TW201406753A - Benzofuran derivative, preparation method and medical use thereof - Google Patents

Abstract

The present invention relates to benzofuran derivatives, the preparation method and medical use thereof. Specifically, the present invention relates to a novel benzofuran derivative represented by formula (I), the preparation methods thereof, the pharmaceutical composition containing the same, the use of the same as a therapeutic agent especially as proton pump inhibitors and potassium-compctitivc acid blockers (P-CABs), wherein the respective substituents of formula (I) are as those defined in the specification.

Description

Benzofuran derivatives, 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-CABs) Medium use.

Peptic ulcer is a common disease, and the incidence rate varies from time to time and from region to region. Usually, the incidence rate is about 10-20% of the total population. With the development of society, people's lifestyle changes, the incidence of peptic ulcer caused by smoking, drinking, emotional stress and drug stimulation is gradually increasing, which is seriously affecting people's work and life. Now the medical community is still unclear about its exact pathogenesis, 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 final common pathway for gastric secretion of H ⁺ , which is present in gastric parietal cells. on the cell membrane of the secretory canaliculus, the degradation of ATP by means of energy supply for H ^+, K ⁺ exchange, specifically the H ⁺ pump into the stomach cavity, stomach acid formed state. A proton pump is a heterodimer composed of two subunits of alpha and beta across the membrane. The α subunit has 10 helical transmembrane segments (M1~M10), which are mainly responsible for the catalytic activity of the enzyme and provide the ATP binding site, and also the binding site of the cation, also known as the catalytic subunit; the 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, convert to sulfoximine compounds under H ⁺ catalysis, and transmembrane with H ⁺ /K ⁺ -ATPase The thiol group on the cysteine residue in the region 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, time of administration on the efficacy of the drug, slow onset of nocturnal acid breakthrough, and instability under acidic conditions (often formulated into enteric preparations, In this case, it takes several hours to show the effect), the dependence on the CYP450 enzyme (there is a huge difference in the plasma concentration of PPIs between different patients, which may lead to a huge difference in the acid-suppressing effect between different patients), etc. Therapeutic effect and clinical application. 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.

Potassium-Competitive Acid Blockers (P-CABs) act as a new class of acid inhibitors to inhibit the activity of H ⁺ /K ⁺ -ATPase 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, and the ionized form inhibits H ⁺ /K ⁺ -ATPase by ionic binding, preventing H ⁺ transport and acid secretion into the gastric cavity, without the need to concentrate on the microcapsules of the gastric parietal cells. And the start of microtubules and acid can rapidly increase the pH value in the stomach, and the enzyme activity recovers 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, and some of the P-CABs have entered Phase II 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 currently disclosed, including WO2005041961, 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.

The object of the present invention is to provide a compound of the formula (I), and their tautomers, meso, racemates, enantiomers, diastereomers, mixtures thereof And pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs. The structure of the general formula (I) is as follows:

Wherein: 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(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC Substituting (O) a substituent of R ⁶ or -C(O)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, the ring group An alkyl group, a heterocyclic group, an aryl group or a heteroaryl group is further optionally one or more selected from the group consisting of halogen, cyano, hydroxy, amine, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl ,heterocyclyl, aryl,heteroaryl, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC(O) Substituted by a substituent of R ⁶ or -C(O)OR ⁶ ; R ^{3 is} selected from a hydrogen atom or an alkyl group; and 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 alkane Alkoxy, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently desired One step is selected from one or more selected from the group consisting of halogen, nitro, cyano, hydroxy, amine, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC(O)R ⁶ or -C(O)OR ⁶ Substituted; 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, the alkoxy group, the cycloalkyl group, The heterocyclic group, the aryl group or the heteroaryl group are each independently further optionally one or more selected from the group consisting of halogen, cyano, hydroxy, amine, pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy. Substituted with a substituent of a cycloalkyl, heterocyclic, aryl, heteroaryl, carboxy or carboxylate group; R ⁷ or R ⁸ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic ring a aryl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently further optionally one or more selected from the group consisting of halogen, cyano, hydroxy, and amine groups, as needed. , pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, Substituted alkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate group substituted with a group; and 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 thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is an alkyl group, preferably a C ₁ -C ₄ alkyl group.

In another embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof 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 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, 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 or a diastereomer thereof 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 or a diastereomer thereof 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 further optionally selected from one or more selected from halogen or -OR ⁶ Substituted by a substituent, R ⁶ is an alkyl group which is further substituted by one or more substituents selected from a cycloalkyl group as needed.

In another embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is an aryl group, wherein the aryl group is further substituted with one or more substituents selected from halogen or -OR ⁶ as needed, and R ⁶ is an alkane a group, preferably a C ₁ -C ₄ alkyl group, which alkyl group is further substituted by one or more substituents selected from a cycloalkyl group, preferably a C ₃ -C ₆ cycloalkyl group. More preferably, it is a cyclopropyl group; the aryl group means a 6 to 14 membered all-carbon monocyclic or fused polycyclic group having a conjugated π-electron system, preferably 6 to 10 membered aryl groups, more preferably benzene. Or benzotetrahydrofuranyl, most preferably phenyl.

In another embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a heteroaryl group, the heteroaryl group being a heteroaromatic system comprising from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the hetero atom Including oxygen, sulfur and nitrogen; preferably a heteroaromatic ring containing 5 to 10 ring atoms, wherein 1 to 4 hetero atoms selected from oxygen, sulfur or nitrogen; more preferably 5 to 6 ring atoms A heteroaromatic ring containing from 1 to 4 heteroatoms selected from oxygen, sulfur or nitrogen, most preferably a pyridyl group.

