CN114105962A

CN114105962A - Compound containing sulfonamide structure, preparation method and application thereof, and pharmaceutical composition and application thereof

Info

Publication number: CN114105962A
Application number: CN202111248634.5A
Authority: CN
Inventors: 黄伟; 杨光富; 陈涛; 赵树立; 龚溢; 王明书
Original assignee: Nanjing Shuohui Pharmaceutical Technology Co ltd
Current assignee: Nanjing Shuohui Pharmaceutical Technology Co ltd
Priority date: 2021-10-26
Filing date: 2021-10-26
Publication date: 2022-03-01

Abstract

The invention relates to the field of medicaments, and discloses a compound containing a sulfonamide structure, a preparation method and application thereof, a pharmaceutical composition and application thereofThe compounds provided are useful as therapeutic agents, particularly as inhibitors of gastric acid secretion and potassium ion competitive acid blockers (P-CABs).

Description

Compound containing sulfonamide structure, preparation method and application thereof, and pharmaceutical composition and application thereof

Technical Field

The invention relates to the field of medicines, and particularly relates to a compound containing a sulfonamide structure, a preparation method and application thereof, and a pharmaceutical composition and application thereof.

Background

Proton Pump Inhibitors (PPIs), represented by omeprazole, strongly and persistently inhibit gastric acid secretion by inhibiting H +/K + -atpase on gastric parietal cells, and PPIs are widely used for treating acid-related diseases such as gastroesophageal reflux disease, peptic ulcer, helicobacter pylori infection, upper gastrointestinal bleeding, Zollinger-Ellison syndrome, and the like.

Since 1988, the long-term clinical application shows that PPI has the defects of instability, short half-life, influence by CYP2C19 gene polymorphism, limited administration time, slow effect and the like, and clinically needs an antacid medicament with quicker effect, stronger acid inhibition effect and longer pH maintenance time.

Potassium-Competitive Acid Blockers (P-CABs) Potassium-Competitive Acid Blockers (P-CABs) are a novel Acid-inhibitory drug that directly compete with K + for binding sites on H +/K + -ATPase in ionic form, while inhibiting H +/K + -ATPase in both resting and activated states, thereby effectively inhibiting gastric Acid secretion. Compared with the traditional proton pump inhibitor, the P-CABs have the characteristics of lipophilicity, alkalescence, high dissociation constant and stability under the condition of low pH.

Compared with a Proton Pump Inhibitor (PPI), the P-CAB is a lipophilic weak base, has quicker acid inhibition effect and lasting effect, and is not easy to generate the acid breakthrough phenomenon at night; and the P-CAB medicines have good stability, do not need to be prepared into an enteric-coated dosage form and are not influenced by gene polymorphism. .

However, the representative P-cab vonoprazan that has been marketed also presents a certain safety risk in clinical applications, such as hepatotoxicity and the like. Thus, although a series of potassium-competitive acid blockers have been disclosed, there is still a need to develop compounds with more abundant structural types, and new compounds that may have better tissue distribution and other drug-forming properties.

Disclosure of Invention

The object of the present invention is to overcome the aforementioned drawbacks of the prior art and to provide a new class of compounds having the efficacy of potassium-competitive acid blockers.

In order to achieve the above object, a first aspect of the present invention provides a compound having a sulfonamide structure, which has a structure represented by formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

in the formula (I), the compound represented by the formula (I),

x is CH₂Or CH (CH)₃)；

R¹Is H, substituted or unsubstituted C₁-C₄Alkyl of (C)₁-C₃Alkoxy of (a), a six-membered saturated heterocycloalkyl group containing 1-2 oxygen atoms, a substituted or unsubstituted six-membered saturated heterocycloalkyl group containing 1-2 nitrogen atoms, -C₁-C₄alkylene-O-C of₁-C₃Alkyl, substituted or unsubstituted C₃-C₆Saturated cycloalkyl groups of (A) a (B) a (C) a (C) b) a (C) a (C) b) a (C) a (C) a (C) and (C) a (C) a (C) a (C) a (C) a (C) a (C)₂-phenyl, 3-furyl containing at least two halogen substitutions; r¹Wherein the optional substituents are selected from halogen, hydroxy, C₁-C₃Alkyl of (C)₁-C₃At least one of aldehyde groups of (a);

R²is 3-pyridyl, substituted or unsubstituted phenyl; r²Optionally present inThe substituent is selected from halogen and C₁-C₆Alkyl of (C)₁-C₆Alkoxy of, -O-C₁-C₄alkylene-O-C of₁-C₃Alkyl of (2), C substituted by 1-6 halogens₁-C₃Alkyl of (2), C substituted by 1-6 halogens₁-C₃Alkoxy, cyano, -O-C₁-C₄alkylene-C of₃-C₆At least one of cycloalkyl groups of (a);

R³is C₁-C₃Alkyl groups of (a);

R⁴is H, C₁-C₃Alkoxy, halogen of (a);

R⁵and R⁶One of H and the other selected from F, C₁-C₃Alkyl group of (1).

The second aspect of the present invention provides a process for preparing a compound having a sulfonamide structure, which has a structure represented by formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

the method comprises the following steps: carrying out contact reaction on a compound shown as a formula (II) and a compound shown as a formula (III);

wherein, in formula (I), formula (II) and formula (III), the definitions of each group are the same as those described in the first aspect.

A third aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the first aspect or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

A fourth aspect of the present invention provides the use of a compound of the first aspect or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the third aspect, in the manufacture of a medicament for an H +/K + -ATPase inhibitor and/or in the manufacture of a medicament for a potassium ion competitive acid blocker.

A fifth aspect of the present invention provides the use of a compound as described in the first aspect or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the third aspect, in the manufacture of a medicament for the treatment or prevention of peptic ulcer, zollinger-ellison 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 ulcers resulting from post-operative stress.

The present invention provides the aforementioned compounds as therapeutic agents, particularly as gastric acid secretion inhibitors and potassium ion competitive acid blockers (P-CABs).

Detailed Description

The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.

Unless stated to the contrary, the following terms used herein have the following meanings.

“C₁-C₆The "alkyl group" of (a) means a saturated alkyl group comprising a straight chain of 1 to 6 carbon atomsOr a branched alkyl group. Such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. For "C₁-C₄The alkyl group "and the like have similar definitions, only in terms of the total number of carbon atoms, and the present invention will not be described in detail.

“C₁-C₆The "alkoxy group" of (a) means a saturated alkoxy group, including a straight or branched chain alkoxy group of 1 to 6 carbon atoms. Such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy, and the like. For "C₁-C₄Alkoxy group of (1), "" C₁-C₃The "alkoxy group" and the like have similar definitions, only in terms of the total number of carbon atoms, and the present invention will not be described in detail.

"six-membered saturated heterocycloalkyl group containing 1 to 2 oxygen atoms" means that 1 to 2 ring atoms in the six-membered saturated heterocycloalkyl group are oxygen atoms, for example, tetrahydropyranyl group, dioxane group and the like.

"substituted or unsubstituted C₃-C₆The "cycloalkyl group" of (a) means that the number of ring-forming atoms is 3 to 6, for example, 3, 4,5 or 6, and the ring-forming atoms are all C atoms, and any position in the cycloalkyl group which may be substituted by a group defined in the present invention.

"substituted or unsubstituted piperidinyl" means that any position in the piperidine ring that can be substituted with a group as defined herein.

“-O-C₁-C₄alkylene-O-C of₁-C₂By "alkyl" is meant that the group is attached to the parent nucleus structure through O and the terminal alkyl group is methyl or ethyl.

