Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to a novel class of benzofuran derivatives, a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as a gastric acid secretion inhibitor and a potassium ion competitive acid blocker (P- Medium use of CABs).
• a novel class of benzofuran derivatives a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as a gastric acid secretion inhibitor and a potassium ion competitive acid blocker (P- Medium use of CABs).
• Peptic ulcer is a common disease, and the incidence rate varies from time to time and from region to region. The usual incidence rate is about 10 to 20% of the total population.
• the usual incidence rate is about 10 to 20% of the total population.
• Proton Pump also known as gastric acid pump
• H + /K + -adenosine triphosphatase H + /K + -ATPase
• H + and K + exchange are performed by ATP degradation, and the ⁇ + is specifically pumped into the gastric cavity to form a strong acid state in the stomach.
• a proton pump is a heterodimer consisting of two subunits of alpha and beta across the membrane.
• the a subunit has 10 helical transmembrane segments ( ⁇ 1 ⁇ 10), which are mainly responsible for the catalytic activity of the enzyme and provide a ruthenium binding site, and also a cation binding site, also known as a catalytic subunit; functional expression of the enzyme
• a single transmembrane beta subunit is required to participate.
• PPIs are weak base and lipophilic compounds that can rapidly pass through the cell membrane of the stomach wall, accumulate in the strong acid secretion tubules, and convert to sulfenamide compounds under H + catalysis, and H + /K + -ATPase transmembrane region
• the thiol group on the cysteine residue is covalently bound to form a disulfide bond, which inactivates the proton pump, thereby inhibiting central or peripherally mediated gastric acid secretion.
• the first generation of PPIs significantly inhibited gastric acid secretion stimulated by basal, nocturnal gastric acid, pentagastrin, and test meals.
• the effect of time of administration on the efficacy of the drug slow acid onset at night, and instability under acidic conditions (often formulated into enteric preparations, this In a case where it takes several hours to show the effect), dependence on CYP450 enzyme (a large difference in blood concentration of PPIs between different patients, which may lead to a huge difference in acid suppression between different patients), etc. Effects and clinical applications.
• the new generation of PPIs has obvious advantages in the treatment of Gastroesophageal Reflux Disease (GERD) and other acid-related diseases.
• GSD Gastroesophageal Reflux Disease
• P-CABs potassium-competitive acid blockers
• H + /K + -ATPase activity by competitively binding H + , and its mechanism of action is significantly different.
• the above PPIs can therefore be referred to as acid pump blockers.
• P-CABs are lipophilic, weakly basic, have a high dissociation constant and are stable at low pH.
• P-CABs are immediately ionized, ionized form Inhibition of H + /K + -ATPase by ionic binding, preventing H + transport and acid secretion into the gastric cavity, without the activation of microcapsules and microtubules and acid concentrated in the cells of the stomach wall, can rapidly increase the pH value in the stomach , the enzyme activity is restored after dissociation. Humans and animals can absorb quickly after oral administration and reach the peak plasma concentration. Clinical and animal studies have also shown that P-CABs are more effective than PPIs or H2 blockers and have a higher pH-raising effect. Some of the P-CABs have entered the sputum and phase III clinical studies. P-CABs have the following potential advantages: rapid onset, maximum effect in 1 hour; blood concentration is linearly related to oral dose, suggesting that the drug can easily achieve the best acid suppression state.