Typical compounds of the invention include, but are not limited to:

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

The present invention also relates to a compound of the formula (IA) or a tautomer, enantiomer, diastereomer, mesogen, racemate, or a mixture thereof, or Its pharmaceutically acceptable salt:

It can be used as an intermediate for synthesizing a compound represented by the general formula (I), wherein: R ^{1 is} selected from an aryl group or a heteroaryl group, wherein the aryl group or heteroaryl group is further optionally selected from one or more selected from the group consisting of halogen and cyanogen. Base, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, -OR ⁶ , heterocyclyl, aryl, heteroaryl, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -S( O) substituted with a substituent of _m R ⁶ , -C(O)R ⁶ , -OC(O)R ⁶ or -C(O)OR ⁶ ; R ^{2 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a hetero a cycloalkyl, aryl or heteroaryl group, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, amine, alkane , haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -S(O) _m Substituted with a substituent of R ⁶ , —C(O)R ⁶ , —OC(O)R ⁶ or —C(O)OR ⁶ ; each of R ⁴ or R ^{5 is} independently selected from a hydrogen atom, a halogen, a cyano group, Nitro, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl Each of them is further independently selected from one or more selected from the group consisting of halogen, nitro, cyano, hydroxy, amine, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, as needed. , heteroaryl, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC(O)R ⁶ or -C(O Substituted by a substituent of 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 And a cycloalkyl, heterocyclyl, aryl or heteroaryl group, each independently further optionally one or more selected from the group consisting of halogen, cyano, hydroxy, amine, pendant oxy, alkyl, haloalkyl, hydroxyalkane Substituted with a substituent of a group, an alkoxy group, a cycloalkyl 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 ring An alkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently further optionally one or more selected from the group consisting of halogen and cyano. , hydroxy, amine, pendant oxy, alkyl, haloalkyl Substituted with a hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate substituent; PG is an amine protecting group, preferably a third butoxy a carbonyl group; and 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 or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein PG is a third butoxycarbonyl group.

In a particular embodiment of the invention, a compound of the formula (IA) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is an alkyl group, preferably a C ₁ -C ₄ alkyl group.

In another embodiment of the present invention, a compound of the formula (IA) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof 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 or a diastereomer thereof 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 or a diastereomer thereof 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 further optionally selected from one or more selected from halogen or -OR ⁶ Substituted by a substituent, R ⁶ is an alkyl group, preferably a C ₁ -C ₄ alkyl group, and the alkyl group is further substituted by one or more substituents selected from a cycloalkyl group, preferably a cycloalkyl group. It is a C ₃ -C ₆ cycloalkyl group, more preferably a cyclopropyl group. 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 benzo tetrahydrofuranyl, most preferably phenyl; refers to the heteroaryl group containing 1 to 4 heteroatoms, 5-14 heteroaromatic systems ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen; R ¹ is preferably Is a heteroaromatic ring containing 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 The heteroaromatic ring of a hetero atom of oxygen, sulfur or nitrogen is preferably a pyridyl group.

In another embodiment of the present invention, a compound of the formula (IA) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from aryl, wherein the aryl group is further substituted with one or more substituents selected from halogen or -OR ⁶ as needed, R ⁶ is An alkyl group which is further substituted by one or more substituents selected from a cycloalkyl group as needed.

In another embodiment of the present invention, a compound of the formula (IA) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof 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 mesomer, a racemate, an enantiomer, a diastereomer thereof, or A method of the form of a mixture, or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

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 amine protecting group; and R ¹ to R ⁵ are as defined in the formula (I), wherein R ^{3 is} preferably 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 or a non-isomer thereof is prepared as described above. A method of enantiomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein PG is a third 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 Its pharmaceutically acceptable salt:

It can be used as an intermediate for synthesizing a compound represented by the general formula (I), wherein: R ^{1 is} selected from an aryl group or a heteroaryl group, wherein the aryl group or heteroaryl group is further further selected from one or more selected from the group consisting of halogen and cyanide. Base, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, -OR ⁶ , heterocyclyl, aryl, heteroaryl, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -S( O) is substituted with a substituent of _m R ⁶ , -C(O)R ⁶ , -OC(O)R ⁶ or -C(O)OR ⁶ ; R ⁴ or R ⁵ are each independently selected from a hydrogen atom, a halogen, A cyano, nitro, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or The heteroaryl groups are each independently further optionally selected from one or more selected from the group consisting of halogen, nitro, cyano, hydroxy, amine, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl. , aryl, heteroaryl, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC(O)R ⁶ or - C (O) oR ⁶ is substituted with a substituent; R ⁶ is selected from hydrogen, alkyl, hydroxy, halo, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein The alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group are each independently further optionally one or more selected from the group consisting of halogen, cyano, hydroxy, amine, pendant oxy, alkyl. Substituted with a haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate substituent; R ⁷ or R ⁸ are each independently selected from hydrogen An 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 are each independently further optionally one or more Selected from halogen, cyano, hydroxy, amine, pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylic acid ester Substituted by a substituent; and m is 0, 1 or 2.

In another embodiment of the present invention, a compound of the formula (IB) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof 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 or a diastereomer thereof 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 or a diastereomer thereof 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 further optionally selected from one or more selected from halogen or -OR ⁶ Substituted by a substituent, R ⁶ is an alkyl group, preferably a C ₁ -C ₄ alkyl group, and the alkyl group is further substituted by one or more substituents selected from a cycloalkyl group, the cycloalkyl group. It is preferably a C ₃ -C ₆ cycloalkyl group, more preferably a cyclopropyl group. 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 benzene group. and tetrahydrofuranyl, most preferably a phenyl group; a heteroaryl means a heteroaromatic system comprising one to four hetero atoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen; R ¹ representing It is preferably a heteroaromatic ring containing 5 to 10 ring atoms, which contains 1 to 4 hetero atoms selected from oxygen, sulfur or nitrogen; more preferably 5 to 6 ring atoms, including 1 to 4 rings The heteroaromatic ring of a hetero atom of oxygen, sulfur or nitrogen is preferably a pyridyl group.

In another embodiment of the present invention, a compound of the formula (IB) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from aryl, wherein the aryl group is further substituted with one or more substituents selected from halogen or -OR ⁶ as needed, R ⁶ is An alkyl group which is further substituted by one or more substituents selected from a cycloalkyl group as needed.

