WO2014019442A1

WO2014019442A1 - Benzofuran derivatives, preparation method and medical use thereof

Info

Publication number: WO2014019442A1
Application number: PCT/CN2013/079031
Authority: WO
Inventors: 兰炯; 董庆; 吴晓; 孙飘扬
Original assignee: 上海恒瑞医药有限公司; 江苏恒瑞医药股份有限公司
Priority date: 2012-08-03
Filing date: 2013-07-09
Publication date: 2014-02-06
Also published as: CN104039776B; TW201406753A; CN104039776A

Abstract

The present invention relates to benzofuran derivatives, the preparation method and medical use thereof. Specifically, the present invention relates to novel benzofuran derivatives represented by formula (I), the preparation method thereof, the pharmaceutical composition containing said derivative, the use of said derivative as a therapeutic agent especially as gastric acid secretion inhibitors and potassium-competitive acid blockers (P-CABs), wherein the respective substituent of formula (I) is defined as those in the specification.

Description

Benzofuran derivative, preparation method thereof and application thereof in medicine

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). Background technique

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. With the development of society, changes in people's lifestyles, the incidence of peptic ulcers caused by smoking, drinking, emotional stress and drug stimulation are gradually increasing, which is seriously affecting people's work and life. It is still unclear about the exact pathogenesis of the medical community, but inhibition of gastric acid secretion has become the accepted method of choice for the treatment of such diseases.

Since the first Proton Pump Inhibitors (PPIs) were launched in 1988, several PPIs have been on the market worldwide. After years of clinical application, PPIs have become the drug of choice for the treatment of gastric acid-related diseases. Proton Pump, also known as gastric acid pump, is essentially H ⁺ /K ⁺ -adenosine triphosphatase (H ⁺ /K ⁺ -ATPase), which is the ultimate common pathway for gastric secretion of H ⁺ , which is present in gastric parietal cells. On the cell membrane of the secretory tubule, H ⁺ and K ⁺ exchange are performed by ATP degradation, and the Η ^{+ 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 (Μ1~Μ10), 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. However, due to limitations in pharmacokinetics and pharmacodynamics, including bioavailability, 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. Compared with the first generation of PPIs, the new generation of PPIs has obvious advantages in the treatment of Gastroesophageal Reflux Disease (GERD) and other acid-related diseases.

As a new class of antacids, potassium-competitive acid blockers, P-CABs, inhibit 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. In an acidic environment, 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.

A series of patent applications for potassium competing acid blockers (P-CABs) are disclosed, including WO200504196K WO2006134460 WO2009041447 or WO2010021149.

Although a series of potassium competitive acid blocker (P-CABs) inhibitors have been disclosed, there is still a need to develop new compounds with better pharmacodynamics, and the design of the present invention has a general formula (I) The compound of the structure shown, and the compound having such a structure was found to exhibit excellent effects and effects. Summary of the invention

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:

Its towel:

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;

m is 0, 1, or 2. In a particular embodiment of the invention, 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. In another embodiment of the present invention, 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. In another embodiment of the present invention, a compound represented by the formula (1)) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom. In another embodiment of the present invention, 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. In another embodiment of the present invention, 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. In another embodiment of the invention, 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 π-electron system The polycyclic group is preferably a 6 to 10 membered aryl group, more preferably a phenyl group or a benzotetrahydrofuranyl group, and most preferably a phenyl group. In another embodiment of the present invention, 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.

Form, or a pharmaceutically acceptable salt thereof. The present invention also relates to a compound of the formula (Ι-Α) or a tautomer, enantiomer, diastereomer, mesogen, racemate, formula thereof, Or a pharmaceutically acceptable salt thereof:

( Ι-Α It can be used as an intermediate for synthesizing a compound represented by the general formula (I), wherein:

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 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;

m is 0, 1, or 2. In another embodiment of the present invention, 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. In a particular embodiment of the invention, a compound of the formula (IA) 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. In another embodiment of the present invention, 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 ⁴ is a hydrogen atom. In another embodiment of the present invention, 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 ⁵ is a hydrogen atom. In another embodiment of the present invention, 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. Further, the aryl group means a 6 to 14 membered all-carbon monocyclic or fused polycyclic group having a conjugated π-electron system, and 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. In another embodiment of the present invention, a compound of the formula (Ι-Α) 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. In another embodiment of the present invention, 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

( I-A ) ( ! )

The compound of the formula (IA) is deprotected in a solvent under acidic conditions to give a compound of the formula (I); Wherein: PG is an amino protecting group; 1^~1 ^{5 is} as defined in the formula (I), wherein R ³ is preferably a hydrogen atom < In another embodiment of the invention, one is as described above 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:

It can be used as an intermediate for synthesizing a compound represented by the general formula (I), wherein:

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 ;

m is 0, 1, or 2. In another embodiment of the present invention, 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. In another embodiment of the present invention, 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 ⁵ is a hydrogen atom. In another embodiment of the present invention, 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. Further, the aryl group means a 6 to 14 membered all-carbon monocyclic or fused polycyclic group having a conjugated π-electron system, and 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. In another embodiment of the present invention, a compound of the formula (Ι-Β) 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. In another embodiment of the present invention, 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 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 method of the mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