• P-CABs potassium competing acid blockers
• the object of the present invention is to provide a compound represented by the formula (I), and tautomers, mesomers, racemates, enantiomers, diastereomers thereof, Mixture forms and pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs. as follows:
• R 1 is selected from an aryl or heteroaryl group, wherein the aryl or heteroaryl group is further further selected from one or more selected from the group consisting of halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, OR 6 , heterocyclyl, aryl, heteroaryl, -NR 7 R 8 , -C(0)NR 7 R 8 -S(0) m R 6 -C(0)R 6 -OC(0)R Substituted by a substituent of 6 or -C(0)OR 6 ;
• R 2 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further one Or a plurality selected from the group consisting of halogen, cyano, hydroxy, amino, alkyl, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 7 R 8 Substituted by a substituent of -C(0)NR 7 R 8 -S(0) m R 6 -C(0)R 6 -OC(0)R 6 or -C(0)OR 6 ;
• R 3 is selected from a hydrogen atom or an alkyl group
• R 4 or R 5 are each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein said alkane Base, alkoxy group, cycloalkyl group, heterocyclic group,
• the aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, nitro, cyano, hydroxy, amino, alkyl, alkyl, hydroxyalkyl, alkoxy, cycloalkyl ,heterocyclyl, aryl,heteroaryl, -NR 7 R 8 , -C(0)NR 7 R 8 -S(0) m R 6 -C(0)R 6 -OC(0)R 6 or Substituted by a substituent of -C(0)OR 6 ;
• R 6 is selected from a hydrogen atom, an alkyl group, a hydroxyl group, a halogen, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic ring
• the radical, aryl or heteroaryl are each, independently, optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, amino, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkane. Substituted by a substituent of a heterocyclic group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;
• R 7 or R 8 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or hetero group
• the aryl groups are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, amino, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, Substituted with a substituent of an aryl, heteroaryl, carboxy or carboxylate group;
• n 0, 1, or 2.
• a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 2 is an alkyl group, preferably an alkyl group.
• a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer A form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom.
• a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer A form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 is a hydrogen atom.
• a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 1 is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is optionally further further selected from one or more selected from halogen or - Substituted by a substituent of OR 6 , R 6 is an alkyl group, and the alkyl group is optionally further substituted with one or more substituents selected from a cycloalkyl group.
• a compound of formula (I) or tautomerized thereof a form, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is an aryl group, wherein the aryl group Optionally further substituted by one or more substituents selected from halogen or -OR 6 , R 6 is alkyl, preferably alkyl, said alkyl optionally further further selected from one or more selected from cycloalkyl Substituted by a substituent, the cycloalkyl group is preferably a C 3 -C 6 cycloalkyl group, more preferably a cyclopropyl group; the aryl group means a 6 to 14 membered all carbon monocyclic or thick having a conjugated ⁇ -electron system
• the polycyclic group is preferably a 6 to 10 membered aryl group, more preferably a
• a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 1 is a heteroaryl group, said heteroaryl group means a heteroaromatic system comprising 1 to 4 hetero atoms, 5 to 14 ring atoms Wherein the hetero atom comprises oxygen, sulfur and nitrogen; preferably a heteroaromatic ring containing from 5 to 10 ring atoms, wherein from 1 to 4 heteroatoms selected from oxygen, sulfur or nitrogen; more preferably from 5 to 6 A ring atom, wherein the heteroaromatic ring contains from 1 to 4 heteroatoms selected from oxygen, sulfur or nitrogen, most preferably a pyridyl group.
• the present invention also relates to a compound of the formula ( ⁇ - ⁇ ) or a tautomer, enantiomer, diastereomer, mesogen, racemate, formula thereof, Or a pharmaceutically acceptable salt thereof:
• R 1 is selected from an aryl or heteroaryl group, wherein the aryl or heteroaryl group is further further selected from one or more selected from the group consisting of halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, OR 6 , heterocyclyl, aryl, heteroaryl, -NR 7 R 8 , -C(0)NR 7 R 8 -S(0) m R 6 -C(0)R 6 -OC(0)R Substituted by a substituent of 6 or -C(0)OR 6 ;
• R 2 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further one Or a plurality selected from the group consisting of halogen, cyano, hydroxy, amino, alkyl, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 7 R 8 Substituted by a substituent of -C(0)NR 7 R 8 -S(0) m R 6 -C(0)R 6 -OC(0)R 6 or -C(0)OR 6 ;
• R 4 or R 5 are each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein said alkane
• the radical, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, nitro, cyano, hydroxy, amino, alkyl, Alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 7 R 8 , -C(0) NR 7 R 8 , -S(0) m R 6 Substituted with a substituent of -C(0)R 6 -OC(0)R 6 or -C(0)OR 6 ;
• R 6 is selected from a hydrogen atom, an alkyl group, a hydroxyl group, a halogen, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic ring
• the radical, aryl or heteroaryl are each, independently, optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, amino, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkane. Substituted by a substituent of a heterocyclic group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;
• R 7 or R 8 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or hetero group
• the aryl groups are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, amino, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, Substituted by a substituent of an aryl, heteroaryl, carboxy or carboxylate group;
• PG is an amino protecting group, preferably a tert-butoxycarbonyl group
• n 0, 1, or 2.