In another embodiment of the present invention, a compound of the formula (IB) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof 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 mesomer, a racemate, an enantiomer, a diastereomer thereof, or A method of the form of a mixture, or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

The compound of the formula (IB) is reacted with an amine compound to give a compound of the formula (I); wherein: R ¹ to R ⁵ are as defined in the compound of the 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, a mesogen, a racemate thereof, 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, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable drug thereof Use of a salt, or a pharmaceutical composition comprising the same, for 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, enantiomer thereof A conformation, 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 thereof, a racemate, an enantiomer, a diastereomer A composition, or a mixture thereof, or a pharmaceutically acceptable salt thereof, 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, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable drug thereof Use of a 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, 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, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable drug thereof A salt to be used, 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, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable drug thereof Use of a 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 of competitively blocking potassium ions, the method comprising administering to a patient in need of treatment an effective treatment An amount of a compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer, 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, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable drug thereof A salt used, 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 salt thereof Or a pharmaceutical composition comprising the same for the preparation or treatment 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 hyperacidity caused by post-operative stress or Use in ulcerated drugs; or in the preparation of a medicament for inhibiting upper gastrointestinal bleeding due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress. Among them, peptic ulcer includes, but is not limited to, gastric ulcer, duodenal ulcer or anastomotic ulcer; symptomatic gastroesophageal reflux disease (symptomatic GERD) includes, but is not limited to, non-erosive reflux disease or gastroesophageal reflux disease without esophagus to inflammation.

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 hyperacidity caused by post-operative stress Or a method of ulcerating; or a method of inhibiting upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress, the method comprising administering to the patient in need of treatment a therapeutically effective amount of the formula ( 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. 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 gastroesophageal reflux disease without esophagitis.

Another aspect of the invention 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 drug thereof A 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'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 a drug that is hyperacidic or ulcerated; or as a drug that inhibits upper gastrointestinal bleeding due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis, or invasive stress. Peptic ulcers include, but are not limited to, gastric ulcer, duodenal ulcer or anastomotic ulcer; symptomatic Gastroesophageal reflux disease (symptomatic GERD) includes, but is not limited to, non-erosive reflux disease or gastroesophageal reflux disease without esophagitis.

(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, t-butyl, n-pentyl, 1,1-dimethylpropane 1,1,2-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-glycol Base, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2- Dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethyl Hexyl, 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-diethyl-pentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl group, and various branched chain isomers thereof. More preferred are lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, Dibutyl, 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-methyl A pentyl group, a 2,3-dimethylbutyl group, 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. , alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, Heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, -OR ⁶ , -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC(O)R ⁶ , -NR ⁷ C(O)R ⁸ , -NR ⁷ C(O)OR ⁸ or -C(O)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 a cycloalkyl ring containing from 3 to The 10 carbon atoms, the most preferred cycloalkyl ring contains 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene 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 bispirocycloalkane, depending on the number of common spiro atoms between the ring and the ring. base. More preferably 4 members / 4 members, 4 members / 5 members, 4 members / 6 members, 5 members / 5 members or 5 members / 6 members of the monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include

"Fused cycloalkyl" refers to 5 to 20 members, each ring of the system sharing an all-carbon polycyclic group of an adjacent pair of carbon atoms 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, tricyclic, tetracyclic or polycyclic fused cycloalkyl group may be classified according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5 member/5 member or 5 member/6 member bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups include

"Bridge cycloalkyl" refers to 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-electron 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, tetrahydronaphthalene Base, 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, alkynyl, alkoxy, alkylthio. Base, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, pendant oxy, -OR ⁶ , -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC (O) R ⁶ , -NR ⁷ C(O)R ⁸ , -NR ⁷ C(O)OR ⁸ or -C(O)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(O) _m ( Wherein m is a hetero atom of the integer 0 to 2), but does not include a ring moiety of -OO-, -OS- 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, and 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" refers to a polycyclic heterocyclic group of 5 to 20 members, sharing a single atom (called a spiro atom) between the monocyclic rings, wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) _m The 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 single spiroheterocyclyl group, a dispiroheterocyclic group or a polyspiroheterocyclic 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 4 members / 4 members, 4 members / 5 members, 4 members / 6 members, 5 members / 5 members or 5 members / 6 members of the monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include

"Fused heterocyclyl" refers to 5 to 20 members, each ring in the system sharing 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(O) _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. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5 member/5 member or a 5 member/6 member bicyclic fused heterocyclic ring. base. Non-limiting examples of fused heterocyclic groups include

"Bridge heterocyclyl" refers to a 5 to 14 member, any two rings sharing two polycyclic heterocyclic groups of atoms that are not directly bonded, these may contain one or more double bonds, but none of the rings are fully conjugated A π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) _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 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 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, non-limiting examples comprising: 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, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, pendant oxy, -OR ⁶ , -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC (O) R ⁶ , -NR ⁷ C(O)R ⁸ , -NR ⁷ C(O)OR ⁸ or -C(O)OR ⁶ .

"Aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (i.e., a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:

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, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, -OR ⁶ , -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC(O)R ⁶ , -NR ⁷ C(O)R ⁸ , -NR ⁷ C(O)OR ⁸ or -C(O)OR ⁶ .

"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. It is preferably 5 to 10 members. The heteroaryl group is preferably 5 or 6 members such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:

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, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -OR ⁶ , -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC(O)R ⁶ , -NR ⁷ C(O)R ⁸ , -NR ⁷ C(O)OR ⁸ or -C(O)OR ⁶ .

"Alkoxy" means -O-(alkyl) 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 alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, decyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, -OR ⁶ , -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC(O R ⁶ , -NR ⁷ C(O)R ⁸ , -NR ⁷ C(O)OR ⁸ or -C(O)OR ⁶ .

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

"Hydroxy" refers to 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 -NO ₂ .

"Benzyl" refers to -CH ₂ - phenyl.

"Sideoxy" means =0.

"Carboxy" refers to -C(O)OH.

"Carboxylic acid ester group" means -C(O)O(alkyl) or (cycloalkyl) wherein alkyl, cycloalkyl are as defined above.