( I-B )

The compound of the formula (I-B) is reacted with an amine compound to give a compound of the formula (I);

Wherein: ^~11 ^{5 is} as defined in the compound of formula (I). Further, another aspect of the present invention relates to 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 . 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). 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. 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 a pharmaceutical composition comprising the same Things. 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. 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. 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. Detailed description of the invention

Unless otherwise stated, the following terms used in the specification and claims have the following meanings. "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, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4- Ethylhexyl, 2-methyl-2-ethylpentyl, 2 -methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl , 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. 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. π 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. . 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. Non-limiting real

"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 π-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 π 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. Non-limiting examples of 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. Non-limiting examples of 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. Spirocycloalkane

"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 π-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. It may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl group according to the number of constituent rings, preferably a bicyclic or tricyclic ring, more preferably a 5-member/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. . Non-limiting examples of 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 π-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. 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. Non-application of bridged cycloalkyl groups:

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,

Wait. 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 π-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. Amino, arginyl, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cyclodecylthio, heterocycle Alkylthio group, -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 .

"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. Thio, 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 .

"Haloalkyl" means an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.

"Hydroxy" means an -OH group.

"Hydroxyalkyl" 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 .

"Cyano" means -CN.

"Nitro" means -N0 ₂ .

"Benzyl" refers to -CH ₂ - phenyl.

"Oxo group" means =0.

"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.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "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.

m and R ^{6 to} R ⁸ are as defined in the compound of the formula (I). Method for synthesizing the compound of the present invention

In order to accomplish the synthetic purposes of the present invention, the present invention employs the following synthetic technical solutions:

a compound of the formula (I), or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a compound thereof 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

The 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). Wherein 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, and 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:

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. The reductive amination of the compound (IB) with the amine compound (e) under the action of a reducing agent such as sodium borohydride gives the compound of the formula (I). Wherein R to R ⁵ are as defined in the formula (I).

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. 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 invention is further described in the following examples, but these examples are not intended to limit the scope of the invention. Experimental methods in which no specific conditions are specified in the examples of the present invention are generally carried out according to conventional conditions or according to the conditions recommended by the raw material or commodity manufacturer. Reagents not specified for specific sources, are routine reagents purchased by the market. Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide ( ) ΜΛ - ί 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.

Column chromatography generally uses Yantai Yellow Sea 200~300 mesh silica gel as a carrier.

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.

In the examples, the reactions were all carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified.

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.

In the examples, the solution in the reaction means an aqueous solution unless otherwise specified.

In the examples, 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). 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. Example 1

L-Π-ίbenzofuran-2-ylsulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methylmethylamine

1 a 1 b 1 c 1

First step

1-(2-Fluorophenyl)-1H-pyrrole-3 under ice bath with l-(benzofuran-2-ylsulfonyl)-5-P-fluorophenyl)-1H-pyrrole-3-carbaldehyde - Formaldehyde la (100 mg, 0.53 mmol, prepared according to the prior art WO2007026916) was dissolved in 4 mL of tetrahydrofuran, sodium hydride (106 mg, 60%) was added to the reaction mixture, and the reaction mixture was stirred for 30 minutes. Further, benzofuran-2-sulfonyl chloride lb (172 mg, 0.79 mmol, prepared according to the prior art WO2006047302) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with water and EtOAc (EtOAc (EtOAc)EtOAc. The mixture was dried, filtered, and evaporated tolululululululululululululululululululululu -1H-pyrrole-3-carbaldehyde lc (131 mg, white solid), Yield: 67.2%.

MS m/z (ESI): 370.1 [M+l]

Second step

lG-(benzofuran-2-ylsulfonyl)fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine 1-(;benzofuran-2-ylsulfonyl)-5 -0 fluorophenyl) -1H-pyrrole-3-carbaldehyde lc (130 mg, 0.35 mmol) was dissolved in 1.5 mL of methylamine (25%) and stirred for 2 hr. Sodium borohydride (40 mg, 1.05 mmol) was added, and the reaction was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjj -1H-pyrrol-3-yl)methylmethylamine 1 C57 mg, yellow oil), Yield: 42.5%.

MS m/z (ESI): 385.2 [M+l]

1H NMR (400 MHz, COCl ₃ -d ₆ ): δ 7.64-7.66 (m, 1H), 7.50-7.53 (m, 3H), 7.35-7.46 (m, 2H) 7.27-7.27 (m, 1H), 7.13 -7.17 (m, 1Η), 7.04-7.09 (m, 3H), 6.40 (m, 2H), 3.75 (s, 2H), 2.53 (s, 3H) Example 2

-Π-ίbenzofuran-2-ylsulfonyl)-5-(2-chlorophenyl)-1H-pyrrole-3-yl)-N-methylmethylamine

First step

((1-(benzofuran-2-ylsulfonyl)-5-bromo-1H-pyrrol-3-yl)methyl) (methyl)carbamic acid tert-butyl ester, under ice bath, sodium hydride (0.5 g , 60%) was added to 20 mL of tetrahydrofuran solution, and ((5-bromo-1H-pyrrol-3-yl)methylxmethyl)carbamic acid tert-butyl ester 2a (1.80 g, 6.22 mmol, according to the present Prepared by the literature WO2008108380), after the addition, the reaction was stirred for 30 minutes. To the reaction liquid, benzofuran-2-sulfonyl chloride lb (1.34 g, 6.22 mmol) was added portionwise, and the mixture was stirred and evaporated, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with 10 mL of aq. EtOAc. EtOAc (EtOAc m. Filtration, concentrating the filtrate, and the residue obtained from silica gel column chromatography elute -Methyl)methyl (meth)carbamate tert-butyl ester 2b (1.45 g, pale yellow solid), Yield: 49.7%.

