),7.03-6.98(m,1H),6.46(d,J＝4Hz,1H),4.12(s,2H),2.71(s,3H).
Example 13
1- (5- (2-Fluorophenyl) -1- ((3- (furan-2-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methyl methylamine
1- (1- ((3-Chlorophenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methylmethylamine 5c (50 mg,0.132 mmol), 2-furanboronic acid (22 mg,0.198 mmol), potassium carbonate (36 mg,0.264 mmol), tris (dibenzylideneacetone) dipalladium (12 mg,0.0132 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (13 mg,0.0264 mmol), 1, 4-dioxane (1 mL) and water (0.2 mL) were successively added to a microwave tube, and after three times of nitrogen substitution, they were subjected to a microwave reaction at 120℃for 1 hour. The reaction solution was cooled, then water (10 mL) was added, followed by extraction with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated aqueous sodium chloride (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was prepared by liquid phase (acetonitrile/water (0.05% trifluoroacetic acid in water) gradient rinse) to give compound 1- (5- (2-fluorophenyl) -1- ((3- (furan-2-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methyl methylamine 13 (19.5 mg, brown oil, 38.9% yield).
MS m/z(ESI)：380.3[M+H]。
1H NMR(400MHz,MeOD):δ7.94(d,J＝8.0Hz,1H),7.78(s,1H),7.62(d,J＝12.0Hz,2H),7.53-7.43(m,2H),7.38(d,J＝8.0Hz,1H),7.16-7.09(m,2H),7.03(t,J＝10.0Hz,1H),6.82(d,J＝4.0Hz,1H),6.57(d,J＝4.0Hz,1H),6.38(d,J＝4.0Hz,1H),4.09(s,2H),2.69(s,3H).
Example 14
1- (5- (2-Fluorophenyl) -1- ((3- (furan-3-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methyl methylamine
1- (1- ((3-Chlorophenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methylmethylamine 5c (50 mg,0.132 mmol), 3-furanboronic acid (22 mg,0.198 mmol), potassium carbonate (36 mg,0.264 mmol), tris (dibenzylideneacetone) dipalladium (12 mg,0.0132 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (13 mg,0.0264 mmol), 1, 4-dioxane (1 mL) and water (0.2 mL) were successively added to a microwave tube, and after three times of nitrogen substitution, they were subjected to a microwave reaction at 120℃for 1 hour. The reaction solution was cooled, then water (10 mL) was added, followed by extraction with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated aqueous sodium chloride (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was prepared by liquid phase (acetonitrile/water (0.05% trifluoroacetic acid in water) gradient rinse) to give compound 1- (5- (2-fluorophenyl) -1- ((3- (furan-3-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methyl methylamine 14 (25 mg, brown oil, 49.8% yield).
MS m/z(ESI)：380.3[M+H]。
1H NMR(400MHz,MeOD):δ7.87(d,J＝8.0Hz,1H),7.83(m,1H),7.78(d,J＝12.0Hz,1H),7.61(d,J＝8.0Hz,1H),7.58-7.35(m,4H),7.14-7.05(m,3H),6.70(d,J＝4.0Hz,1H),6.38(d,J＝4.0Hz,1H),4.09(s,2H),2.69(s,3H).
Example 15
1- (5- (2-Fluorophenyl) -1- ((5- (thiophen-2-yl) pyridin-3-yl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide
1- (1- ((5-Bromopyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl ] -N-methylmethylamine 4c (30 mg,0.07 mmol), thiophen-2-ylboronic acid (18 mg,0.14 mmol), potassium carbonate (30 mg,0.21 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (5.2 mg,0.01 mmol), 1, 4-dioxane (1.0 mL) and water (0.2 mL) were sequentially added to a eggplant-shaped bottle and placed in an oil bath heated to 80℃in advance after four times of oil pump ventilation (argon) to react for 1 hour, after the reaction was completed, the reaction was returned to room temperature, the catalyst was removed by filtration, and the crude product was purified by liquid phase preparation (acetonitrile/water (containing 0.05% aqueous ammonia) gradient to give 1- (5- (thiophen-2-yl) pyridin-3-yl) -1H-pyrrol-3-yl ] -N-methylformamide (15 mg, colorless oil, yield, 15.5%).