"C substituted by 1-3 halogens₁-C₃Alkyl of (2) means C₁-C₃Any substitutable position in the alkyl group of (a) is substituted with 1 to 3 halogens.

“-O-C₁-C₄alkylene-C of₃-C₆The "cycloalkyl group" means that the group is bonded to the parent structure through O and the terminal alkyl group is C₃-C₆A cycloalkyl group of (a).

"halogen" means fluorine, chlorine, bromine or iodine.

The invention "optionally present" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does or does not.

"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:

(1) salts with acids are obtained by reaction of the free base of the parent compound with inorganic acids including hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, and the like, or with organic acids including acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid, malonic acid, and the like.

(2) The acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or is complexed with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.

"pharmaceutical composition" refers to the combination of one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, with another chemical ingredient, such as a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration process to an animal.

By "pharmaceutically acceptable carrier" is meant an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, such as, but not limited to: calcium carbonate, calcium phosphate, various sugars (e.g., lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic or methacrylic polymers, gelatin, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil or hydrogenated or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil, and the like.

As described above, the first aspect of the present invention provides a compound having a sulfonamide structure, which has a structure represented by formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

in the formula (I), the compound represented by the formula (I),

x is CH₂Or CH (CH)₃)；

R²is 3-pyridyl, substituted or unsubstituted phenyl; r²Wherein the optional substituents are selected from halogen, C₁-C₆Alkyl of (C)₁-C₆Alkoxy of, -O-C₁-C₄alkylene-O-C of₁-C₃Alkyl of (2), C substituted by 1-6 halogens₁-C₃Alkyl of (2), C substituted by 1-6 halogens₁-C₃Alkoxy, cyano, -O-C₁-C₄alkylene-C of₃-C₆At least one of cycloalkyl groups of (a);

R³is C₁-C₃Alkyl groups of (a);

R⁴is H, C₁-C₃Alkoxy, halogen of (a);

According to a preferred embodiment, in formula (I),

x is CH₂Or CH (CH)₃)；

R¹Is H, substituted or unsubstituted C₁-C₄Alkyl of (C)₁-C₃Alkoxy of (a), a six-membered saturated heterocycloalkyl group containing 1-2 oxygen atoms, a substituted or unsubstituted six-membered saturated heterocycloalkyl group containing 1-2 nitrogen atoms, -C₁-C₄alkylene-O-C of₁-C₃Alkyl, substituted or unsubstituted C₃-C₆Saturated cycloalkyl groups of (A) a (B) a (C) a (C) b) a (C) a (C) b) a (C) a (C) a (C) and (C) a (C) a (C) a (C) a (C) a (C) a (C)₂-phenyl, 3-furyl containing at least two halogen substitutions; r¹Wherein the optional substituents are selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, n-propyl, isopropyl, C₁-C₂At least one of aldehyde groups of (a);

R²is 3-pyridyl, substituted or unsubstituted phenyl; r²Wherein the optional substituents are selected from the group consisting of fluorine, chlorine, bromine, iodine, C₁-C₆Alkyl of (C)₁-C₆Alkoxy of, -O-C₁-C₄Alkylene group of (a)O-C₁-C₂Alkyl of (2), C substituted by 1-3 halogens₁-C₃Alkyl of (2), C substituted by 1-3 halogens₁-C₃Alkoxy, cyano, -O-C₁-C₄alkylene-C of₃-C₆At least one of cycloalkyl groups of (a);

R³is methyl, ethyl, n-propyl or isopropyl;

R⁴is H, methoxy, ethoxy, n-propoxy, isopropoxy, fluoro, chloro or bromo;

R⁵and R⁶One of which is H and the other is selected from F, methyl, ethyl, n-propyl, isopropyl.

According to another preferred embodiment, in formula (I),

x is CH₂Or CH (CH)₃)；

R¹Is H, substituted or unsubstituted C₁-C₄Alkyl of (C)₁-C₃Alkoxy of (a), a six-membered saturated heterocycloalkyl group containing 1-2 oxygen atoms, a substituted or unsubstituted six-membered saturated heterocycloalkyl group containing 1-2 nitrogen atoms, -C₁-C₄alkylene-O-C of₁-C₃Alkyl, substituted or unsubstituted C₃-C₆Saturated cycloalkyl groups of (A) a (B) a (C) a (C) b) a (C) a (C) b) a (C) a (C) a (C) and (C) a (C) a (C) a (C) a (C) a (C) a (C)₂-phenyl, 3-furyl containing at least two halogen substitutions; r¹Wherein the optional substituent is at least one of fluorine, chlorine, hydroxyl, methyl, ethyl, n-propyl, isopropyl and glyoxal;

R²is 3-pyridyl, substituted or unsubstituted phenyl; r²Wherein the optional substituents are selected from the group consisting of fluorine, chlorine, bromine, C₁-C₆Alkyl of (C)₁-C₆Alkoxy of, -O-C₁-C₄Alkylene of (A)radical-O-C₁-C₂Alkyl of (2), C substituted by 1-3 halogens₁-C₃Alkyl of (2), C substituted by 1-3 halogens₁-C₃Alkoxy, cyano, -O-C₁-C₄alkylene-C of₃-C₆At least one of cycloalkyl groups of (a);

R³is methyl or ethyl;

R⁴is H, methoxy or fluoro;

According to still another preferred embodiment, in formula (I),

x is CH₂Or CH (CH)₃)；

R¹Is H, methyl, isopropyl, tert-butyl, hydroxy-substituted tert-butyl, difluoromethyl, methoxy, dioxane, substituted or unsubstituted piperidinyl, -C₁-C₄alkylene-O-C of₁-C₃Alkyl, substituted or unsubstituted C₃-C₆Saturated cycloalkyl groups of (A) a (B) a (C) a (C) b) a (C) a (C) b) a (C) a (C) a (C) and (C) a (C) a (C) a (C) a (C) a (C) a (C)₂-phenyl, 3-furyl containing at least two halogen substitutions; r¹Wherein the optional substituent is at least one of fluorine, chlorine, hydroxyl, methyl, ethyl and aldehyde group;

R²is 3-pyridyl, substituted or unsubstituted phenyl; r²Wherein the optional substituents are selected from the group consisting of fluorine, chlorine, bromine, C₁-C₆Alkyl of (C)₁-C₆Alkoxy of, -O-C₁-C₄alkylene-O-C of₁-C₂Alkyl of (2), C substituted by 1-3 halogens₁-C₃Alkyl of (2), C substituted by 1-3 halogens₁-C₃Alkoxy, cyano of、-O-C₁-C₄alkylene-C of₃-C₆At least one of cycloalkyl groups of (a);

R³is methyl or ethyl;

R⁴is H, methoxy or fluoro;

According to a particularly preferred embodiment, the compound of formula (I) is selected from any one of compound 1 to compound 100.

The pharmaceutically acceptable salts of the structure of formula (I) of the present invention include, but are not limited to, the hydrochloride salt form.

The present invention does not require any particular method for preparing the compounds of the first aspect, and those skilled in the art can easily determine an appropriate preparation method by combining the features of the structural formulae provided by the present invention with the technical means known in the field of organic synthesis. Also, the examples of the present invention exemplify some of the methods for preparing specific compounds, and those skilled in the art can determine the specific methods for preparing the remaining compounds according to these exemplarily provided methods.

And, preferably, in order to obtain a compound having a higher yield and purity, the present invention provides the process described in the second aspect for preparing a compound having a sulfonamide structure, which has a structure represented by formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein, in formula (I), formula (II) and formula (III), the definitions of the respective groups are the same as those described in the first aspect.