The "amino protecting group" is such that the amine group remains unchanged during the reaction of other parts of the molecule, and the amine group is protected with a group which is easily removed. Non-limiting examples include indolyl, alkylcarbonyl, alkoxycarbonyl, benzhydryl, aralkylcarbonyl, aralkoxycarbonyl, trityl, orthophthalenyl, N, N a dimethylaminomethylene group, a substituted formyl group, and the like. These groups may optionally be substituted with from 1 to 3 substituents selected from halogen, alkoxy or nitro. The amino protecting group is preferably a third butoxycarbonyl group.

"As needed" or "as needed" 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, and the description includes a case where a heterocyclic group is substituted with an alkyl group and a case where a heterocyclic group is not substituted with an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted 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 amine 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 comprising 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 the administration of the organism, and to facilitate the absorption of the active ingredient 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) of the present invention or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable drug thereof The preparation method of the salt used includes the following steps:

The azole compound (a) is reacted with the benzofuran sulfonium chloride compound (b) in a solvent under basic conditions to obtain a benzofuransulfonyl-substituted pyrrole compound (c), a benzofuransulfonyl-substituted pyrrole The compound (c) and the R ¹ -substituted boronic acid ester or boric acid are subjected to catalytic catalysis in a solvent under basic conditions to obtain R ¹ , benzofuransulfonyl-substituted pyrrole compound (IA), R ¹ The benzofuransulfonyl-substituted azole compound (IA) is deprotected in a solvent under acidic conditions to give a compound of the formula (I). Wherein X is a halogen; and R ¹ to R ⁵ are as defined in the compound of the formula (I), wherein R ^{3 is} preferably a hydrogen atom; and PG is an amine protecting group, preferably a third 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 including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, potassium t-butoxide, and the inorganic base. Classes 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 hydrazine or N,N-dimethylformamide.

The pyrrole formaldehyde compound (d) is reacted with the benzofuransulfonyl chloride compound (b) in a solvent under basic conditions to obtain a benzofuransulfonyl-substituted pyrrole formaldehyde compound (IB), which is substituted with a benzofuransulfonyl group. The reductive amination of the pyrrole formaldehyde 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 ¹ 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 inorganic bases. Bases 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 triethoxy borohydride, sodium cyanoborohydride or lithium aluminum hydride.

Solvents used include, but are not limited to, tetrahydrofuran, dichloromethane, 1,4-dioxane, water, methanol, ethanol, dimethyl hydrazine or N,N-dimethylformamide.

The invention is further described in the following examples, which are not intended to limit the scope of the invention.

The experimental methods in the examples of the present invention which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the raw material or the manufacturer of the commodity. Reagents without specific source are routine reagents purchased from 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 hydrazine ( DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four. Methyl decane (TMS), chemical shifts are given in units of 10 ^-6 (ppm).

The measurement of the MS was carried out using a FINNIGAN 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 chromatography column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm chromatography column).

The average value of ₅₀ measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

The thin layer chromatography tannin plate uses Yantai Huanghai HSGF254 or Qingdao GF254 tannin sheet. The specification of the tannin sheet used for thin layer chromatography (TLC) is 0.15mm~0.2mm. The specification for thin layer chromatography separation and purification is 0.4mm~0.5. Mm silicone board.

Tube column chromatography generally uses Yantai Yellow Sea 200~300 mesh silicone as 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, unless otherwise specified, the reactions were all carried out under an argon atmosphere or a nitrogen atmosphere.

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 not according to the polarity of the compound Adjust with the same.

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 The system, D: n-hexane, 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

1-(1-(benzofuran-2-ylsulfonyl)-5-(2-fluorophenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine

first step

1-(benzofuran-2-ylsulfonyl)-5-(2-fluorophenyl)-1 H -pyrrole-3-carbaldehyde

5-(2-Fluorophenyl)-1 H -pyrrole-3-carbaldehyde 1a (100 mg, 0.53 mmol, prepared according to the existing literature WO2007026916) was dissolved in 4 mL of tetrahydrofuran under ice bath, and hydrogenation was added to the reaction mixture. Sodium (106 mg, 60%) was added and the reaction mixture was stirred for 30 min. Further, benzofuran-2-sulfonium chloride 1b (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 was quenched with water, and the mixture was evaporated with ethyl acetate (5 mL×3), and the organic phase was combined, and the aqueous phase was adjusted to pH <1 with 6M hydrochloric acid and extracted with dichloromethane (100 mL×2). Drying, filtration, and concentrating the filtrate under reduced pressure, and the residue obtained was purified to the titled product 1-(benzofuran-2-ylsulfonyl)-5-(2-fluoro Phenyl)-1 H -pyrrole-3-carbaldehyde 1c (131 mg, white solid), yield: 67.2%.

MS m/z (ESI): 370.1 [M+1]

Second step

1-(1-(benzofuran-2-ylsulfonyl)-5-(2-fluorophenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine

1-(Benzofuran-2-ylsulfonyl)-5-(2-fluorophenyl)-1 H -pyrrole-3-carbaldehyde 1c (130 mg, 0.35 mmol) was dissolved in 1.5 mL of methylamine solution ( In 25%), stir for 2 hours. 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. EtOAc mjjjjjjjjj Phenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine 1 (57 mg, yellow oil), yield: 42.5%.

MS m/z (ESI): 385.2 [M+1]

¹ H NMR (400 MHz, CDCl 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, 1H), 7.04-7.09 (m, 3H), 6.40 (m, 2H), 3.75 (s, 2H), 2.53 (s, 3H)

Example 2

1-(1-(benzofuran-2-ylsulfonyl)-5-(2-chlorophenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine

first step

((1-(benzofuran-2-ylsulfonyl)-5-bromo-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl ester

Under ice bath, sodium hydride (0.5 g, 60%) was added to 20 mL of tetrahydrofuran solution, and ((5-bromo-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid was added in portions. Tributyl ester 2a (1.80 g, 6.22 mmol, prepared according to the prior art WO2008108380) was added and the reaction was stirred for 30 minutes. To the reaction liquid, benzofuran-2-sulfonium chloride 1b (1.34 g, 6.22 mmol) was added portionwise, and the mixture was stirred, and the ice bath was removed, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with 10 mL of aq. EtOAc EtOAc (EtOAc (EtOAc) the filtrate was concentrated by silica gel column chromatography using eluant system C The resulting residue was purified to give the title product ((1- (benzofuran-2-yl sulfo acyl) -5-bromo -1 H - pyrrole - 3-Benzyl)methyl)(methyl)aminocarbamic acid 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)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl ester