MS m/z(ESI)：428.4[M+H]。
1H NMR(400MHz,MeOD):δ9.09(s,1H),8.53(s,1H),8.23(s,1H),7.84(s,1H),7.79(s,1H),7.63(d,J＝4.8Hz,1H),7.52(d,J＝3.6Hz,1H),7.48-7.46(m,1H),7.21-7.17(m,3H),7.05(t,J＝8.8Hz,1H),6.44(s,1H),4.10(s,2H),2.70(s,3H).
Example 16
1- (5- (2-Fluorophenyl) -1- ((5- (furan-3-yl) pyridin-3-yl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide
1- (1- ((5-Bromopyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl ] -N-methylmethylamine 4c (30 mg,0.07 mmol), thiophen-2-ylboronic acid (18 mg,0.16 mmol), potassium carbonate (30 mg,0.21 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (5.2 mg,0.01 mmol), 1, 4-dioxane (1.0 mL) and water (0.2 mL) were sequentially added to a eggplant-shaped bottle and placed in an oil bath heated to 80℃in advance after four times of oil pump ventilation (argon) to react for 1 hour, after the reaction was completed, the reaction was returned to room temperature, the catalyst was removed by filtration, and the crude product was purified by liquid phase preparation (acetonitrile/water (containing 0.05% aqueous ammonia) gradient to give 1- (5- (2-fluorophenyl) -1- ((5- (furan-3-yl) pyridin-3-yl) -1H-pyrrol-3-yl ] -N-methylformamide (12 mg, colorless oily substance, yield, 41.41%).
MS m/z(ESI)：412.3[M+H]。
1H NMR(400MHz,MeOD):δ8.99(d,J＝1.6Hz,1H),8.52(d,J＝2.0Hz,1H),8.07(s,1H),7.84(d,J＝4.0Hz,1H),7.66(s,1H),7.54(s,1H),7.47-7.43(m,1H),7.18-7.14(m,2H),7.07(t,J＝8.8Hz,1H),6.82(s,1H),6.34(d,J＝1.2Hz,1H),3.58(s,2H),2.33(s,3H).
Test case
Determination of inhibition of H +/K+ ATPase enzyme Activity by Compounds
The following experiments were performed to determine the inhibition of H +/K+ ATPase enzyme activity by the compounds of the present invention.
Experimental materials
(1) Enzyme-labeled instrument: PLATE READER SpectraMax M5 (MD)
(2) Malachite green (SIGMA ALDRICH, 213020-25G)
(3) Ammonium molybdate (SIGMA ALDRICH, 277908-20G)
(4)ATP(Sigma Aldrich,A1852-1VL)
(5)400 (Polysucrose 400) (Sigma-Aldrich, 100G, F2637MFC 00081599)
(6) Protein concentration determination reagent box (Thermofisher, 23227)
Buffer solution preparation
(1) Homogenization buffer: 1.21g of tris, 85.58g of sucrose and 0.29g of ethylenediamine tetraacetic acid were weighed into 900mL of deionized water, the pH of the solution was adjusted to 6.8 with 12M hydrochloric acid, and then deionized water was added to a volume of 1000mL.
(2) 7.5% Ficoll layered solution: homogenization buffer +7.5% (W/W)400 (Polysucrose 400).
(3) 50ML of buffer 1, 2.5mL of 1M Tris-HCl pH 6.5, 0.25mL of 1M magnesium chloride, 0.05mL of 10mM valine mycin and 47.2mL of deionized water were taken and mixed well.
(4) 20ML of buffer 2 19.6mL of the prepared buffer 1 was added with 0.4mL of 1M potassium chloride.
(5) 10X H +/K+ ATPase working solution: the H +/K+ ATPase was titrated and the enzyme diluted 30-fold with buffer 1. In the reaction, 5. Mu.L of the diluted solution was taken into 50. Mu.L of the reaction system.
(6) 10X ATP working solution: 100mM ATP is released to 5mM with buffer 1. mu.L of the diluted solution was taken into 50. Mu.L of the reaction system, i.e., the final concentration of ATP was 500. Mu.M.