According to a particularly preferred embodiment, the compounds according to the invention are obtained by a process as shown in the following synthetic schemes, the conditions of the substituents involved in the synthetic schemes being in accordance with the correspondence described hereinbefore.

The present invention is not particularly limited to the parameter conditions in the aforementioned synthetic routes, and those skilled in the art can perform the synthesis by using the parameters known in the art, and the synthesis parameter conditions of some specific compounds are exemplarily given hereinafter, and those skilled in the art should not be construed as limiting the present invention.

As mentioned above, the third aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the first aspect or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

The present invention does not particularly require pharmaceutically acceptable carriers, excipients or diluents, and may be various substances known in the art, and the present invention will not be described herein in detail, and those skilled in the art will not be construed as limiting the present invention.

The fourth aspect of the present invention provides the use of a compound referred to in the first aspect above, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition referred to in the third aspect, in the manufacture of a medicament for an H +/K + -ATPase inhibitor and/or in the manufacture of a medicament for a potassium ion competitive acid blocker.

A fifth aspect of the present invention provides the use of a compound according to the first aspect above, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect above, in the manufacture of a medicament for the treatment or prophylaxis of peptic ulcer, zollinger-ellison 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 ulcers resulting from post-operative stress.

Particularly preferably, the peptic ulcer includes at least one of gastric ulcer, duodenal ulcer and stomal ulcer; the symptomatic gastroesophageal reflux disease includes at least one of non-erosive reflux disease and non-esophagitis gastroesophageal reflux disease.

Preferably, the aforementioned pharmaceutical composition of the present invention and the aforementioned compound can be used for the preparation of a gastric acid secretion inhibitor.

Preferably, the present invention provides a method for inhibiting gastric acid secretion, which comprises administering to a patient in need thereof an effective amount of the aforementioned compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

Hereinbefore, in addition to pharmaceutically acceptable carriers, adjuvants commonly used in pharmacy may be included, such as: antibacterial agents, antifungal agents, antimicrobial agents, shelf-stable agents, hueing agents, solubilizing agents, thickening agents, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, sweeteners, pigments, flavors or combinations thereof, and the like.

The present invention will be described in detail below by way of examples. In the following examples, the raw materials used below are all common commercial products unless otherwise specified.

Preparation example 1: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 1

Step 1: preparation of 5-bromo-1H-pyrrole-3-carbaldehyde

Pyrrole-3-carbaldehyde (52.6mmol) and tetrahydrofuran (THF,100mL) were added to a two-necked round-bottomed flask and cooled to-78 ℃ in a low temperature magnetic stirrer, and bromosuccinimide (NBS,52.6mmol) dissolved in N, N-dimethylformamide (DMF,30mL) was added dropwise to the reaction system. After the dropwise addition, the reaction is continued for 1h, and the temperature is increased to-10 ℃ for continuous reaction for 1 h. TLC monitored the starting material reaction was complete. Ice water was added to the system, followed by extraction with ethyl acetate (200 mL. times.2), washing with saturated brine (150 mL. times.2), merging of the organic phases, drying over anhydrous sodium sulfate, concentration under reduced pressure to give a brown solid, washing with isopropyl ether, and suction filtration to give a white solid with a yield of 49.4%.

Step 2: preparation of tert-butyl ((5-bromo-1H-pyrrol-3-yl) methyl) (methyl) carbamate

5-bromo-1H-pyrrole-3-carbaldehyde (17.2mmol), 33 wt% methylamine in methanol (34.4mmol) and methanol (40mL) were added to a single-neck round-bottom flask and stirred at room temperature (25 ℃ C., same below) for 1H, and sodium borohydride (25.8mmol) was added portionwise in an ice bath and stirring continued for 1H. TLC monitored the starting material reaction was complete. Adding 50mL of water into the system, stirring for 10min, transferring the reaction system into a separating funnel in batches by using ethyl acetate (300mL), washing by using saturated saline (150mL multiplied by 3), drying by using anhydrous sodium sulfate, dissolving the product by using acetonitrile (30mL), dropwise adding di-tert-butyl dicarbonate (20.6mmol), stirring for 30min at room temperature, monitoring by TLC that the reaction of the raw material is completely carried out, transferring the reaction system into the separating funnel in batches by using ethyl acetate (300mL), washing by using the saturated saline (150mL multiplied by 3), drying by using the anhydrous sodium sulfate of an organic phase, concentrating under reduced pressure, mixing samples, purifying by column chromatography, concentrating under reduced pressure to obtain brown oily liquid, and obtaining the yield of 79.5%.

And step 3: preparation of tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate

60mL of ultra-dry tetrahydrofuran was charged in a single-neck round-bottom flask, cooled to 0 ℃, sodium hydride (47.2mmol) was added, tert-butyl ((5-bromo-1H-pyrrol-3-yl) methyl) (methyl) carbamate (13.5mmol) dissolved in 10mL of N, N-dimethylformamide was slowly added dropwise, stirring was carried out at 0 ℃ for 30min, and then 15-crown-5 (40.5mmol) was added dropwise, then pyridine-3-sulfonyl chloride (20.2mmol) is added dropwise, stirring is continued for 30min at 0 ℃ after the addition is finished, then stirring the mixture for 30min at room temperature, monitoring the complete reaction of the raw materials by TLC, pouring the system into ice water, extracting the mixture by ethyl acetate (200mL multiplied by 2), washing the mixture by saturated saline solution (150mL multiplied by 2), combining organic phases, drying the organic phases by anhydrous sodium sulfate, concentrating the organic phases under reduced pressure, and purifying the organic phases by column chromatography to obtain light yellow solid with the yield of 82.1 percent.

And 4, step 4: preparation of 3-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenol

To the reaction tube were added 4-bromo-3-fluoro-phenol (262mmol), pinacol diborate (314mmol), palladium tetrakistriphenylphosphine (13.1mmol), potassium acetate (524 mmol). After nitrogen gas was purged 3 times, 400mL of 1, 4-dioxane was added, and the mixture was stirred at 130 ℃ for 12 hours, and the completion of the reaction of the starting materials was monitored by TLC. Adding ice water into the system, extracting, drying the organic phase by anhydrous sodium sulfate, decompressing, concentrating and purifying by column chromatography to obtain white solid with the yield of 51.5 percent.

And 5: preparation of tert-butyl ((5- (2-fluoro-4-hydroxyphenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate (2.3mmol), 3-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (3.49mmol), tetrakistriphenylphosphine palladium (0.233mmol), sodium bicarbonate (6.96mmol), nitrogen gas was purged 3 times, DME (20mL), H under nitrogen protection, and the reaction tube was charged with tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate (3.49mmol), tetrakistriphenylphosphine palladium (0.233mmol), and sodium bicarbonate (6.96mmol)₂O (5mL), reacted at 100 ℃ for 2 h. TLC monitored the starting material reaction was complete. The reaction system was transferred to a separatory funnel with ethyl acetate (150mL), washed with saturated brine (100 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give a pale yellow solid with a yield of 69.8%.