MS m/z (ESI): 413.1 [M-55]

Second step

((1-(benzofuran-2-ylsulfonyl)-5-(2-chlorophenyl)-1H-pyrrol-3-yl)methyl) (methyl)carbamic acid tert-butyl ester ((1) - (benzofuran-2-ylsulfonyl)-5-bromo-1H-pyrrol-3-yl)methyl)(methyl)carbamic acid tert-butyl ester 2b (100 mg, 0.21 mmol), 2-chloro- Phenylboronic acid (34 mg, 0.23 mmol) and sodium carbonate (34 mg, 0.32 mmol) were added to 6 mL of a mixed solvent of 1,4-dioxane and water (V/V=5:1). After stirring well, [1,1'-bis(;diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol) was added, and the mixture was heated to 100 ° C, and the reaction was stirred for 2 hours. 50 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the residue was purified by thin layer chromatography To give the title product ((1-(benzofuran-2-ylsulfonyl)-5-(2-chlorophenyl)-1H-pyrrol-3-yl)methylxmethyl)carbamic acid tert-butyl ester 2c (47 mg, light yellow oil), Yield: 44.8%.

MS m/z (ESI): 445.2 [M-55] third step

lG-(benzofuran-2-ylsulfonyl)chlorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine 1-(benzofuran-2-ylsulfonyl)chlorophenyl -1H-pyrrol-3-yl)methyl X methyl) tert-butyl carbamate 2c (47 mg, 0.09 mmol) was added to 5 mL of dichloromethane and trifluoroacetic acid (V/V = 4: l). The solvent was stirred for 1 hour in a solvent. The reaction solution was concentrated under reduced pressure, and then 5 mL aqueous ammonia and 40 mL of dichloromethane were added, and the mixture was stirred and then allowed to stand. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue obtained was purified to give the title product 1-(1-(benzofuran-2-ylsulfonyl)-5-(2-chlorophenyl)-1H-pyrrol-3-yl)methylmethylamine 2 C23 Mg, light yellow oil), Yield: 49.0%.

MS m/z (ESI): 401.2 [M+l]

1H NMR (400 MHz, CDC1 ₃ ) δ 7.60-7.62 (m, 1H), 7.45-7.50 (m, 3H), 7.33-7.35 (m, 3H) 7.27-7.32 (m, 2H), 7.01-7.02 (m , 1H), 6.31-6.32 (m, 1H), 3.71 (s, 2H), 2.50 (s, 3H) Example 3

L-Π-ίbenzofuran-2-ylsulfonyl)--(4-fluorophenyl)-1H-pyrrole-3-yl)methylmethylamine

First step

((1-(benzofuran-2-ylsulfonyl)-5-(4-fluorophenyl)-1H-pyrrol-3-yl)methyl) (methyl)carbamic acid tert-butyl ((1- (benzofuran-2-ylsulfonyl)-5-bromo-1H-pyrrol-3-yl)methyl)(methyl)carbamic acid tert-butyl ester 2b (150 mg, 0.32 mmol) 4-fluorophenylboronic acid 3a (49 mg, 0.35 mmol) and sodium carbonate (51 mg, 0.48 mmol) were added to 6 mL of a mixture solvent of 1,4-dioxane and water (V/V=5:1), added, stirred. After uniform addition, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (23 mg, 0.03 mmol) was added, and the mixture was heated to 100 ° C, and the reaction was stirred for 2 hours. 50 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the residue was purified by thin layer chromatography , the title product ((1-(benzofuran-2-ylsulfonyl)-5-(4-fluorophenyl)-1H-pyrrol-3-yl)) Tert-butyl (methyl)carbamate 3b (72 mg, pale yellow oil), yield: 46.5%.

MS m/z (ESI): 429.2 [M-55]

Second step

L-(benzofuran-2-ylsulfonyl)-5-(4-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine 1-(benzofuran-2-yl) Sulfonyl)-5-(4-fluorophenyl)-1H-pyrrol-3-yl)methylXmethyl)-tert-butyl carbamate 3b (72 mg, 0.15 mmol) was added to 5 mL of dichloromethane and In a mixed solvent of fluoroacetic acid (V/V = 4:1), the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and then 5 mL aqueous ammonia and 40 mL of dichloromethane were added, and the mixture was stirred and then allowed to stand. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue obtained is purified to give the titled product 1-(1-(benzofuran-2-ylsulfonyl)-5-(4-fluorophenyl)-1H-pyrrol-3-yl)methylmethylamine 3 C27 Mg, pale yellow solid), Yield: 47.4%.