• a compound of the formula (IA) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer A form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein PG is t-butoxycarbonyl.
• a compound of the formula (IA) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 1 is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is optionally further further selected from one or more selected from halogen or - Substituted by a substituent of OR 6 , R 6 is an alkyl group, preferably a C alkyl group, and the alkyl group is optionally further substituted with one or more substituents selected from a cycloalkyl group, preferably a cycloalkyl group C 3 to C 6 cycloalkyl, more preferably cyclopropyl.
• aryl group means a 6 to 14 membered all-carbon monocyclic or fused polycyclic group having a conjugated ⁇ -electron system
• R 1 is preferably a 6- to 10-membered aryl group, more preferably a phenyl group or a benzo group.
• Tetrahydrofuranyl most preferably phenyl; said heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen; R 1 is preferably a heteroaromatic ring comprising 5 to 10 ring atoms, wherein 1 to 4 hetero atoms selected from oxygen, sulfur or nitrogen; more preferably 5 to 6 ring atoms, wherein 1 to 4 are selected from oxygen
• the heteroaromatic ring of a hetero atom of sulfur or nitrogen is most preferably a pyridyl group.
• a compound of the formula ( ⁇ - ⁇ ) or a tautomer, a mesogen, a racemate, an enantiomer, a non-pair a conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 1 is selected from aryl, wherein the aryl group is optionally further substituted with one or more substituents selected from halogen or -OR 6 Substituting, R 6 is an alkyl group, and the alkyl group is optionally further substituted with one or more substituents selected from a cycloalkyl group.
• a compound of the formula (IA) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 1 is selected from heteroaryl.
• Another aspect of the invention relates to the preparation of a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising
• the compound of the formula (IA) is deprotected in a solvent under acidic conditions to give a compound of the formula (I);
• PG is an amino protecting group
• 1 ⁇ 1 5 is as defined in the formula (I), wherein R 3 is preferably a hydrogen atom ⁇
• R 3 is preferably a hydrogen atom ⁇
• Preparation of a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a mixture thereof or a mixture thereof A method of using a salt wherein PG is a tert-butoxycarbonyl group.
• the present invention also relates to a compound of the formula (IB) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof:
• R 1 is selected from an aryl or heteroaryl group, wherein the aryl or heteroaryl group is further further selected from one or more selected from the group consisting of halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, OR 6 , heterocyclyl, aryl, heteroaryl, -NR 7 R 8 , -C(0)NR 7 R 8 -S(0) m R 6 -C(0)R 6 -OC(0)R Substituted by a substituent of 6 or -C(0)OR 6 ;
• R 4 or R 5 are each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein said alkane
• the radical, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, nitro, cyano, hydroxy, amino, alkyl, Alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 7 R 8 , -C(0)NR 7 R 8 -S(0) m R 6 - Substituted by a substituent of C(0)R 6 -OC(0)R 6 or -C(0)OR 6 ;
• R 6 is selected from a hydrogen atom, an alkyl group, a hydroxyl group, a halogen, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic ring
• the radical, aryl or heteroaryl are each, independently, optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, amino, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkane. Substituted by a substituent of a heterocyclic group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;
• R 7 or R 8 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or hetero group
• the aryl groups are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, amino, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, Substituted with a substituent of an aryl, heteroaryl, carboxy or carboxylate group;
• n 0, 1, or 2.
• a compound of the formula (IB) or a mutual mutation thereof a form, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom.
• a compound of the formula (IB) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 1 is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is optionally further further selected from one or more selected from halogen or - Substituted by a substituent of OR 6 , R 6 is an alkyl group, preferably a C alkyl group, and the alkyl group is optionally further substituted with one or more substituents selected from a cycloalkyl group, preferably a cycloalkyl group C 3 to C 6 cycloalkyl, more preferably cyclopropyl.
• aryl group means a 6 to 14 membered all-carbon monocyclic or fused polycyclic group having a conjugated ⁇ -electron system
• R 1 is preferably a 6- to 10-membered aryl group, more preferably a phenyl group or a benzo group.