(7) MLG color development liquid: 0.12% malachite green, 7.5% ammonium molybdate, 11% Tween-20 at 100:25:2, and adding 15 mu L of the mixture into each hole during detection.
Dilution of the Compounds
(1) The compound was diluted with DMSO to 10 times the desired working fluid concentration.
(2) The above compound was diluted 10-fold with buffer 1 to obtain a 10X compound working solution.
(3) 10% DMSO buffer 1: DMSO was diluted 10-fold with buffer 1.
Experimental procedure
H +/K+ ATPase extraction
(1) The stomach tissue of the rabbits was isolated, rinsed with tap water, and the blood and food residues were removed.
(2) The bottom of the stomach tissue was thoroughly washed with a pre-chilled NaCl solution at 0 ℃ to remove surface mucus.
(3) The peeled mucosa was placed in a sample bag or 50mL centrifuge tube, quickly frozen in a liquid nitrogen tank and stored for 12 hours.
(4) The frozen tissue was removed, minced with surgical scissors, added with pre-chilled homogenization buffer (4 mL/g tissue) at 0deg.C, and homogenized in a tissue homogenizer for 2-10min.
(5) Homogenizing. If larger tissue particles are present, the larger tissue particles may be removed by centrifugation (600 g (relative centrifugal force), 10 min). Then the supernatant was transferred to a clean centrifuge tube, centrifuged for 30min at 20000g (relative centrifugal force), then transferred to a clean centrifuge tube, further centrifuged for 90min at 100000g (relative centrifugal force) and the pellet was collected.
(6) Re-suspending the precipitate with homogenizing buffer solution, blowing off uniformly, adding 7.5% Ficoll layering solution at equal ratio, centrifuging for 90min with 100000g (relative centrifugal force), and collecting precipitate.
(7) The homogenate buffer was resuspended for precipitation, blown off evenly, and the protein concentration was measured using Bradford. The tubes are frozen at-80 ℃ for standby.
H +/K+ ATPase Activity assay
The kit is divided into a solvent control group, a test sample group and a blank group. To the corresponding wells of the test sample group and the vehicle control group, 35. Mu.L of buffer 2 was added, respectively. 35. Mu.L of buffer 1 was added to the wells of the blank. Then, 5. Mu.l of 10 XCompound working solution was added to the wells of the test sample group, and mixed well, and 5. Mu.l of buffer 1 containing 10% DMSO was added to the wells of the vehicle control group and the blank group. To all wells, 5. Mu.L of 10 Xenzyme working solution was added, mixed well and incubated at 37℃for 30min. Mu.l of 10 XATP working solution was added to all wells and incubated at 37℃for 20min. Finally, 15. Mu.l of MLG chromogenic solution was added to all wells and incubated at room temperature for 5-30min with mixing. The OD 620nm reading was detected by an enzyme-labeled instrument, once every 5 min.
Data analysis
The inhibition rate was calculated using the following formula: inhibition ratio (IC 50) = [ OD (vehicle control) -OD (test sample) ]/[ OD (vehicle control) - (OD (blank) ]x100%
TABLE 2
Conclusion: the compounds in the examples have significant inhibitory activity against H +/K+ ATPase.

Claims (10)

1. A compound of formula (I) or a tautomer, enantiomer, diastereomer, mixture, or pharmaceutically acceptable salt thereof,
X 1 and X 2 are independently selected from C or N; x 1 and X 2 may be the same or different;
R 1 is selected from one of H, F, cl and CH 3;
Y 1 is selected from one of O and S;
y 2 is selected from one of C and N.
2. A compound of formula (II) or a tautomer, enantiomer, diastereomer, mixture, or pharmaceutically acceptable salt thereof,
X 1 and X 2 are independently selected from C or N; x 1 and X 2 may be the same or different;
R 1 is selected from one of H, F, cl and CH 3;
Y 1 is selected from one of C and N;
Y 2 and Y 3 are selected from one of C, O and S.
3. A compound of formula (III) or a tautomer, enantiomer, diastereomer, mixture, or pharmaceutically acceptable salt thereof,
X 1 and X 2 are independently selected from C or N; x 1 and X 2 may be the same or different;
R 1 is selected from one of H, F, cl and CH 3;
y 4 is selected from one of O and S.