MS m/z (ESI): 385.2 [M+l]

1H NMR (400 MHz, CDC1 ₃ ) δ 7.58-7.60 (m, 1H), 7.47-7.48 (m, 2H), 7.40-7.42 (m, 1H) 7.28-7.31 (m, 1H), 7.25-7.27 (m , 2H), 6.96-6.99 (m, 3H), 6.24-6.25 (m, 1H), 3.66 (s, 2H), 2.49 (s, 3H) Example 4

L-Π-ίbenzofuran-2-ylsulfonyl)-5-(3-methoxyphenyl)-1H-pyrrole-3-yl)-N-methylmethylamine

first step

1-(benzofuran-2-ylsulfonyl)-5-hydroxyphenyl)-lH-pyrrole-3-yl)methyl X-methyl)carbamic acid tert-butyl ester

((1-(Benzofuran-2-ylsulfonyl)-5-bromo-1H-pyrrol-3-yl)methyl)(methyl)carbamic acid tert-butyl ester 2b (300 mg, 0.64 mmol) 3 -Hydroxybenzeneboronic acid 4a (97 mg, 0.71 mmol) and sodium carbonate (188 mg, 0.96 mmol) were added to 12 mL of a mixture of 1,4-dioxane and water (V/V = 5:1). After the addition, the mixture was stirred well, and then [1,1'-bis(;diphenylphosphino)ferrocene]palladium dichloride (C44 mg, 0.06 mmol) was added thereto, and the mixture was heated to 100 ° C, and the reaction was stirred for 2 hours. Add 60 mL of ethyl acetate to the reaction solution and wash with saturated sodium chloride solution. The title compound ((1-(benzofuran-2-ylsulfonyl)) was obtained from EtOAc (EtOAc) -5-(3-Hydroxyphenyl)-1H-pyrrol-3-yl)methylXmethyl)carbamic acid tert-butyl ester 4b (160 mg,yield of pale yellow oil), yield: 51.8%. MS m/z (ESI): 427.2 [M-55]

Second step

((1-(Benzofuran-2-ylsulfonyl)-5-(3-methoxyphenyl)-1H-pyrrole-3-yl)methyl) tert-butyl (methyl)carbamate

((1-(Benzofuran-2-ylsulfonyl)-5-(3-hydroxyphenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamic acid tert-butyl ester 4b C80 mg , 0.17 mmol) was added to 5 mL of N,N-dimethylformamide, cooled in an ice bath, sodium hydride (12 mg, 0.25 mmol) was added portionwise, and the reaction was stirred for 30 minutes. Iodoformamidine (36 mg, 0.25 mmol) was added to the reaction mixture, and the mixture was added, the ice bath was removed, and the mixture was stirred at room temperature for 1 hour. The 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%.

MS m/z (ESI): 441.3 [M-55]

third step

1-(1-(benzofuran-2-ylsulfonyl)-5-(3-methoxyphenyl)-1H-pyrrol-3-yl)-N-methylmethylamine ((1-( Benzofuran-2-ylsulfonyl)-5-(3-methoxyphenyl)-1H-pyrrol-3-yl)methyl) tert-butyl (methyl)carbamate 4c (37 mg, 0.07 1 ^^1) was added to a mixed solvent of 5 dichloromethane and trifluoroacetic acid (^/¥=4:1), and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and then 3 mL aqueous ammonia and 50 mL of dichloromethane were added, and the mixture was stirred and then allowed to stand. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue obtained is purified to give the title product 1-(1-(benzofuran-2-ylsulfonyl)-5-(3-methoxyphenyl)-1H-pyrrol-3-yl)methylmethylamine 4 C12 mg, pale yellow oil), Yield: 40.0%. MS m/z (ESI): 397.2 [M+l]

1H NMR (400 MHz, CDC1 ₃ ) δ 7.56-7.58 (m, 1H), 7.46-7.47 (m, 2H), 7.40-7.42 (m, 1H) 7.30-7.32 (m, 1H), 7.17-7.19 (m , 1H), 6.91-6.92 (m, 1H), 6.78-6.87 (m, 2H), 6.77-6.78 (m, 1H), 6.24-6.25 (m, 1H), 3.67 (s, 3H), 3.66 (s , 2H), 2.48 (s, 3H) Example 5

Benzofuran-2-ylsulfonyl)-5-(3-(cyclopropylmethoxy)phenyl)-1H-pyrrol-3-yl)-N-methylmethylamine

first step

((1-(benzofuran-2-ylsulfonyl)-5-(3-(cyclopropylmethoxy)phenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamic acid Tert-butyl ester

Under the protection of an argon atmosphere, ((1-(benzofuran-2-ylsulfonyl)-5-(3-hydroxyphenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamic acid tert-Butyl ester 4b (80 mg, 0.17 mmol), bromomethylcyclopropane 5a (45 mg, 0.33 mmol) and potassium carbonate (35 mg, 0.26 mmol) were added to 5 mL of N,N-dimethylformamide Heat to 60 ° C and stir the reaction for 5 hours. 50 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. , the title product (G-(benzofuran-2-ylsulfonyl)-5-H cyclopropylmethoxy)phenyl)-1H-pyrrol-3-yl)methylxmethyl)carbamic acid Butyrate 5b (45 mg, pale yellow solid), Yield: 50.6%.