• Tetrahydrofuranyl most preferably phenyl; said heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen; R 1 is preferably a heteroaromatic ring comprising 5 to 10 ring atoms, wherein 1 to 4 hetero atoms selected from oxygen, sulfur or nitrogen; more preferably 5 to 6 ring atoms, wherein 1 to 4 are selected from oxygen
• the heteroaromatic ring of a hetero atom of sulfur or nitrogen is most preferably a pyridyl group.
• a compound of the formula ( ⁇ - ⁇ ) or a tautomer, a mesogen, a racemate, an enantiomer, a non-pair a conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 1 is selected from aryl, wherein the aryl group is optionally further substituted with one or more substituents selected from halogen or -OR 6 Substituting, R 6 is an alkyl group, and the alkyl group is optionally further substituted with one or more substituents selected from a cycloalkyl group.
• Another aspect of the invention relates to the preparation of a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, Or a method of the mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising the steps of:
• ⁇ 11 5 is as defined in the compound of formula (I).
• a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the formula (I) or a tautomer thereof, a mesogen, a foreign body A rot, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
• Another aspect of the invention relates to a compound of the formula (I) or a tautomer, racemate, enantiomer, diastereomer thereof, or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the preparation of a gastric acid secretion inhibitor.
• Another aspect of the invention relates to a method of inhibiting gastric acid secretion comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a tautomer, racemate, pair thereof a conjugate, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
• Another aspect of the invention relates to a compound of the formula (I) or a tautomer, racemate, enantiomer, diastereomer thereof, or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, as a gastric acid secretion inhibitor.
• Another aspect of the invention relates to a compound of the formula (I) or a tautomer, racemate, enantiomer, diastereomer thereof, or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the preparation of an H + /K + -adenosine triphosphatase (H + /K + -ATPase) inhibitor.
• Another aspect of the invention relates to a method of inhibiting H + /K + -adenosine triphosphatase (H + /K + -ATPase), the method comprising administering to a patient in need of treatment a therapeutically effective amount of the formula (I) a compound, or a tautomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, or a pharmaceutical composition thereof .
• H + /K + -adenosine triphosphatase H + /K + -ATPase
• Another aspect of the invention relates to a compound of the formula (I) or a tautomer, racemate, enantiomer, diastereomer thereof, or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, which is an H + /K + - adenosine triphosphatase (H + /K + -ATPase) inhibitor.
• Another aspect of the invention relates to a compound of the formula (I) or a tautomer, racemate, enantiomer, diastereomer thereof, or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the preparation of potassium ion competitive acid blockers (P-CABs).
• Another aspect of the invention relates to a method for competing acid to block potassium ions, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a foreign body A rot, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
• Another aspect of the invention relates to a compound of the formula (I) or a tautomer, racemate, enantiomer, diastereomer thereof, or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, as a potassium ion competitive acid blocker (P-CABs).
• P-CABs potassium ion competitive acid blocker
• the present invention also relates to a compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable compound thereof A salt, or a pharmaceutical composition comprising the same, for the treatment or prevention of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease ( Symptomatic GERD), Barrett's esophagitis, functional dyspepsia, Helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, non-steroidal anti-inflammatory drugs (NSAIDs) caused by ulcers or post-operative stress Use in a drug having hyperacidity or ulceration; or in the preparation of a medicament for inhibiting upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress.
• Peptic ulcers include, but are not limited to, gastric ulcers, duodenal ulcers or anastomotic ulcers; symptomatic gastroesophageal reflux disease (symptomatic GERD) includes, but is not limited to, non-erosive reflux disease or no esophagitis Gastroesophageal reflux disease.
• symptomatic GERD symptomatic gastroesophageal reflux disease
• Another aspect of the invention relates to the treatment or prevention of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), Barrett's esophagitis, functional dyspepsia, Helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, non-steroidal anti-inflammatory drugs (NSAIDs) caused by ulcers or post-operative stress-induced gastric acid a method of multiple or ulceration; or a method of inhibiting upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress, the method comprising administering a therapeutically effective amount to a patient in need of treatment a compound represented by (I) or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, a pharmaceutically acceptable salt thereof, or
• Peptic ulcers include, but are not limited to, gastric ulcer, duodenal ulcer or anastomotic ulcer; symptomatic gastroesophageal reflux disease (symptomatic GERD) These include, but are not limited to, non-erosive reflux disease or gastroesophageal reflux disease without esophagitis.