((1-(benzofuran-2-ylsulfonyl)-5-bromo-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl ester 2b (100 mg, 0.21) Methyl), 2-chloro-phenylboronic acid (34 mg, 0.23 mmol) and sodium carbonate (34 mg, 0.32 mmol) were added sequentially to 6 mL of a mixture of 1,4-dioxane and water (V/V = 5:1). After the addition, the mixture was stirred well, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol) was further 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 solution, and the mixture was washed with a saturated sodium chloride aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the obtained residue Product ((1-(benzofuran-2-ylsulfonyl)-5-(2-chlorophenyl)-1 H -pyrrol-3-yl)methyl)(methyl)carbamic acid tert-butyl Ester 2c (47 mg, pale yellow oil), yield: 44.8%.

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

third step

1-(1-(benzofuran-2-ylsulfonyl)-5-(2-chlorophenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine

((1-(benzofuran-2-ylsulfonyl)-5-(2-chlorophenyl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl The ester 2c (47 mg, 0.09 mmol) was added to 5 mL of a mixed solvent 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 5 mL of aqueous ammonia and 40 mL of methylene chloride was added, and the mixture was stirred, and the mixture was allowed to stand. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The title product 1-(1-(benzofuran-2-ylsulfonyl)-5-(2-chlorophenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine 2 (23 mg) , pale yellow oil), Yield: 49.0%.

MS m/z (ESI): 401.2 [M+1]

¹ H NMR (400 MHz, CDCl 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

1-(1-(benzofuran-2-ylsulfonyl)-5-(4-fluorophenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine

first step

((1-(benzofuran-2-ylsulfonyl)-5-(4-fluorophenyl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl ester

((1-(benzofuran-2-ylsulfonyl)-5-bromo-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl ester 2b (150 mg, 0.32 Methyl) 4-fluorophenylboronic acid 3a (49 mg, 0.35 mmol) and sodium carbonate (51 mg, 0.48 mmol) were added to a mixture of 6 mL 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 (23 mg, 0.03 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 solution, and the mixture was washed with a saturated sodium chloride aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the obtained residue Product ((1-(benzofuran-2-ylsulfonyl)-5-(4-fluorophenyl)-1 H -pyrrol-3-yl)methyl)(methyl)carbamic acid tert-butyl Ester 3b (72 mg, pale yellow oil), yield: 46.5%.

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

Second step

1-(1-(benzofuran-2-ylsulfonyl)-5-(4-fluorophenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine

((1-(benzofuran-2-ylsulfonyl)-5-(4-fluorophenyl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl The ester 3b (72 mg, 0.15 mmol) was added to 5 mL of a mixed solvent 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 5 mL of aqueous ammonia and 40 mL of methylene chloride was added, and the mixture was stirred, and the mixture was allowed to stand. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The title product 1-(1-(benzofuran-2-ylsulfonyl)-5-(4-fluorophenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine 3 (27 mg) , pale yellow solid), Yield: 47.4%.

MS m/z (ESI): 385.2 [M+1]

_{^{1 H NMR (400MHz, CDCl 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

1-(1-(benzofuran-2-ylsulfonyl)-5-(3-methoxyphenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine

first step

((1-(benzofuran-2-ylsulfonyl)-5-(3-hydroxyphenyl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl ester

((1-(benzofuran-2-ylsulfonyl)-5-bromo-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl ester 2b (300 mg, 0.64 Methyl), 3-hydroxyphenylboronic acid 4a (97 mg, 0.71 mmol) and sodium carbonate (188 mg, 0.96 mmol) were sequentially added to 12 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 (44 mg, 0.06 mmol) was added thereto, and the mixture was heated to 100 ° C, and the reaction was stirred for 2 hours. 60 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, Product ((1-(benzofuran-2-ylsulfonyl)-5-(3-hydroxyphenyl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl Ester 4b (160 mg, pale yellow oil), yield: 51.8%.

MS m/z (ESI): 427.2 [M-55]

Second step

((1-(benzofuran-2-ylsulfonyl)-5-(3-methoxyphenyl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid third Butyl ester

((1-(benzofuran-2-ylsulfonyl)-5-(3-hydroxyphenyl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl The ester 4b (80 mg, 0.17 mmol) was added to 5 mL of N,N -dimethylformamide, cooled in ice-bath, and sodium hydride (12 mg, 0.25 mmol) was added portionwise, and the reaction was stirred for 30 minutes. Methyl iodide (36 mg, 0.25 mmol) was added to the reaction mixture, and the mixture was added, and 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 a saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated The resulting residue was purified to give the title product ((1-(benzofuran-2-ylsulfonyl)-5-(3-methoxyphenyl)-1 H -pyrrol-3-yl). Methyl) (meth) carbamic acid tert-butyl ester 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)-1 H -pyrrol-3-yl) -N -methylmethylamine

((1-(benzofuran-2-ylsulfonyl)-5-(3-methoxyphenyl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid Tributyl ester 4c (37 mg, 0.07 mmol) was added to 5 mL of a mixed solvent of dichloromethane and trifluoroacetic acid (V/V = 4:1), and the reaction was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc (3 mL), EtOAc (EtOAc) The title product 1-(1-(benzofuran-2-ylsulfonyl)-5-(3-methoxyphenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine 4 was obtained. (12 mg, pale yellow oil), yield: 40.0%.

MS m/z (ESI): 397.2 [M+1]

_{^{1 H NMR (400MHz, CDCl 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

1-(1-(benzofuran-2-ylsulfonyl)-5-(3-(cyclopropylmethoxy)phenyl)-1 H -pyrrol-3-yl) -N -methylmethyl amine

first step

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

Under the protection of an argon atmosphere, ((1-(benzofuran-2-ylsulfonyl)-5-(3-hydroxyphenyl)-1 H -pyrrol-3-yl)methyl)(methyl) Tributyl carbamic acid 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 The mixture was heated to 60 ° C and stirred for 5 hours. 50 mL of ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated sodium chloride aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the obtained residue Product ((1-(benzofuran-2-ylsulfonyl)-5-(3-(cyclopropylmethoxy)phenyl)-1 H -pyrrol-3-yl)methyl) (methyl) ) butyl butyl carbamate 5b (45 mg, pale yellow solid), yield: 50.6%.