MS m/z (ESI): 481.3 [M-55]

Second step

1-G-(benzofuran-2-ylsulfonyl)-5-(3-(cyclopropylmethoxy)phenyl)-1H-pyrrole-3-yl)-N-methylmethylamine

((1-(Benzofuran-2-ylsulfonyl)-5-(3-(cyclopropylmethoxy)phenyl)-1H-pyrrol-3-yl)methylXmethyl)carbamic acid tert-Butyl ester 5b (45 mg, 0.08 mmol) was added to a mixed solvent of 5 mL of dichloromethane and trifluoroacetic acid (V/V = 4:1), and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and then, 3 mL aqueous ammonia and 40 mL of dichloromethane were added, and the mixture was stirred and then allowed to stand. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. A resulting residue was purified to give the title product l- (l- (benzofuran-2-yl-sulfonyl) - ₅ - (3- (cyclopropylmethoxy) phenyl) lH-pyrrol-3-yl Methylmethylamine 5 (14 mg, pale yellow solid), Yield: 37.8%.

MS m/z (ESI): 437.5 [M+l]

1H NMR (400 MHz, CDC1 ₃ ) δ 7.56-7.58 (m, 1H), 7.46-7.47 (m, 2H), 7.40-7.42 (m, 1H) 7.30-7.32 (m, 1H), 7.16-7.18 (m , 1H), 6.93-6.95 (m, 2H), 6.84-6.86 (m, 1H), 6.72-6.73 (m, 1H), 6.24-6.25 (m, 1H), 3.67 (s, 2H), 3.60-3.61 (m, 2H), 2.49 (s, 3H), 1.20-1.22 (m _: 1H), 0.60-0.63 (m, 2H), 0.28-030 (m, 2H) Example 6

L-Π-ίbenzofuran-2-ylsulfonyl)-5H-pyrrole-3-yl)methylmethylamine

First step

((1-(Benzofuran-2-ylsulfonyl)-5-(4-chlorophenyl)-1H-pyrrole-3-yl)methyl) tert-butyl (methyl)carbamate

((1-(Benzofuran-2-ylsulfonyl)-5-bromo-1H-pyrrol-3-yl)methyl)(methyl)carbamic acid tert-butyl ester 2b (100 mg, 0.21 mmol) 4 -Chlorophenylboronic acid 6a (34 mg, 0.23 mmol) and sodium carbonate (34 mg, 0.32 mmol) were added to 6 mL of a mixture solvent of 1,4-dioxane and water (V/V = 5:1). After the addition, the mixture was stirred well, and then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol) was added thereto, and the mixture was heated to 100 ° C, and the reaction was stirred for 2 hours. 50 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the residue was purified by thin layer chromatography To give the title product ((1-(benzofuran-2-ylsulfonyl)-5-(4-chlorophenyl)-1H-pyrrol-3-yl)methylxmethyl)carbamic acid tert-butyl ester 6b (43 mg, pale yellow solid), Yield: 41.0%.

MS m/z (ESI): 413.1 [M-55]

Second step

lG-(benzofuran-2-ylsulfonyl)-5-(4-chlorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine ((1-(benzofuran-2) -ylsulfonyl)-5-(4-chlorophenyl)-1H-pyrrol-3-yl)methyl) tert-butyl (methyl)carbamate 6b (43 mg, 0.08 mmol) added to 5 mL of dichloro In a mixed solvent of methane and trifluoroacetic acid (V/V = 4:1), the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and then 3 mL aqueous ammonia and 50 mL of dichloromethane were added, and the mixture was stirred and then allowed to stand. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue obtained is purified to give the titled product 1-(1-(benzofuran-2-ylsulfonyl)-5-(4-chlorophenyl)-1H-pyrrol-3-yl)methylmethylamine 6 C13 Mg, light yellow oil), Yield: 38.2%. MS m/z (ESI): 401.2 [M+l]

1H NMR (400 MHz, CDC1 ₃ ) δ 7.58-7.60 (m, 1H), 7.47-7.48 (m, 2H), 7.41-7.42 (m, 1H) 7.32-7.34 (m, 1H), 7.29-7.32 (m , 1H), 7.22-7.24 (m, 2H), 7.21-7.22 (m, 1H), 7.01-7.02 (m, 1H), 6.26-6.27 (m, 1H), 3.68 (s, 2H), 2.48 (s , 3H) Example 7

1-Π--2-ylsulfonyl)-5-(2,3- -5-yl)-1H-pyrrole-3-yl)-N-methylmethylamine

First step

((L- (benzofuran - ² - yl) -5- ^(2, 3-dihydro-benzofuran-5-yl) lH-pyrrol-3-yl) methyl) (methyl) amino Tert-butyl formate