Step 6: (S) -1- (5- (4- ((1, 4-dioxan-2-yl) methoxy) -2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine hydrochloride

The stirrer was set to 80 ℃ for preheating, and tert-butyl ((5- (2-fluoro-4-hydroxyphenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate (0.43mmol,1.0eq), triphenylphosphine (0.866mmol,2.0eq), (2S) -1, 4-dioxane-2-methanol (0.866mmol,2.0eq), and 10mL of toluene were added to a single-neck round-bottomed flask and dissolved by heating and stirring. Diisopropyl azodicarboxylate (0.866mmol,2.0eq) was added dropwise when the temperature rose to 80 ℃ and stirred for 30min at 80 ℃ with TLC monitoring of the completion of the starting material reaction. After directly concentrating the system under reduced pressure, 2mL of ethyl acetate solution of hydrogen chloride and 2mL of ethyl acetate were added, the mixture was stirred at room temperature for 12 hours, and the completion of the reaction of the starting materials was monitored by TLC. The hydrochloride salt of compound 1 was obtained by suction filtration in 50% yield as a yellow solid.

¹H NMR(600MHz,Methanol-d₄)δ8.88(d,J＝4.8Hz,1H),8.65(s,1H),8.07(d,J＝8.4Hz,1H),7.81(s,1H),7.75–7.69(m,1H),7.02(t,J＝8.4Hz,1H),6.79(d,J＝8.4Hz,1H),6.72(d,J＝11.4Hz,1H),6.42(s,1H),4.10(s,2H),4.08–4.01(m,2H),4.00–3.95(m,1H),3.92–3.88(m,1H),3.86–3.82(m,1H),3.81–3.71(m,2H),3.67–3.61(m,1H),3.58–3.53(m,1H),2.71(s,3H).

Preparation example 2: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 2

The preparation of this preparation is similar to that of preparation 1, except that:

replacing the (2S) -1, 4-dioxane-2-methanol of step 6) with an equimolar amount of cyclobutylmethanol gave the hydrochloride salt of compound 2 as a white solid in 24% yield from step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.87–8.83(m,1H),8.61(s,1H),8.01(d,J＝8.4Hz,1H),7.80(s,1H),7.68–7.63(m,1H),7.00(t,J＝8.4Hz,1H),6.76(d,J＝8.4Hz,1H),6.69–6.62(m,1H),6.40(d,J＝1.8Hz,1H),4.10(s,2H),4.00(d,J＝6.6Hz,2H),2.86–2.77(m,1H),2.72(s,3H),2.23–2.11(m,2H),2.08–1.89(m,4H).

Preparation example 3: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 3

replacing the (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of cyclopentylmethanol gave the hydrochloride salt of compound 3 as a white solid in 31% yield in one step in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.87(d,J＝4.8Hz,1H),8.63(s,1H),8.05(d,J＝8.4Hz,1H),7.81(d,J＝2.4Hz,1H),7.72–7.66(m,1H),7.00(t,J＝8.4Hz,1H),6.76(d,J＝8.4Hz,1H),6.67(d,J＝11.4Hz,1H),6.41(d,J＝1.8Hz,1H),4.10(s,2H),3.92(d,J＝6.6Hz,2H),2.72(s,3H),2.44–2.32(m,1H),1.92–1.83(m,2H),1.75–1.58(m,4H),1.47–1.35(m,2H).

Preparation example 4: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 4

The preparation of this preparation is similar to that of preparation 1, except that: (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of cyclohexylmethanol to give the hydrochloride salt of compound 4 as a white solid in a one-step yield of 35% in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.84(d,J＝5.4Hz,1H),8.60(s,1H),8.06–7.99(m,1H),7.76(d,J＝2.4Hz,1H),7.68–7.62(m,1H),6.97–6.90(m,1H),6.70(dd,J＝8.4,2.4Hz,1H),6.63–6.57(m,1H),6.36(d,J＝2.4Hz,1H),4.04(s,2H),3.78(d,J＝6.6Hz,2H),2.66(s,3H),1.88–1.62(m,6H),1.35–1.15(m,3H),1.12–0.98(m,2H).

Preparation example 5: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 5

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4, 4-difluoro-cyclohexanemethanol to give the hydrochloride salt of compound 5 as a white solid in 37% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.85(dd,J＝4.8,1.8Hz,1H),8.60(d,J＝2.4Hz,1H),8.00(dt,J＝8.4,1.8Hz,1H),7.79(d,J＝1.8Hz,1H),7.65(dd,J＝8.4,4.8Hz,1H),7.00(t,J＝8.4Hz,1H),6.76(dd,J＝8.4,2.4Hz,1H),6.68(dd,J＝11.4,2.4Hz,1H),6.40(d,J＝1.8Hz,1H),4.09(s,2H),3.91(d,J＝6.0Hz,2H),2.71(s,3H),2.15–2.05(m,2H),2.01–1.92(m,3H),1.91–1.75(m,2H),1.51–1.40(m,2H).

Preparation example 6:

this preparation serves to illustrate the synthesis of compound 6:

the preparation of this preparation is similar to that of preparation 1, except that: (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give compound 6 as a white solid in 34% yield in step 6).

¹H NMR(400MHz,DMSO-d₆)δ8.86(dd,J＝4.8,1.8Hz,1H),8.57(d,J＝2.4Hz,1H),7.88(dt,J＝8.4,1.8Hz,1H),7.61(dd,J＝8.4,4.8Hz,1H),7.45(d,J＝1.8Hz,1H),7.00(t,J＝8.4Hz,1H),6.85(dd,J＝12.0,2.4Hz,1H),6.78(dd,J＝8.4,2.4Hz,1H),6.30(d,J＝1.8Hz,1H),3.90(dd,J＝11.4,4.8Hz,4H),3.49(s,2H),2.24(s,3H),2.10–1.96(m,1H),1.75–1.63(m,2H),1.44–1.20(m,4H).

Preparation example 7: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 7

the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of tetrahydropyran-2-methanol to give the hydrochloride of compound 7 as a white solid in a one-step yield of 40% in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.89(dd,J＝4.8,1.8Hz,1H),8.65(d,J＝2.4Hz,1H),8.07(d,J＝8.4Hz,1H),7.81(d,J＝1.8Hz,1H),7.72(dd,J＝8.4,4.8Hz,1H),7.01(t,J＝8.4Hz,1H),6.79(dd,J＝8.4,2.54Hz,1H),6.70(dd,J＝11.4,2.4Hz,1H),6.42(d,J＝1.8Hz,1H),4.10(s,2H),4.04–3.97(m,3H),3.79–3.72(m,1H),3.58–3.50(m,1H),2.71(s,3H),1.96–1.88(m,1H),1.76–1.43(m,5H).

Preparation example 8: this preparation serves to illustrate the synthesis of the hydrochloride salt of compound 8:

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 8 as a white solid in 25% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.86(dd,J＝4.8,1.6Hz,1H),8.62(d,J＝2.4Hz,1H),8.04–7.98(m,1H),7.81(d,J＝1.8Hz,1H),7.65(dd,J＝8.4,4.8Hz,1H),7.01(t,J＝8.4Hz,1H),6.76(dd,J＝8.4,2.4Hz,1H),6.67(dd,J＝12.0,2.4Hz,1H),6.41(d,J＝1.8Hz,1H),4.35–4.29(m,1H),4.10(s,2H),4.01(dd,J＝11.8,4.2Hz,2H),3.50–3.40(m,2H),2.72(s,3H),1.92–1.80(m,2H),1.70–1.62(m,1H),1.58–1.42(m,2H),1.32(d,J＝6.0Hz,3H).

Preparation example 9: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 9

The preparation of this preparation is similar to that of preparation 1, except that: pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3, 5-difluorobenzenesulfonyl chloride as a yellow solid in a yield of 70%.