• symptomatic GERD symptomatic gastroesophageal reflux disease
• Another aspect of the invention relates to a compound of the formula (I) or a tautomer, racemate, enantiomer, diastereomer thereof, or a mixture thereof, or A medicinal salt, or a pharmaceutical composition comprising the same, for treating or preventing peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal Reflux disease (symptomatic GERD), Barrett esophagitis, functional dyspepsia, Helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, non-steroidal anti-inflammatory drugs (NSAIDs) caused by ulcers or after surgery A drug that causes hyperacidity or ulceration caused by stress; or a drug that inhibits upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis, or invasive stress.
• NSAIDs non-steroidal anti-inflammatory drugs
• Peptic ulcers include, but are not limited to, gastric ulcers, duodenal ulcers or anastomotic ulcers; symptomatic gastroesophageal reflux disease (symptomatic GERD) includes, but is not limited to, non-erosive reflux disease or no esophagitis Gastroesophageal reflux disease.
• symptomatic GERD symptomatic gastroesophageal reflux disease
• Alkyl means a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms is preferred, and an alkyl group having 1 to 6 carbon atoms is more preferred.
• Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,
• lower alkyl groups having 1 to 6 carbon atoms More preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
• the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Block, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -OR-NR 7 R 8 , -C(0)NR 7 R 8 -S(0) m R 6 -C(0)R 6 , -OC(0)R 6 , -NR 7 C(0)R 8 , -NR 7 C(0)OR 8 or -C(0)OR 6 .
• Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises from 3 to 10 The carbon atom, most preferably the cycloalkyl ring contains from 3 to 6 carbon atoms.
• Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Alkenyl, cyclooctyl and the like.
• Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
• Spirocycloalkyl means a polycyclic group of 5 to 20 members which shares a carbon atom (referred to as a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings are fully conjugated. ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
• the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the ring and the ring.
• fused cycloalkyl means 5 to 20 members, each ring of the system sharing an adjacent carbon atom of an all-carbon polycyclic group with other rings in the system, wherein one or more rings may contain one or more Two double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
• the bicyclic ring, the tricyclic ring, the tetracyclic ring or the polycyclic fused ring alkyl group may be classified according to the number of the constituent rings, and preferably a bicyclic ring or a tricyclic ring, more preferably.
• Non-limiting examples of fused cycloalkyl groups include
• Bridge cycloalkyl means 5 to 20 members, any two rings sharing two carbon-free all-carbon polycyclic groups, which may contain one or more double bonds, but none of the rings have a total The ⁇ electronic system of the yoke. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
• bridged cycloalkyl groups include
• the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydrogen Naphthyl, benzocycloheptyl and the like.
• the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio Base, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, oxo, -OR 6 , -NR 7 R 8 , -C(0)NR 7 R 8 , -S(0) m R 6 , -C(0)R 6 , -OC(0 R 6 , -NR 7 C(0)R 8 , -NR 7 C(0)OR 8 or -C(0)OR 6 .
• Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(0) m ( Wherein m is a hetero atom of the integer 0 to 2), but does not include a ring moiety of -0-0-, -0-S- or -SS-, and the remaining ring atoms are carbon.
• It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the heterocycloalkyl ring contains from 3 to 10 ring atoms, more preferably the heterocycloalkyl ring contains from 5 to 6 ring atoms.
• monocyclic heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like.
• Polycyclic heterocycloalkyl groups include spiro, fused, and bridged heterocyclic groups.
• spiroheterocyclyl means a polycyclic heterocyclic group of 5 to 20 members in which one atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(0) m A hetero atom (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
• the spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of common spiro atoms between the rings, preferably a monospirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospirocycloalkyl.