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

Second step

1-(1-(benzofuran-2-ylsulfonyl)-5-(3-(cyclopropylmethoxy)phenyl)-1 H -pyrrol-3-yl) -N -methylmethyl amine

((1-(Benzofuran-2-ylsulfonyl)-5-(3-(cyclopropylmethoxy)phenyl)-1 H -pyrrol-3-yl)methyl)) The tert-butyl carbazate 5b (45 mg, 0.08 mmol) was added to 5 mL of a mixed solvent 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 evaporated, and then evaporated and evaporated. to give the title product l- (l- (benzofuran-2-yl sulfo acyl) -5- (3- (cyclopropylmethoxy) phenyl) -1 H - pyrrol-3-yl) - N - Methylmethylamine 5 (14 mg, pale yellow solid), yield: 37.8%.

MS m/z (ESI): 437.5 [M+1]

_{^{1 H NMR (400MHz, CDCl 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

1-(1-(benzofuran-2-ylsulfonyl)-5-(4-chlorophenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine

first step

((1-(benzofuran-2-ylsulfonyl)-5-(4-chlorophenyl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl ester

((1-(benzofuran-2-ylsulfonyl)-5-bromo-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl ester 2b (100 mg, 0.21) Methyl) 4-chlorobenzeneboronic acid 6a (34 mg, 0.23 mmol) and sodium carbonate (34 mg, 0.32 mmol) were added to a mixture of 6 mL of 1,4-dioxane and water (V/V = 5:1). After the addition, the mixture was stirred well, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol) was further 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 solution, and the mixture was washed with a saturated sodium chloride aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the obtained residue Product ((1-(benzofuran-2-ylsulfonyl)-5-(4-chlorophenyl)-1 H -pyrrol-3-yl)methyl)(methyl)carbamic acid tert-butyl Ester 6b (43 mg, pale yellow solid), yield: 41.0%.

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

Second step

1-(1-(benzofuran-2-ylsulfonyl)-5-(4-chlorophenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine

((1-(benzofuran-2-ylsulfonyl)-5-(4-chlorophenyl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl The ester 6b (43 mg, 0.08 mmol) was added to 5 mL of a mixed solvent of dichloromethane and trifluoroacetic acid (V/V = 4:1), and the reaction was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc (3 mL), EtOAc (EtOAc) The title product 1-(1-(benzofuran-2-ylsulfonyl)-5-(4-chlorophenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine 6 (13 mg) , pale yellow oil), yield: 38.2%.

MS m/z (ESI): 401.2 [M+1]

_{^{1 H NMR (400MHz, CDCl 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-(1-(benzofuran-2-ylsulfonyl)-5-(2,3-dihydrobenzofuran-5-yl)-1 H -pyrrol-3-yl) -N -methyl Methylamine

first step

((1-(benzofuran-2-ylsulfonyl)-5-(2,3-dihydrobenzofuran-5-yl)-1 H -pyrrol-3-yl)methyl) (methyl ) tert-butyl carbamic acid

((1-(benzofuran-2-ylsulfonyl)-5-bromo-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl ester 2b (150 mg, 0.32 Methyl), 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 the mixed solvent, after the addition, stirring was uniform, and then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (23 mg, 0.03 mmol) was added. Heat to 100 ° C and stir the reaction for 2 hours. 50 mL of ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated sodium chloride aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the obtained residue Product ((1-(benzofuran-2-ylsulfonyl)-5-(2,3-dihydrobenzofuran-5-yl)-1 H -pyrrol-3-yl)methyl) (A Tert-butyl carbamic acid tert-butyl ester 7b (83 mg, pale yellow oil), yield: 51.2%.

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

Second step

1-(1-(benzofuran-2-ylsulfonyl)-5-(2,3-dihydrobenzofuran-5-yl)-1 H -pyrrol-3-yl) -N -methyl Methylamine

((1-(benzofuran-2-ylsulfonyl)-5-(2,3-dihydrobenzofuran-5-yl)-1 H -pyrrol-3-yl)methyl) (a The tert-butyl 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. After the reaction mixture was concentrated under reduced pressure, 2 mL aqueous ammonia and 50 mL of methylene chloride was added, and the mixture was stirred, and the mixture was allowed to stand. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The title product 1-(1-(benzofuran-2-ylsulfonyl)-5-(2,3-dihydrobenzofuran-5-yl)-1 H -pyrrol-3-yl) -N was obtained. Methylmethylamine 7 (36 mg, light yellow oil), yield: 53.7%.

MS m/z (ESI): 409.3 [M+1]

_{^{1 H NMR (400MHz, CDCl 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,1H), 6.96-6.98 (m, 2H), 6.67-6.69 (m, 1H), 6.17-6.18 (m, 1H), 4.58 (t, J = 8.8 Hz, 2H), 3.65 (s, 2H) , 3.07 (t, J = 8.8 Hz, 2H), 2.48 (s, 3H)

Example 8

1-(1-(benzofuran-2-ylsulfonyl)-5-(3-chlorophenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine

first step

((1-(benzofuran-2-ylsulfonyl)-5-(3-chlorophenyl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl ester

((1-(benzofuran-2-ylsulfonyl)-5-bromo-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl ester 2b (100 mg, 0.21) Methyl), 3-chlorophenylboronic acid 8a (34 mg, 0.23 mmol) and sodium carbonate (34 mg, 0.32 mmol) were added sequentially to 6 mL of 1,4-dioxane and water (V/V=5:1) mixed 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. 40 mL of ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated sodium chloride aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Product ((1-(benzofuran-2-ylsulfonyl)-5-(3-chlorophenyl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl Ester 8b (51 mg, pale yellow solid), yield: 48.6%.