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3, 5-difluorobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 61% yield.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 9 as a white solid in 28% yield in one step in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.74(d,J＝11.4Hz,1H),7.38(t,J＝9.0Hz,1H),7.09–6.95(m,3H),6.75(d,J＝8.4Hz,1H),6.66(d,J＝11.4Hz,1H),6.40(s,1H),4.36–4.28(m,1H),4.09(s,2H),4.02–3.92(m,2H),3.50–3.38(m,2H),2.71(s,3H),1.92–1.79(m,2H),1.69–1.39(m,3H),1.30(d,J＝6.0Hz,3H).

Preparation example 10: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 10

pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-trifluoromethylbenzenesulfonyl chloride as a yellow solid in a yield of 70%.

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-trifluoromethylbenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 60% yield.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 10 as a white solid in 35% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.03(d,J＝7.8Hz,1H),7.89–7.72(m,3H),7.60(s,1H),6.99(t,J＝8.4Hz,1H),6.75(d,J＝8.4Hz,1H),6.64(d,J＝11.4Hz,1H),6.39(d,J＝2.4Hz,1H),4.35–4.29(m,1H),4.11(s,2H),4.05–3.99(m,2H),3.51–3.44(m,2H),2.72(s,3H),1.95–1.85(m,2H),1.71–1.65(m,1H),1.60–1.45(m,2H),1.33(d,J＝6.6Hz,3H).

Preparation example 11: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 11

pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-fluoro-4-methylbenzenesulfonyl chloride as a yellow solid in 73% yield.

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-fluoro-4-methylbenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 63% yield.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 11 as a white solid in 31% yield in one step in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.75(s,1H),7.40(t,J＝7.8Hz,1H),7.24(d,J＝8.4Hz,1H),7.06(d,J＝8.4Hz,1H),7.00(t,J＝8.4Hz,1H),6.75(d,J＝8.4Hz,1H),6.69–6.64(m,1H),6.38(s,1H),4.37–4.30(m,1H),4.10(s,2H),4.04–3.99(m,2H),3.47(t,J＝12.0Hz,2H),2.72(s,3H),2.34(s,3H),1.96–1.83(m,2H),1.71–1.63(m,1H),1.57–1.43(m,2H),1.33(d,J＝6.0Hz,3H).

Preparation example 12: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 12

pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 2, 5-difluorobenzenesulfonyl chloride as a yellow solid in a yield of 72%.

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (2, 5-difluorobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 61% yield.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 12 as a white solid in 40% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.76(s,1H),7.52–7.45(m,1H),7.35–7.28(m,1H),6.93(t,J＝8.4Hz,1H),6.89–6.84(m,1H),6.67(dd,J＝8.4,2.4Hz,1H),6.51(dd,J＝11.4,2.4Hz,1H),6.39(d,J＝2.4Hz,1H),4.28–4.20(m,1H),4.10(s,2H),3.97(dd,J＝11.4,4.2Hz,2H),3.46–3.34(m,2H),2.70(s,3H),1.88–1.77(m,2H),1.65–1.55(m,1H),1.54–1.36(m,2H),1.26(d,J＝6.0Hz,3H).

Preparation example 13: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 13

The preparation of this preparation is similar to that of preparation 1, except that: pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-cyanobenzenesulfonyl chloride as a yellow solid in 71% yield.

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-cyanobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 60% yield.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 13 as a white solid in 36% yield in one step in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.84(s,1H),8.59(s,1H),7.94(d,J＝6.6Hz,1H),7.79(s,1H),7.60(s,1H),6.97(d,J＝8.4Hz,1H),6.73(d,J＝7.2Hz,1H),6.62(d,J＝11.4Hz,1H),6.39(s,1H),4.33–4.24(m,1H),4.10(s,2H),2.71(s,3H),1.99–1.90(m,1H),1.85–1.76(m,3H),1.73–1.68(m,1H),1.66–1.56(m,1H),1.38–1.05(m,8H).

Preparation example 14: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 14

Step 1: preparation of 5-bromo-1- ((3-methoxyphenyl) sulfonyl) -1H-pyrrole-3-carbaldehyde

Adding pyrrole-3-formaldehyde (11.5mmol) into a single-neck round-bottom flask, dissolving in 25mL of ultra-dry tetrahydrofuran, cooling to 0 ℃, slowly adding sodium hydride (1.61g, 60% in kerosene, 40.0mmol), then dropwise adding 3-methoxybenzenesulfonyl chloride (17.2mmol), continuing stirring at 0 ℃ for 30min after the dropwise adding is finished, then stirring at room temperature for 30min, monitoring the completion of the reaction of the raw materials by TLC, pouring the system into ethyl acetate (200mL multiplied by 2) in ice water for extraction, washing with saturated saline (150 multiplied by 2), combining organic phases, drying with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and purifying by column chromatography to obtain a light yellow solid with the yield of 90.0%.

Step 2: preparation of 5-bromo-1- ((3-hydroxyphenyl) sulfonyl) -1H-pyrrole-3-carbaldehyde

A three-necked round bottom flask was charged with 5-bromo-1- ((3-methoxyphenyl) sulfonyl) -1H-pyrrole-3-carbaldehyde (10.3mmol) and ultra-dry dichloromethane (CH)₂Cl₂50mL) was placed in a low temperature magnetic stirrer and cooled to-78 deg.C, then BBr was added₃(51.7mmol) was added dropwise to the reaction system. After the dropwise addition, the mixture is transferred to an ice bath condition to be stirred for 30 min. TLC monitored the starting material reaction was complete. Adding ice water into the system, extracting with EA (200mL multiplied by 2), washing with saturated brine (150mL multiplied by 2), combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, mixing samples, purifying by column chromatography, and concentrating under reduced pressure to obtain yellow solid with the yield of 58.0%.

And step 3: preparation of tert-butyl ((5-bromo-1- ((3-hydroxyphenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate

To a single neck round bottom flask was added methylamine hydrochloride (15.2mmol) and methanol (CH)₃OH, 50mL) was placed in a low temperature magnetic stirrer and cooled to-40 deg.C, then 5-bromo-1- ((3-hydroxyphenyl) sulfonyl) -1H-pyrrole-3-carbaldehyde (15.1mmol) and sodium cyanoborohydride (52.5mmol) were added and the temperature was naturally raised to room temperature. TLC monitored the completion of the reaction of the starting material, the reaction system was transferred in portions to a separatory funnel with ethyl acetate (300mL), washed with saturated brine (150 mL. times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a brown yellow oil, the product was dissolved in acetonitrile (30mL), di-tert-butyl dicarbonate (17.3mmol) and sodium bicarbonate (42.8mmol) were added, and stirred overnight at 50 ℃ in an oil bath, TLC monitored the completion of the reaction of the starting material with ethyl acetate (300mL), the reaction system was transferred in portions to a separatory funnel with saturated brine (150 mL. times.3), dried over anhydrous sodium sulfate of the organic phase, concentrated under reduced pressure and stirred, purified by column chromatography, and concentrated under reduced pressure to give a brown oil with a yield of 44.0%.

And 4, step 4: preparation of tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate

The stirrer was set to 80 ℃ and preheated, and tert-butyl ((5-bromo-1- ((3-hydroxyphenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate (0.89mmol), triphenylphosphine (1.79mmol), ethylene glycol monomethyl ether (1.79mmol) and toluene (10 mL) were added to a single-neck round-bottom flask and dissolved by heating with stirring. Diisopropyl azodicarboxylate (1.79mmol) was added dropwise when the temperature rose to 80 deg.C, stirred at 80 deg.C for 10min and TLC monitored for completion of the starting material reaction. The system is directly decompressed and concentrated, dichloromethane with 2mL is loaded by a wet method, and the white solid is obtained by column chromatography purification, with the yield of 70.0%.