• “Fused heterocyclic group” means 5 to 20 members, each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more a bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
• fused heterocyclic groups include
• “Bridge heterocyclyl” refers to a polycyclic heterocyclic group of 5 to 14 members in which two rings share two atoms which are not directly bonded, and these may contain one or more double bonds, but none of the rings have a complete conjugation
• a ⁇ -electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. 7 to 10 yuan.
• a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
• the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group,
• the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio Base, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, oxo, -OR 6 , -NR 7 R 8 , -C(0)NR 7 R 8 -S(0) m R 6 -C(0)R 6 , -OC(0)R 6 , -NR 7 C(0)R 8 , -NR 7 C(0)OR 8 or -C(0)OR 6 .
• Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as phenyl. And naphthyl.
• the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring,
• the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, alkane.
• Heteroaryl means a heteroaromatic system containing from 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 5 to 10 yuan.
• the heteroaryl group is preferably a 5- or 6-membered compound such as a furyl group, a thienyl group, a pyridyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group, a tetrazolyl group or the like.
• the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the parent structure is attached
• the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio Base, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, -OR 6 , -NR 7 R 8 , -C(0)NR 7 R 8 , -S(0) m R 6 , -C(0)R 6 , -OC(0)R 6 -NR 7 C(0)R 8 , -NR 7 C(0)OR 8 or -C(0)OR 6 .
• Alkoxy means -o-(indenyl) and -o-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
• the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of an alkyl group, an alkenyl group, a block group, an alkoxy group, and an alkane group.
• Haloalkyl means an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
• Haldroxy means an -OH group.
• Hydroalkyl means an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.
• Halogen means fluoro, chloro, bromo or iodo.
• Amino means -NH 2 .
• Neitro means -N0 2 .
• Benzyl refers to -CH 2 - phenyl.
• Carboxy means -C(0)OH.
• the "carboxylate group” means -C(0)0(alkyl) or (cycloalkyl), wherein the alkyl group and the cycloalkyl group are as defined above.
• amino protecting group is used to keep the amino group unchanged when the other parts of the molecule are reacted.
• the group to be removed protects the amino group.
• Non-limiting examples include formyl, alkylcarbonyl, alkoxycarbonyl, benzoyl, aralkylcarbonyl, aralkoxycarbonyl, trityl, phthaloyl, N,N-dimethyl Aminoaminomethylene, substituted silyl, and the like. These groups may be optionally substituted with from 1 to 3 substituents selected from halogen, alkoxy or nitro.
• the amino protecting group is preferably a tert-butoxycarbonyl group.
• heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, including the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
• Substituted means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms are independently substituted with each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
• “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
• the purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity.
• the preparation method of the medicinal salt comprises the following steps:
• the azole compound (a) and the benzofuransulfonyl chloride compound (b) are reacted in a solvent under basic conditions to obtain a benzofuransulfonyl-substituted pyrrole compound (C), a benzofuransulfonyl-substituted pyrrole compound ( C) and
• R 1 -substituted boronic acid ester or boric acid is subjected to catalytic catalysis in a solvent under basic conditions to obtain R benzofuransulfonyl-substituted pyrrole compound (IA), R benzofuransulfonyl-substituted pyrrole
• the compound (IA) is deprotected in a solvent under acidic conditions to give a compound of the formula (I).
• X is a halogen
• R 5 is as defined in the compound of formula (I) wherein R 3 is preferably a hydrogen atom
• PG is an amino protecting group, preferably a tert-butoxycarbonyl group.
• Agents that provide acidic conditions include, but are not limited to, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid.
• the alkaline condition reagent includes an organic base and an inorganic base
• the organic base includes, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, potassium t-butoxide
• Inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or cesium carbonate.
• Catalysts include, but are not limited to, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tetrakistriphenylphosphine palladium, palladium dichloride, palladium acetate or tris(dibenzylidene) Acetone) dipalladium.
• Solvents used include, but are not limited to, tetrahydrofuran, dichloromethane, 1,4-dioxane, water, methanol, ethanol, dimethyl sulfoxide or N,N-dimethylformamide.
• Option II tetrahydrofuran, dichloromethane, 1,4-dioxane, water, methanol, ethanol, dimethyl sulfoxide or N,N-dimethylformamide.