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

Second step

1-(1-(benzofuran-2-ylsulfonyl)-5-(3-chlorophenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine

((1-(benzofuran-2-ylsulfonyl)-5-(3-chlorophenyl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl The ester 8b (51 mg, 0.10 mmol) was added to 5 mL of a mixed solvent 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 evaporated, and then evaporated and evaporated. The title product 1-(1-(benzofuran-2-ylsulfonyl)-5-(3-chlorophenyl)-1 H -pyrrol-3-yl) -N -methylmethylamine 8 (15 mg) , pale yellow oil), yield: 36.6%.

MS m/z (ESI): 401.2 [M+1]

_{^{1 H NMR (400MHz, CDCl 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-(1-(benzofuran-2-ylsulfonyl)-5-(pyridin-3-yl)-1 H -pyrrol-3-yl) -N -methylmethylamine

first step

((1-(benzofuran-2-ylsulfonyl)-5-(pyridin-3-yl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl ester

((1-(benzofuran-2-ylsulfonyl)-5-bromo-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl ester 2b (100 mg, 0.21) Methyl), pyridine-3-boronic acid 9a (29 mg, 0.23 mmol) and sodium carbonate (34 mg, 0.32 mmol) were added sequentially to 6 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 (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 solution, and the mixture was washed with a saturated sodium chloride aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the obtained residue Product ((1-(benzofuran-2-ylsulfonyl)-5-(pyridin-3-yl)-1 H -pyrrol-3-yl)methyl)(methyl)carbamic acid tert-butyl Ester 9b (43 mg, pale yellow solid), yield: 43.0%.

MS m/z (ESI): 468.2 [M+1]

Second step

1-(1-(benzofuran-2-ylsulfonyl)-5-(pyridin-3-yl)-1 H -pyrrol-3-yl) -N -methylmethylamine

((1-(benzofuran-2-ylsulfonyl)-5-(pyridin-3-yl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl The ester 9b (43 mg, 0.09 mmol) was added to a mixed solvent of 2.5 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 2 mL aqueous ammonia and 30 mL of methylene chloride was added, and the mixture was stirred, and the mixture was allowed to stand. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The title product 1-(1-(benzofuran-2-ylsulfonyl)-5-(pyridin-3-yl)-1 H -pyrrol-3-yl) -N -methylmethylamine 9 (12 mg) was obtained. , pale yellow oil), yield: 35.3%.

MS m/z (ESI): 368.2 [M+1]

_{^{1 H NMR (400MHz, CDCl 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-(1-(benzofuran-2-ylsulfonyl)-5-(pyridin-4-yl)-1 H -pyrrol-3-yl) -N -methylmethylamine

first step

((1-(benzofuran-2-ylsulfonyl)-5-(pyridin-4-yl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl ester

((1-(benzofuran-2-ylsulfonyl)-5-bromo-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl ester 2b (100 mg, 0.21) Methyl), pyridine-4-boronic acid 10a (29 mg, 0.23 mmol) and sodium carbonate (34 mg, 0.32 mmol) were added sequentially to 6 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 (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 solution, and the mixture was washed with a saturated sodium chloride aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the obtained residue Product ((1-(benzofuran-2-ylsulfonyl)-5-(pyridin-4-yl)-1 H -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+1]

Second step

1-(1-(benzofuran-2-ylsulfonyl)-5-(pyridin-4-yl)-1 H -pyrrol-3-yl) -N -methylmethylamine

((1-(benzofuran-2-ylsulfonyl)-5-(pyridin-4-yl)-1 H -pyrrol-3-yl)methyl)(methyl)aminocarbamic acid tert-butyl The ester 10b (51 mg, 0.11 mmol) was added to 5 mL of a mixed solvent 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 5 mL of aqueous ammonia and 40 mL of methylene chloride was added, and the mixture was stirred, and the mixture was allowed to stand. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The title product 1-(1-(benzofuran-2-ylsulfonyl)-5-(pyridin-4-yl)-1 H -pyrrol-3-yl) -N -methylmethylamine 10 (17 mg) was obtained. , pale yellow oil), yield: 42.5%.

MS m/z (ESI): 368.3 [M+1]

_{^{1 H NMR (400MHz, CDCl 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 case:

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 ⁺ -ATPase) (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 with 100% DMSO to a suitable concentration: 10000, 1000, 100, 10, 1, 0.1 nM; 2. Buffer 1: 50 mmol/L HEPEs-Tris, 5 mmol/L magnesium chloride, pH 6.5; 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 mixed at a ratio of 100:25:2; 6. Porcine 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 3 mol/L concentrated brine for 1-2 minutes, and then wiped dry. The gastric mucosa was separated, chopped, 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 with 300 ml) The slurry was centrifuged at 20000G for 30 minutes to remove the precipitate; the supernatant was centrifuged at 100000G for 90 minutes to take a precipitate; the precipitate was suspended in a 0.25 mol/L sucrose solution and 0.25 mol/L sucrose was added at the bottom to add 7.5% polysucrose, 100000 G for centrifugation. 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 ul of gastric mucosal microsomes (H ⁺ /K ⁺ -ATPase) was added to 79 ul of buffer 2, 1 ul of the compound solution was added, and then 10 ul of 2 mM ATP was added to initiate the reaction. The reaction was carried out at 37 ° C for 30 minutes. The reaction was stopped by adding 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 potassium chloride reaction as a background, was subtracted when calculating the enzyme activity.

IC ₅₀ values for compounds may be obtained by calculating the inhibition rate at different concentrations.