And 5: preparation of 3-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenol

Step 6: preparation of tert-butyl ((1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -5- (2-fluoro-4-hydroxyphenyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate

Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate (2.0mmol), 3-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenol (3.0mmol), tetrakistriphenylphosphine palladium (0.1mmol), sodium bicarbonate (6.10mmol), nitrogen purged 3 times, DME (20mL), H under nitrogen protection₂O (5mL), reacted at 100 ℃ for 2 h. TLC monitored the starting material reaction was complete. The reaction system was transferred to a separatory funnel with ethyl acetate (150mL), washed with saturated brine (100mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give a pale yellow solid in a yield of 69.3%.

And 7: 1- (5- (2-fluoro-4- (1- (tetrahydro-2H-pyran-4-yl) ethoxy) phenyl) -1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine-hydrochloride

The stirrer was set to 90 ℃ and preheated, and tert-butyl ((1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -5- (2-fluoro-4-hydroxyphenyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate (0.64mmol), triphenylphosphine (1.28mmol), 1- (tetrahydro-2H-pyran-4-yl) ethanol (1.12mmol) and toluene (10 mL) were added to the single-neck round-bottom flask and dissolved by heating and stirring. Diisopropyl azodicarboxylate (1.28mmol) was added dropwise when the temperature rose to 80 deg.C, stirred at 80 deg.C for 5min and TLC monitored for completion of the starting material reaction. Directly concentrating the system under reduced pressure to obtain a crude product, adding 2mL of ethyl acetate solution of hydrochloric acid and 2mL of ethyl acetate, stirring at room temperature for 12h, and monitoring the completion of the raw material reaction by TLC. The mixture was filtered by suction to give a yellow oil in 29% yield.

¹H NMR(600MHz,Methanol-d₄)δ7.69(s,1H),7.38(s,1H),7.25–7.18(m,1H),7.11–7.05(m,1H),6.92(d,J＝24.0Hz,2H),6.75–6.69(m,1H),6.66(d,J＝11.4Hz,1H),6.32(s,1H),4.34–4.26(m,1H),4.08–3.96(m,7H),3.72(s,2H),3.50–3.36(m,2H),2.66(s,3H),1.88–1.81(m,2H),1.69–1.60(m,1H),1.57–1.43(m,2H),1.30(s,5H).

Preparation example 15: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 15

pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-methoxybenzenesulfonyl chloride as a yellow solid in 69% yield.

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-methoxybenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 55% yield.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 15 as a gray solid in 45% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.72(s,1H),7.37(t,J＝8.4Hz,1H),7.17(d,J＝8.4Hz,1H),7.07(d,J＝7.8Hz,1H),6.93(t,J＝8.4Hz,1H),6.84(s,1H),6.69(d,J＝9.0Hz,1H),6.62(d,J＝11.4Hz,1H),6.33(s,1H),4.31–4.23(m,1H),4.06(s,2H),3.98(dd,J＝11.4,4.2Hz,2H),3.73(s,3H),3.47–3.38(m,2H),2.68(s,3H),1.90–1.78(m,2H),1.67–1.59(m,1H),1.55–1.39(m,2H),1.28(d,J＝6.0Hz,3H).

Preparation example 16: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 16

pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 2, 6-difluorobenzenesulfonyl chloride as a yellow solid in 67% yield.

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (2, 6-difluorobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 63% yield.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 16 as a white solid in 41% yield in one step in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.71–7.57(m,2H),6.95(t,J＝9.0Hz,2H),6.82(t,J＝8.4Hz,1H),6.55(d,J＝9.0Hz,1H),6.44(d,J＝11.4Hz,1H),6.31(s,1H),4.19–4.14(m,1H),4.03(s,2H),3.90(dd,J＝11.4,4.2Hz,2H),3.34(dt,J＝15.6,7.8Hz,2H),2.63(s,3H),1.81–1.70(m,2H),1.57–1.50(m,1H),1.46–1.30(m,2H),1.18(d,J＝6.0Hz,3H).

Preparation example 17: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 17

The preparation of this preparation is similar to that of preparation 1, except that: pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 2, 4-difluorobenzenesulfonyl chloride as a yellow solid in 68% yield.

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (2, 4-difluorobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 65% yield.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 17 as a white solid in 42% yield in one step in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.92(s,1H),7.53–7.45(m,1H),7.42–7.34(m,1H),7.16–7.09(m,2H),6.86–6.81(m,1H),6.73–6.67(m,1H),6.57–6.53(m,1H),4.47–4.36(m,1H),4.27(s,2H),4.15(dd,J＝11.4,4.2Hz,2H),3.65–3.54(m,2H),2.87(s,3H),2.05–1.94(m,2H),1.82–1.76(m,1H),1.72–1.55(m,2H),1.44(d,J＝6.0Hz,3H).

Preparation example 18: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 18

pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 4-cyanobenzenesulfonyl chloride as a yellow solid in 66% yield.

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (4-cyanobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 63% yield.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 18 as a white solid in 43% yield in one step in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.02(d,J＝8.4Hz,2H),7.95–7.90(m,1H),7.79(d,J＝8.4Hz,2H),7.12(t,J＝8.4Hz,1H),6.89(dd,J＝8.4,2.4Hz,1H),6.81(dd,J＝12.0,2.4Hz,1H),6.55–6.51(m,1H),4.50–4.44(m,1H),4.24(s,2H),4.15(dd,J＝11.4,4.2Hz,2H),3.65–3.56(m,2H),2.86(s,3H),2.08–1.96(m,2H),1.82–1.77(m,1H),1.72–1.57(m,2H),1.46(d,J＝6.0Hz,3H).

Preparation example 19: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 19

pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-fluorobenzenesulfonyl chloride as a yellow solid in 68% yield.

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-fluorophenylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 61% yield.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 19 as a white solid in 48% yield in one step in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.75(d,J＝1.8Hz,1H),7.53(td,J＝8.14,5.4Hz,1H),7.44(td,J＝8.4,2.4Hz,1H),7.34(d,J＝7.8Hz,1H),7.12(dt,J＝8.4,2.4Hz,1H),6.97(t,J＝8.4Hz,1H),6.73(dd,J＝8.4,2.4Hz,1H),6.64(dd,J＝11.4,2.4Hz,1H),6.38(d,J＝2.4Hz,1H),4.33–4.26(m,1H),4.09(s,2H),3.99(dd,J＝11.4,4.2Hz,2H),3.48–3.37(m,2H),2.70(s,3H),1.91–1.81(m,2H),1.68–1.60(m,1H),1.56–1.42(m,2H),1.30(d,J＝6.0Hz,3H).

Preparation example 20: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 20

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1-cyclohexylethanol to give the hydrochloride of compound 20 as a white solid in 49% yield in one step in step 6).

Preparation example 21: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 21

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethylpiperidine to give the hydrochloride salt of compound 21 as a yellow solid in a one-step yield of 33% in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.79(d,J＝4.8Hz,1H),8.50(s,1H),7.96(d,J＝8.4Hz,1H),7.75(s,1H),7.63–7.54(m,2H),6.97(t,J＝8.4Hz,1H),6.74(d,J＝8.4Hz,1H),6.66(d,J＝11.4Hz,1H),6.36(s,1H),4.05(s,2H),3.93(d,J＝6.0Hz,2H),3.46–3.38(m,2H),3.09–2.99(m,2H),2.66(s,3H),2.20–2.12(m,1H),2.09–2.02(m,2H),1.70–1.52(m,2H).