((1-(Benzofuran-2-ylsulfonyl)-5-bromo-1H-pyrrol-3-yl)methyl)(methyl)carbamic acid tert-butyl ester 2b (150 mg, 0.32 mmol) 2 , 3-dihydro-1-benzofuran-5-ylboronic acid 7a (58 mg, 0.35 mmol) and sodium carbonate (51 mg, 0.48 mmol) were added sequentially to 6 mL of 1,4-dioxane and water (V/V=5:1) in a mixed solvent, add and stir well, then add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (23 mg, 0.03 mmol) Heat to 100 ° C and stir the reaction for 2 hours. 50 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the residue was purified by thin layer chromatography , the title product is obtained ((1-(benzofuran-2-ylsulfonyl)-5-(2,3-dihydrobenzofuran-5-yl)-1H-pyrrol-3-yl)methyl-X- Tert-butyl carbamate 7b (83 mg, light yellow oil), yield: 51.2%.

MS m/z (ESI): 453.3 [M-55]

Second step

lG-(benzofuran-2-ylsulfonyl)-5-(2,3-dihydrobenzofuran-5-yl)-1H-pyrrol-3-yl)-N-methylmethylamine 1 benzene And furan-2-ylsulfonyl)-5-(2,3-dihydrobenzofuran-5-yl)-1H-pyrrol-3-yl)methylXmethyl)carbamic acid tert-butyl ester 7b (83 Mg, 0.16 mmol) was added to 8 mL of a mixed solvent of dichloromethane and trifluoroacetic acid (V/V = 3:1), and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, then 2 mL aqueous ammonia and 50 mL Dichloromethane, the mixture was stirred, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. (benzofuran-2-ylsulfonyl)-5-(2,3-dihydrobenzofuran-5-yl)-1H-pyrrol-3-yl)methylmethylamine 7 36 mg, light yellow oil ), Yield: 53.7%.

MS m/z (ESI): 409.3 [M+l]

1H NMR (400 MHz, CDC1 ₃ ) δ 7.58-7.60 (m, 1H), 7.47-7.49 (m, 2H), 7.37-7.38 (m, 1H) 7.33-7.35 (m, 1H), 7.04-7.05 (m , (1,1H) 3.07 (t, / = 8.8 Hz, 2H), 2.48 (s, 3H) Example 8

L-Π-ίbenzofuran-2-ylsulfonyl) ) -1H-pyrrole-3-yl)methylmethylamine

First step

((1-(benzofuran-2-ylsulfonyl)-5-(3-chlorophenyl)-1H-pyrrol-3-yl)methyl) (methyl)carbamic acid tert-butyl ester ((1) - (benzofuran-2-ylsulfonyl)-5-bromo-1H-pyrrol-3-yl)methyl)(methyl)carbamic acid tert-butyl ester 2b (100 mg, 0.21 mmol) 3-chlorobenzeneboronic acid 8a (34 mg, 0.23 mmol) and sodium carbonate (34 mg, 0.32 mmol) were added to 6 mL of a mixed solvent of 1,4-dioxane and water (V/V=5:1), and the mixture was added. After stirring well, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol) was added, and the mixture was heated to 100 ° C, and the reaction was stirred for 3 hours. 40 mL of ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the residue was purified by a thin layer chromatography , the title product ((1-(benzofuran-2-ylsulfonyl)-5-(3-chlorophenyl)-1H-pyrrol-3-yl)methylxmethyl)carbamic acid tert-butyl ester 8b (51 mg, pale yellow solid), Yield: 48.6%.

MS m/z (ESI): 413.1 [M-55]

Second step

lG-(benzofuran-2-ylsulfonyl)-5-chlorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine ((1-(benzofuran-2-) Sulfamoyl)-5-(3-chlorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamic acid tert-Butyl ester 8b (51 mg, 0.10 1 ^^) 1) was added to a mixed solvent of 5 11 dichloromethane and trifluoroacetic acid (^/¥ = 4:1), and the mixture was stirred for 1 hour. After the reaction mixture was concentrated under reduced pressure, 3 mL aqueous ammonia and 40 mL of dichloromethane were added, and the mixture was stirred and then allowed to stand. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue obtained was purified to give the title product 1-(1-(benzofuran-2-ylsulfonyl)-5-(3-chlorophenyl)-1H-pyrrol-3-yl)methylmethylamine 8 C15 Mg, light yellow oil), Yield: 36.6%.

MS m/z (ESI): 401.2 [M+l]

1H NMR (400 MHz, CDC1 ₃ ) δ 7.59-7.61 (m, 1H), 7.48-7.50 (m, 2H), 7.41-7.42 (m, 1H) 7.34-7.35 (m, 2H), 7.24-7.27 (m , 3H), 7.06-7.07 (m, 1H), 6.28-6.29 (m, 1H), 3.67 (s, 2H), 2.48 (s, 3H) Example 9

1-Π-(benzofuran-2-ylsulfonyl)--(pyridin-3-yl)-1H-pyrrole-3-yl)-N-methylmethylamine

First step

((1-(Benzofuran-2-ylsulfonyl)-5-(pyridin-3-yl)-1H-pyrrole-3-yl)methyl) tert-butyl (methyl)carbamate