Third, the experimental results: IC ₅₀ value of the compound

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

Claims (25)

a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof Salt, Wherein: 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(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC Substituting (O) a substituent of R ⁶ or -C(O)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, the ring group An alkyl group, a heterocyclic group, an aryl group or a heteroaryl group is further optionally one or more selected from the group consisting of halogen, cyano, hydroxy, amine, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl ,heterocyclyl, aryl,heteroaryl, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC(O) Substituted by a substituent of R ⁶ or -C(O)OR ⁶ ; R ^{3 is} selected from a hydrogen atom or an alkyl group; and 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 alkane Alkoxy, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently desired The step is one or more selected from the group consisting of halogen, nitro, cyano, hydroxy, amine, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC(O)R ⁶ or -C(O)OR ⁶ Substituted; 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, the alkoxy group, the cycloalkyl group, The heterocyclic group, the aryl group or the heteroaryl group are each independently further optionally one or more selected from the group consisting of halogen, cyano, hydroxy, amine, pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy. Substituted with a substituent of a cycloalkyl, heterocyclic, aryl, heteroaryl, carboxy or carboxylate group; R ⁷ or R ⁸ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic ring a aryl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently further optionally one or more selected from the group consisting of halogen, cyano, hydroxy, and amine groups, as needed. , pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, Substituted alkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate group substituted with a group; and m is 0, 1 or 2. a compound of the formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a compound represented by the formula (1). a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is an alkyl group. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof as described in claim 1 or 2 of the patent application. 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 or a non-pair thereof, as described in any one of claims 1 to 3; a conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof, as described in any one of claims 1 to 4; Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom. A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof according to any one of claims 1 to 5; a conjugate, 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 further optionally selected from one or more selected from halogen or Substituted by a substituent of -OR ⁶ wherein R ⁶ is an alkyl group which is further substituted by one or more substituents selected from cycloalkyl as desired. The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof, as described in any one of claims 1 to 6 a conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is an aryl group which is further optionally substituted by one or more substituents selected from halogen or -OR ⁶ , R ⁶ is an alkyl group which is further substituted by one or more substituents selected from a cycloalkyl group as needed. The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof, as described in any one of claims 1 to 6 a conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is heteroaryl. A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof, as described in any one of claims 1 to 8. Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is: a compound of the formula (IA) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof Salt, Wherein: 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(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC Substituting (O) a substituent of R ⁶ or -C(O)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, the ring group An alkyl group, a heterocyclic group, an aryl group or a heteroaryl group is further optionally one or more selected from the group consisting of halogen, cyano, hydroxy, amine, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl ,heterocyclyl, aryl,heteroaryl, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC(O) Substituting R ⁶ or -C(O)OR ⁶ ; R ⁴ or R ⁵ are each independently selected from the group consisting of 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 the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently further selected from one or more as needed , Nitro, cyano, hydroxy, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁷ R ^8, -C Substituting (O) NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC(O)R ⁶ or -C(O)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 group, aryl group or hetero group The aryl groups are each independently further optionally selected from one or more selected from the group consisting of halogen, cyano, hydroxy, amine, pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl. Substituted with a substituent of an aryl, heteroaryl, carboxy or 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, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently further optionally one or more selected from the group consisting of halogen, cyano, hydroxy, amine, pendant oxy, alkyl, Haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic, aryl Aryl, heteroaryl, carboxyl or carboxylate group substituents; the PG is an amino protecting group; and m is 0, 1 or 2. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a compound represented by the formula (I) described in claim 1 Or a method of the mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: 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 amine protecting group; and R ¹ to R ⁵ are as defined in the first item of the patent application. The method of claim 11, wherein R ³ is a hydrogen atom. 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 form thereof Salt, Wherein: 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(O)NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC Substituting (O) R ⁶ or -C(O)OR ⁶ substituent; R ⁴ or R ⁵ are each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, a hydroxyl group, an alkyl group, an alkoxy group, and a ring. An alkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently further selected from one or more as needed Halogen, nitro, cyano, hydroxy, amine, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁷ R ⁸ , -C Substituting (O) NR ⁷ R ⁸ , -S(O) _m R ⁶ , -C(O)R ⁶ , -OC(O)R ⁶ or -C(O)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 group, aryl group or The aryl groups are each independently further optionally selected from one or more selected from the group consisting of halogen, cyano, hydroxy, amine, pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl. Substituted with a substituent of an aryl, heteroaryl, carboxy or 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, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently further optionally one or more selected from the group consisting of halogen, cyano, hydroxy, amine, pendant oxy, alkyl, Substituted by a substituent of a haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate group; and m is 0, 1 or 2. A compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or A method of the mixture, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: The compound of the formula (IB) is reacted with an amine compound to give a compound of the formula (I); wherein: R ¹ to R ⁵ are as defined in the first item of the patent application. A pharmaceutical composition comprising a compound represented by the formula (I) or a tautomer thereof, a mesogen, or a therapeutically effective amount thereof according to any one of claims 1 to 9 The racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof according to any one of claims 1 to 9 The use of the conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a gastric acid secretion inhibitor. A use of the pharmaceutical composition according to claim 15 for the preparation of a gastric acid secretion inhibitor. A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof according to any one of claims 1 to 9 The use of the conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for the preparation of an H ⁺ /K ⁺ -ATPase inhibitor. A use of the pharmaceutical composition according to claim 15 for the preparation of an H ⁺ /K ⁺ -ATPase inhibitor. A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof according to any one of claims 1 to 9 The use of a conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a potassium ion competitive acid blocker. A use of the pharmaceutical composition according to claim 15 for the preparation of a potassium ion competitive acid retarder. A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof according to any one of claims 1 to 9 Use of the present invention, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of peptic ulcer, Zhuo-Ai 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 hyperacidity or ulceration caused by post-operative stress a drug; or a drug for inhibiting upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress. The use of the pharmaceutical composition according to claim 15 for the treatment or prevention of peptic ulcer, Zhuo-Ai 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 drugs caused by hyperacidity or ulceration after surgery; or A medicament for inhibiting upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress is prepared. The use according to claim 22, wherein the peptic ulcer is selected from the group consisting of a gastric ulcer, a duodenal ulcer or an anastomotic ulcer; the symptomatic gastroesophageal reflux disease is selected from a non-erosive reflux disease or a stomach without esophagitis. Esophageal reflux disease. The use according to claim 23, wherein the peptic ulcer is selected from the group consisting of a gastric ulcer, a duodenal ulcer or an anastomotic ulcer; the symptomatic gastroesophageal reflux disease is selected from a non-erosive reflux disease or a stomach without esophagitis. Esophageal reflux disease.