4. A compound of formula (IV) or a tautomer, enantiomer, diastereomer, mixture, or pharmaceutically acceptable salt thereof,
X 1 and X 2 are independently selected from C or N; x 1 and X 2 may be the same or different;
R 1 is selected from one of H, F, cl and CH 3;
Y 5 is selected from one of O and S.
5. A compound according to any one of claims 1 to 4, or a tautomer, enantiomer, diastereomer, mixture, and pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
1- (5- (2-fluoropyridin-3-yl) -1- ((3- (oxazol-2-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl;
1- (5- (2-fluoropyridin-3-yl) -1- ((3- (furan-2-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide;
1- (5- (2-fluoropyridin-3-yl) -1- ((5- (furan-2-yl) pyridine-3-methyl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide;
1- (5- (2-fluorophenyl) -1- ((5- (thiophen-3-yl) pyridin-3-yl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide;
1- (1- ((3- (benzofuran-2-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methyl methylamine;
1- (1- ((3- (benzo [ b ] thiophen-2-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methylformamide;
1- (1- ((3- (benzo [ b ] thiophen-3-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methylformamide;
1- (1- ((5- (benzo [ b ] thiophen-2-yl) pyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl ] -N-methylformamide;
1- (1- ((5- (benzo [ b ] thiophen-3-yl) pyridin-3-yl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl ] -N-methylformamide;
1- (1- ((3- (benzofuran-2-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methyl methylamine;
1- (1- ((3- (benzofuran-3-yl) phenyl) sulfonyl) -5- (2-fluorophenyl) -1H-pyrrol-3-yl) -N-methyl methylamine;
1- (1- ((5- (benzofuran-3-yl) pyridin-3-yl) (sulfonyl)) -5- (2-fluorophenyl) -1H-pyrrol-3-yl;
1- (5- (2-fluorophenyl) -1- ((3- (furan-2-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methyl methylamine;
1- (5- (2-fluorophenyl) -1- ((3- (furan-3-yl) phenyl) sulfonyl) -1H-pyrrol-3-yl ] -N-methyl methylamine;
1- (5- (2-fluorophenyl) -1- ((5- (thiophen-2-yl) pyridin-3-yl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide;
1- (5- (2-fluorophenyl) -1- ((5- (furan-3-yl) pyridin-3-yl) sulfonyl) -1H-pyrrol-3-yl ] -N-methylformamide.
6. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 4, or a tautomer, enantiomer, diastereomer, mixture, and pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
7. Use of a compound according to any one of claims 1 to 4, or a tautomer, enantiomer, diastereomer, mixture, and pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, for the preparation of a gastric acid secretion inhibitor.
8. Use of a compound according to any one of claims 1 to 4, or a tautomer, enantiomer, diastereomer, mixture, and pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, for the preparation of an H +/K+ -atpase inhibitor.
9. Use of a compound of any one of claims 1 to 4, or a tautomer, enantiomer, diastereomer, mixture, and pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 6, in the preparation of a potassium ion competitive acid blocker.
10. Use of a compound according to any one of claims 1 to 4, or a tautomer, enantiomer, diastereomer, mixture, and pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, for the manufacture of a medicament for the prevention and/or treatment of peptic ulcer, zepine-arg syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, barrett's esophagitis, functional dyspepsia, helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, ulcers caused by non-steroidal anti-inflammatory drugs, or gastric hyperacidity or ulcers caused by postoperative stress; preferably, the symptomatic gastroesophageal reflux disease comprises a non-erosive reflux disease or a gastroesophageal reflux disease without esophagitis; or a tautomer, enantiomer, diastereomer, mixture, pharmaceutically acceptable salt thereof, or pharmaceutical composition according to claim 6, for use in the manufacture of a medicament for inhibiting upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis, or invasive stress; preferably, the peptic ulcer comprises a gastric ulcer, a duodenal ulcer or a stoma ulcer.
CN202211715354.5A 2022-12-29 Aromatic heterocycle substituted arylsulfonyl pyrrole derivative and application thereof Pending CN118271306A (en)

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