((1-(Benzofuran-2-ylsulfonyl)-5-bromo-1H-pyrrol-3-yl)methyl)(methyl)carbamic acid tert-butyl ester 2b (100 mg, 0.21 mmol) pyridine -3-Boronic acid 9a (29 mg, 0.23 mmol) and sodium carbonate (34 mg, 0.32 mmol) were added to 6 mL of 1,4-dioxane and water (V/V = 5:1) solvent. After the addition, the mixture was stirred well, and then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol) was added thereto, and the mixture was heated to 100 ° C, and the reaction was stirred for 3 hours. 50 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the residue was purified by thin layer chromatography To give the title product ((1-(benzofuran-2-ylsulfonyl)-5-(pyridin-3-yl)-1H-pyrrol-3-yl)methylxmethyl)carbamic acid tert-butyl ester 9b (43 mg, pale yellow solid), Yield: 43.0%.

MS m/z (ESI): 468.2 [M+l]

Second step lG-(benzofuran-2-ylsulfonyl)-5-(pyridin-3-yl)-1H-pyrrol-3-yl)-N-methylmethylamine 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) was added to 2.5 mL dichloromethane and In a mixed solvent of fluoroacetic acid (V/V = 4:1), the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and then 2 mL aqueous ammonia and 30 mL of dichloromethane were added, and the mixture was stirred and then allowed to stand. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue obtained is purified to give the titled product 1-(1-(benzofuran-2-ylsulfonyl)-5-(pyridin-3-yl)-1H-pyrrol-3-yl)methylmethylamine 9 ( 12 mg, pale yellow oil Yield: 35.3%.

MS m/z (ESI): 368.2 [M+l]

1H NMR (400 MHz, CDC1 ₃ ) δ 8.61-8.63 (m, 1H), 8.46-8.47 (m, 1H), 7.76-7.78 (m, 1H) 7.60-7.62 (m, 1H), 7.46-7.49 (m , 3H), 7.31-7.34 (m, 2H), 7.06-7.07 (m, 1H), 6.35-6.36 (m, 1H), 3.69 (s, 2H), 2.49 (s, 3H) Example 10

1-Π-(benzofuran-2-ylsulfonyl)-)-1H-pyrrole-3-yl)-N-methylmethylamine

First step

((1-(benzofuran-2-ylsulfonyl)-5-(pyridin-4-yl)-1H-pyrrol-3-yl)methyl) (methyl)carbamic acid tert-butyl ((1- (benzofuran-2-ylsulfonyl)-5-bromo-1H-pyrrol-3-yl)methyl)(methyl)carbamic acid tert-butyl ester 2b (100 mg, 0.21 mmol), pyridine-4-boronic acid 10a (29 mg, 0.23 mmol) and sodium carbonate (34 mg, 0.32 mmol) were added to 6 mL of a mixed solvent of 1,4-dioxane and water (V/V=5:1), and added. After stirring well, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol) was added, and the mixture was heated to 100 ° C, and the reaction was stirred for 3 hours. 50 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the residue was purified by thin layer chromatography , the title product ((1-(benzofuran-2-ylsulfonyl)-5-(pyridin-4-yl)-1H-pyrrol-3-yl)methyl)(methyl)carbamic acid tert-butyl ester 10b (51 mg, pale yellow solid), Yield: 51.0%. MS m/z (ESI): 468.3 [M+l]

Second step

lG-(benzofuran-2-ylsulfonyl)-5-(pyridin-4-yl)-1H-pyrrol-3-yl)-N-methylmethylamine 1-(benzofuran-2-yl) Sulfonyl)-5-(pyridin-4-yl)-1H-pyrrol-3-yl)methylXmethyl)carbamic acid tert-butyl ester 10b (51 mg, 0.11 mmol) was added to 5 mL dichloromethane and In a mixed solvent of fluoroacetic acid (V/V = 4:1), the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and then 5 mL aqueous ammonia and 40 mL of dichloromethane were added, and the mixture was stirred and then allowed to stand. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue obtained is purified to give the titled product 1-(1-(benzofuran-2-ylsulfonyl)-5-(pyridin-4-yl)-1H-pyrrol-3-yl)methylmethylamine 10 ( Yield: 42.5%. MS m/z (ESI): 368.3 [M+l]

1H NMR (400 MHz, CDC1 ₃ ) δ 8.57-8.58 (m, 2H), 7.60-7.62 (m, 1H), 7.48-7.51 (m, 3H) 7.32-7.34 (m, 2H), 7.27-7.28 (m , 1H), 7.09-7.10 (m, 1H), 6.44-6.45 (m, 1H), 3.74 (s, 2H), 2.50 (s, 3H) Test example:

Biological evaluation of H ⁺ /K ⁺ -ATPase

The following in vitro screening assays were used to determine the inhibition of H ⁺ /K ⁺ -ATPase enzymatic activity by the compounds of the invention.