Preparation example 22: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 22

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1-methyl-4-piperidinemethanol to give the hydrochloride salt of compound 22 as a gray solid in 40% yield in one step in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.83(d,J＝5.4Hz,1H),8.54(s,1H),7.98(d,J＝8.4Hz,1H),7.80(s,1H),7.62(s,1H),7.01(d,J＝8.4Hz,1H),6.79(d,J＝8.4Hz,1H),6.71(d,J＝11.2Hz,1H),6.41(d,J＝2.4Hz,1H),3.99(d,J＝5.4Hz,2H),3.63–3.56(m,2H),3.12–3.04(m,2H),2.90(s,2H),2.71(s,3H),2.20–2.12(m,2H),2.01(s,3H),1.77–1.66(m,2H),1.63–1.57(m,1H).

Preparation example 23:

this preparation serves to illustrate the synthesis of the hydrochloride salt of compound 23:

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (4- (hydroxymethyl) piperidin-1-yl) ethanone to give the hydrochloride salt of compound 23 as a white solid in 20% yield in step 6).

¹H NMR(400MHz,Methanol-d₄)δ8.81(dd,J＝4.8,1.8Hz,1H),8.54(d,J＝2.4Hz,1H),8.00–7.94(m,1H),7.77(d,J＝1.8Hz,1H),7.64–7.57(m,1H),6.97(t,J＝8.4Hz,1H),6.74(dd,J＝8.4,2.4Hz,1H),6.65(dd,J＝11.4,2.4Hz,1H),6.37(d,J＝1.8Hz,1H),4.55(d,J＝13.3Hz,1H),4.06(s,2H),3.99(d,J＝14.0Hz,1H),3.90(d,J＝6.2Hz,2H),3.19(t,J＝13.3Hz,1H),2.79–2.62(m,4H),2.14(s,3H),2.13–2.05(s,1H),2.02–1.84(m,2H),1.47–1.32(m,2H).

Preparation example 24: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 24

pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-fluorobenzenesulfonyl chloride as a yellow solid in 71% yield.

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-fluorophenylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 68% yield.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give the hydrochloride of compound 24 as a white solid in 45% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.74(d,J＝1.8Hz,1H),7.68(dd,J＝7.8,1.8Hz,1H),7.53–7.41(m,2H),7.30(d,J＝2.4Hz,1H),6.97(t,J＝8.4Hz,1H),6.76(dd,J＝8.4,2.4Hz,1H),6.66(dd,J＝11.4,2.4Hz,1H),6.36(d,J＝1.8Hz,1H),4.08(s,2H),3.99(dd,J＝11.4,4.2Hz,2H),,3.90(d,J＝6.6Hz,2H),3.48(td,J＝12.0,2.4Hz,2H),,2.70(s,3H),2.15–2.07(m,1H),1.84–1.72(m,2H),1.54–1.41(m,2H).

Preparation example 25: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 25

pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-chlorobenzenesulfonyl chloride as a yellow solid in a yield of 72%.

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-chlorobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 63% yield.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give the hydrochloride salt of compound 25 as a white solid in a one-step yield of 42% in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.74(d,J＝1.8Hz,1H),7.56–7.39(m,2H),7.32(d,J＝7.8Hz,1H),7.16–7.09(m,1H),7.00–6.93(m,1H),6.74(dd,J＝8.4,2.4Hz,1H),6.66(dd,J＝11.4,2.4Hz,1H),6.36(d,J＝1.8Hz,1H),4.08(s,2H),3.99(dd,J＝11.4,4.2Hz,2H),3.89(d,J＝6.6Hz,2H),3.48(td,J＝12.0,2.4Hz,2H),,2.70(s,3H),2.15–2.03(m,1H),1.82–1.71(m,2H),1.53–1.41(m,2H).

Preparation example 26: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 26

pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-fluoro-4-methylbenzenesulfonyl chloride as a yellow solid in a yield of 72%.

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-fluoro-4-methylbenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 65% yield.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give the hydrochloride of compound 26 as a white solid in 44% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.71(d,J＝1.8Hz,1H),7.37(t,J＝7.8Hz,1H),7.20(dd,J＝8.4,1.8Hz,1H),7.06(dd,J＝8.4,1.8Hz,1H),6.98(t,J＝8.4Hz,1H),6.74(dd,J＝8.4,2.4Hz,1H),6.67(dd,J＝11.4,2.4Hz,1H),6.34(d,J＝1.8Hz,1H),4.07(s,2H),4.02–3.96(m,2H),3.89(d,J＝6.6Hz,2H),3.48(td,J＝12.0,2.4Hz,2H),,2.69(s,3H),2.31(s,3H),2.15–2.06(m,1H),1.83–1.74(m,2H),1.54–1.41(m,2H).

Preparation example 27: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 27

pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3, 5-difluorobenzenesulfonyl chloride as a yellow solid in 71% yield.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give the hydrochloride salt of compound 27 as a white solid in 49% yield in one step in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.75(d,J＝1.8Hz,1H),7.43–7.34(m,1H),7.10–6.99(m,3H),6.77(dd,J＝8.4,2.4Hz,1H),6.68(dd,J＝11.4,2.4Hz,1H),6.40(d,J＝2.4Hz,1H),4.09(s,2H),3.99(dd,J＝11.4,4.2Hz,2H),3.90(d,J＝6.6Hz,2H),3.48(td,J＝12.0,1.8Hz,2H),2.71(s,3H),2.15–2.05(m,1H),1.83–1.74(m,2H),1.53–1.42(m,2H).

Preparation example 28: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 28

pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-cyanobenzenesulfonyl chloride as a yellow solid in a yield of 70%.

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-cyanobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 63% yield.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give the hydrochloride of compound 28 as a white solid in 51% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.02(d,J＝7.8Hz,1H),7.81–7.74(m,2H),7.69(t,J＝7.8Hz,1H),7.59(s,1H),6.98(t,J＝8.4Hz,1H),6.77(d,J＝8.4Hz,1H),6.66(d,J＝11.4Hz,1H),6.36(d,J＝1.8Hz,1H),4.08(s,2H),3.99(d,J＝11.4Hz,2H),3.92(d,J＝6.6Hz,2H),3.48(t,J＝12.0Hz,2H),2.70(s,3H),2.15–2.05(m,1H),1.82–1.74(m,2H),1.54–1.44(m,2H).

Preparation example 29: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 29

pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 4-cyanobenzenesulfonyl chloride as a yellow solid in 68% yield.

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (4-cyanobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 59% yield.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give the hydrochloride salt of compound 29 as a white solid in a one-step yield of 42% in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.91–7.84(m,2H),7.76(d,J＝1.8Hz,1H),7.65–7.60(m,2H),6.96(t,J＝8.4Hz,1H),6.74(dd,J＝8.4,2.4Hz,1H),6.67(dd,J＝11.4,2.4Hz,1H),6.37(d,J＝1.8Hz,1H),4.08(s,2H),3.99(dd,J＝11.4,4.2Hz,2H),3.89(d,J＝6.6Hz,2H),3.48(td,J＝12.0,2.4Hz,2H),2.70(s,2H),2.14–2.04(m,1H),1.83–1.73(m,2H),1.53–1.40(m,2H).

Preparation example 30: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 30

The preparation of this preparation is similar to that of preparation 14, except that:

replacing ethylene glycol methyl ether in the step 4) with 2-fluoroethanol with an equimolar amount, and obtaining yellow solid with the yield of 60%.

Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- ((3- (2-fluoroethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 60% yield.

Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of 4-hydroxymethyltetrahydropyran, giving compound 30 as the hydrochloride salt as a white solid in 43% yield in step 7).