• the pyrrole formaldehyde compound (d) is reacted with a benzofuransulfonyl chloride compound (b) in a solvent under basic conditions to obtain a benzofuransulfonyl-substituted pyrrole formaldehyde compound (IB), a benzofuransulfonyl-substituted pyrrole formaldehyde.
• a reducing agent such as sodium borohydride
• the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, potassium t-butoxide, and the like.
• organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, potassium t-butoxide, and the like.
• the inorganic bases mentioned include, but are not limited to, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate.
• Reducing agents include, but are not limited to, sodium borohydride, sodium triacetoxyborohydride, sodium nitrile borohydride or lithium aluminum hydride.
• Solvents used include, but are not limited to, tetrahydrofuran, dichloromethane, 1,4-dioxane, water, methanol, ethanol, dimethyl sulfoxide or N,N-dimethylformamide. Detailed ways
• the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
• NMR nuclear magnetic resonance
• MS mass spectrometry
• the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide ( ) ⁇ - ⁇ 3 ⁇ 4), deuterated chloroform (CDC1 3 ) deuterated methanol (CD 3 OD), and the internal standard was tetramethyl.
• silane CTMS chemical shifts are given 10- 6 Cppm) as a unit.
• the MS was measured using a FINMGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
• the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
• the average inhibition rate of the kinase and the IC 5Q value were determined using a NovoStar plate reader (BMG, Germany).
• the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
• the silica gel plate used for thin layer chromatography (TLC) has a specification of 0.15 mm ⁇ 0.2 mm, and the thin layer chromatography separation and purification product adopts the specification of 0.4 mm. ⁇ 0.5 mm silica gel plate.
• the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc. Companies such as Dare Chemicals.
• An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
• the solution in the reaction means an aqueous solution unless otherwise specified.
• the temperature of the reaction was room temperature unless otherwise specified.
• Room temperature is the optimum reaction temperature, and the temperature range is from 20 ° C to 30 ° C.
• the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
• TLC thin layer chromatography
• the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
• the system of the eluent for column chromatography and the system for developing the thin layer chromatography of the purified compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane and acetone System, D: hexamethylene, E: ethyl acetate, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent.
• A dichloromethane and methanol system
• B n-hexane and ethyl acetate system
• C n-hexane and acetone System
• D hexamethylene
• E ethyl acetate
• the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine and an acidic
• reaction mixture was quenched by the addition of 2 mL of a saturated aqueous solution of ammonium chloride, and 50 mL of ethyl acetate was added, and then washed with saturated sodium chloride solution (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated.
• the resulting residue was purified by chromatography eluting to afford titled product ((1-(benzofuran-2-ylsulfonyl)-5-(3-methoxyphenyl)-1H-pyrrole-3- Tert-butyl)methyl (meth)carbamate 4c (37 mg, pale yellow solid), yield: 44.0%.
• 1-(benzofuran-2-yl) Sulfonyl)-5-(pyridin-3-yl)-1H-pyrrol-3-yl)methylXmethyl)carbamic acid tert-butyl ester 9b 43 mg, 0.09 mmol
• V/V 4:1
• the compound is formulated in 100% DMSO to a suitable concentration: 10000, 1000, 100, 10, 1, O.lnM;
• buffer 1 50mmol / L HEPEs-Tris, 5mmol / L magnesium chloride, pH 6.5;
• ATP Dilute ATP to 2 mM with buffer 1;
• malachite green solution 0.12% malachite green dissolved in 2.5 moles of sulfuric acid, 7.5% ammonium molybdate and 11% Tween 20 when used in a ratio of 100:25:2;
• pig gastric mucosa microsomes (rich in H + /K + -ATPase), the extraction method is sucrose gradient centrifugation: the pig stomach is washed with tap water, immersed in 3mol / L concentrated brine for 1-2 minutes, and then wiped dry. The gastric mucosa was separated, mashed, and then suspended in 0.25 mol/L sucrose, 1 mmol/LEDTA, 10 mmol/L tris-HCl solution; homogenized, (100 g: 330 ml, fully uniform and then added 300 ml) The slurry is centrifuged at 20000G for 30 minutes.
• the IC 5Q value of the compound can be calculated from the inhibition rates at different concentrations.
• the compounds of the present invention have significant inhibitory activity against H + /K + -ATPase.

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