Experimental materials and instruments:

1, pig gastric mucosa microsomes (rich in H ⁺ /K ⁺ -ATPa _Se ) (self-lifting)

2. ATP (sigma-aldrich, A1852-1VL)

3. Malachite green (sigma-aldrich, 213020-25G)

4. Ammonium molybdate (sigma-aldrich, 277908-5G). The experimental steps are briefly described as follows:

First, reagent preparation

1. The compound is formulated in 100% DMSO to a suitable concentration: 10000, 1000, 100, 10, 1, O.lnM;

2, buffer 1 : 50mmol / L HEPEs-Tris, 5mmol / L magnesium chloride, pH 6.5;

3. Buffer 2: 50 mmol/L HEPEs-Tris, 5 mmol/L magnesium chloride, pH 6.5, 10 mmol/L potassium chloride, pH=6.5;

4. ATP: Dilute ATP to 2 mM with buffer 1;

5, 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;

6, 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. Clock, the precipitate was removed; the supernatant was centrifuged at 100,000 G for 90 minutes, and a precipitate was taken; the precipitate was suspended in a 0.25 mol/L sucrose solution and 0.25 mol/L sucrose was added to the bottom to add 7.5% polysucrose, and centrifuged at 100,000 G for 5 hours. The material between the two liquid layers was collected, washed with a 0.25 mol/L sucrose solution while shaking, and the obtained microsomal enzyme was stored at -80 ° C for storage. Second, the experimental process:

10 μl of gastric mucosal microsomes (H ⁺ /K ⁺ -ATPase ) were added to 79 ul of buffer 2, and then 1 ul of the compound solution was added, followed by the addition of 10 ul of 2 mM ATP to initiate the reaction. The reaction was carried out at 37 ° C for 30 minutes. The reaction was terminated by the addition of 30 ul of malachite green solution, equilibrated at room temperature for 20 minutes, and the absorbed light was read at 620 nm.

At the same time, the same volume, without the addition of potassium chloride as a background, was subtracted from the calculation of the enzyme activity. The IC _5Q value of the compound can be calculated from the inhibition rates at different concentrations.

, experimental results: IC of the compound

Conclusion: The compounds of the present invention have significant inhibitory activity against H ⁺ /K ⁺ -ATPase.

Claims

Claims:

A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salt:

Its towel:

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) substituted with a substituent of R 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 Substituting 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 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 ;

m is 0, 1, or 2.

2. A compound of the formula (I) according to claim 1 or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is an alkyl group.

3. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to claim 1 or 2. Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom.

The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 3; Isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom.

The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 4; Isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom.

The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 5; Isomer, 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 selected from one or more selected from halogen or Substituted by a substituent of -OR ⁶ wherein R ⁶ is alkyl, said alkyl optionally being further substituted with one or more substituents selected from cycloalkyl.

The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 6. Isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is an aryl group, which is optionally further substituted with one or more substituents selected from halogen or -OR ⁶ , R ⁶ is an alkyl group, which is optionally further substituted with one or more substituents selected from cycloalkyl groups.

The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 6. Isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is heteroaryl.

The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 8. Isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is:

10. A compound of the formula (IA) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, or a mixture thereof Salt:

( I-A )

among them:

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, cyclodecyl group, heterocyclic group, aryl group or heteroaryl group is optionally further one Or a plurality selected from the group consisting of halogen, cyano, hydroxyl, Amino, alkyl, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁷ R ⁸ , -C(0)NR ⁷ R ⁸ , Substituted by a substituent of S(0) _m R ⁶ , -C(0)R ⁶ , -OC(0)R ⁶ or -C(0)OR ⁶ ;

PG is an amino protecting group;

m is 0, 1, or 2.

11. A compound of the formula (I) according to claim 1 or a tautomer, a mesogen, a racemate, an enantiomer thereof, a diastereomer Method of the body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method

Deprotection of a compound of the formula (IA) in a solvent under acidic conditions affords a compound of the formula (I); wherein: PG is an amino protecting group; 1^~1 ⁵ is as defined in claim 1, wherein R ³ is preferred It is a hydrogen atom.

12. A compound of the formula (Ι-Β) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof: Its towel:

m is 0, 1, or 2.

13. A compound of the formula (I) according to claim 1 or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. A method of the body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: A compound of the formula (IB) is reacted with an amine compound to give a compound of the formula (I);

Wherein: 1^~1 ⁵ is as defined in claim 1.

A pharmaceutical composition comprising a therapeutically effective amount of the compound of the formula (I) according to any one of claims 1 to 9 or a tautomer thereof, mesogenic a form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 9. Use of the isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 for the preparation of a gastric acid secretion inhibitor.

The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 9. Use of the isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 for the preparation of an H ⁺ /K+-ATP _aSe inhibitor.

The compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 9. Use of the isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 for the preparation of a potassium ion competitive acid retarder.

The compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 9. The isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 for the treatment or prevention of peptic ulcer, Zhuo-Eye 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 after surgery Use in drugs that cause hyperacidity or ulceration; or in the preparation of inhibition due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress The use of drugs for upper gastrointestinal bleeding.

The use according to claim 18, wherein the peptic ulcer is selected from the group consisting of a gastric ulcer, a duodenal ulcer or an anastomotic ulcer; and the symptomatic gastroesophageal reflux disease is selected from a non-erosive reflex Fluidic disease or gastroesophageal reflux disease without esophagitis.