¹H NMR(600MHz,Methanol-d₄)δ7.74(d,J＝1.8Hz,1H),7.40(t,J＝8.4Hz,1H),7.24(dd,J＝8.4,2.6Hz,1H),7.11(d,J＝8.4Hz,1H),6.94(t,J＝8.4Hz,1H),6.89(t,J＝2.4Hz,1H),6.72(dd,J＝8.4,2.4Hz,1H),6.65(dd,J＝11.4,2.4Hz,1H),6.34(d,J＝1.8Hz,1H),4.80–4.64(m,2H),4.22–4.11(m,2H),4.08(s,2H),4.03–3.95(m,2H),3.88(d,J＝6.0Hz,2H),3.53–3.44(m,2H),2.69(s,3H),2.17–2.02(m,1H),1.85–1.72(m,2H),1.54–1.39(m,2H).

Preparation example 31: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 31

ethylene glycol methyl ether in step 4) was replaced by an equimolar amount of n-pentanol, a yellow solid, yield 62%.

Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- ((3- (pentyloxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 62% yield.

Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of 4-hydroxymethyltetrahydropyran, giving compound 31 as the hydrochloride salt as a white solid in 20% yield in step 7).

¹H NMR(600MHz,Methanol-d₄)δ7.72(d,J＝1.8Hz,1H),7.37(t,J＝8.4Hz,1H),7.17(dd,J＝8.4,2.4Hz,1H),7.08(d,J＝7.8Hz,1H),6.96(t,J＝8.4Hz,1H),6.82(t,J＝2.4Hz,1H),6.72(dd,J＝8.4,2.4Hz,1H),6.66(dd,J＝11.4,2.4Hz,1H),6.32(d,J＝2.4Hz,1H),4.07(s,2H),4.00(dd,J＝12.0,4.2Hz,2H),3.91–3.81(m,4H),3.48(t,J＝12.0Hz,2H),2.69(s,3H),2.16–2.05(m,1H),1.83–1.71(m,4H),1.54–1.36(m,6H),0.96(t,J＝7.0Hz,3H).

Preparation example 32: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 32

replacing ethylene glycol methyl ether in step 4) with an equimolar amount of 3-methoxy-1-propanol as a yellow solid with a yield of 64%.

Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of 1- (5-bromo-1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine as a yellow solid in 64% yield.

Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of 4-hydroxymethyltetrahydropyran, giving compound 32 as the hydrochloride salt as a white solid in 25% yield in step 7).

¹H NMR(600MHz,Methanol-d₄)δ7.71(s,1H),7.38(t,J＝8.4Hz,1H),7.19(d,J＝8.4Hz,1H),7.09(d,J＝7.8Hz,1H),6.96(t,J＝8.4Hz,1H),6.87–6.81(m,1H),6.73(d,J＝8.4Hz,1H),6.68–6.61(m,1H),6.32(s,1H),4.07(s,2H),4.02–3.94(m,4H),3.89(d,J＝6.6Hz,2H),3.55(t,J＝6.0Hz,2H),3.49(t,J＝12.0Hz,2H),3.35(s,3H),2.69(s,3H)2.15–2.06(m,1H),2.04–1.96(m,2H),1.82–1.74(m,2H),1.53–1.43(m,2H).

Preparation example 33: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 33

ethylene glycol methyl ether in step 4) was replaced with an equimolar amount of cyclopropylmethanol as a yellow solid in 61% yield.

Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of 1- (5-bromo-1- ((3- (cyclobutylmethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methyl methylamine as a yellow solid in 62% yield.

Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 33 as a white solid in 34% yield in step 7).

¹H NMR(400MHz,Methanol-d₄)δ7.75(d,J＝1.8Hz,1H),7.39(t,J＝8.4Hz,1H),7.21(dd,J＝8.4,2.54z,1H),7.13–7.07(m,1H),6.97(t,J＝8.4Hz,1H),6.88(t,J＝2.4Hz,1H),6.73(dd,J＝8.4,2.4Hz,1H),6.67(dd,J＝11.4,2.4Hz,1H),6.36(d,J＝2.4Hz,1H),4.38–4.29(m,1H),4.10(s,2H),4.02(dd,J＝11.4,4.2Hz,2H),3.88(d,J＝6.6Hz,2H),3.53–3.40(m,2H),2.82–2.67(m,4H),2.20–2.10(m,2H),2.08–1.80(m,6H),1.70–1.62(m,1H),1.60–1.42(m,2H),1.33(d,J＝6.0Hz,3H).

Preparation example 34: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 34

ethylene glycol methyl ether in step 4) was replaced with an equimolar amount of cyclopentyl methanol as a yellow solid in 61% yield.

Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of 1- (5-bromo-1- ((3- (cyclopentylmethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methyl methylamine as a yellow solid in 62% yield.

Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of 4-hydroxymethyltetrahydropyran, giving compound 34 as the hydrochloride salt as a white solid in a one-step yield of 46% in step 7).

¹H NMR(400MHz,Methanol-d₄)δ7.72(d,J＝2.0Hz,1H),7.37(t,J＝8.4Hz,1H),7.17(dd,J＝8.4,2.4Hz,1H),7.09(dd,J＝7.6,1.6Hz,1H),6.96(t,J＝8.4Hz,1H),6.81(t,J＝2.4Hz,1H),6.72(dd,J＝8.4,2.4Hz,1H),6.66(dd,J＝11.4,2.4Hz,1H),6.33(d,J＝1.6Hz,1H),4.07(s,2H),3.99(dd,J＝11.4,4.2Hz,2H),3.88(d,J＝6.6Hz,2H),3.75(d,J＝6.6Hz,2H),3.48(td,J＝12.0,1.8Hz,2H),2.69(s,3H),2.38–2.25(m,1H),2.15–2.01(m,1H),1.91–1.74(m,4H),1.73–1.56(m,4H),1.54–1.41(m,2H),1.40–1.29(m,2H).

Preparation example 35: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 35

replacing ethylene glycol methyl ether in the step 4) with an equimolar amount of 2-fluoroethanol, a yellow solid, yield 62%.

Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of 1- (5-bromo-1- ((3- (2-fluoroethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine as a yellow solid in 61% yield.

Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of cyclohexylmethanol gave compound 35 as the hydrochloride salt as a white solid in 45% yield in step 7).

¹H NMR(600MHz,Methanol-d₄)δ7.73(d,J＝1.8Hz,1H),7.40(t,J＝8.4Hz,1H),7.24(dd,J＝8.4,2.4Hz,1H),7.10(d,J＝7.8Hz,1H),6.94(t,J＝8.4Hz,1H),6.89(t,J＝2.4Hz,1H),6.70(dd,J＝8.4,2.4Hz,1H),6.62(dd,J＝11.4,2.4Hz,1H),6.33(d,J＝1.8Hz,1H),4.80–4.62(m,2H),4.21–4.11(m,2H),4.08(s,2H),3.81(d,J＝6.6Hz,2H),2.69(s,3H),1.94–1.77(m,6H),1.41–1.21(m,4H),1.18–1.07(m,2H).

Preparation example 36: this preparation is illustrative of the procedure for the synthesis of hydrochloride salt of compound 36

ethylene glycol methyl ether in step 4) was replaced by an equimolar amount of n-pentanol, a yellow solid, yield 64%.

Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of 1- (5-bromo-1- ((3- (pentyloxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methyl methylamine as a yellow solid in 60% yield.

Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of cyclohexylmethanol gave compound 36 as the hydrochloride salt as a white solid in 19% yield in one step in step 7).

¹H NMR(600MHz,Methanol-d₄)δ7.73(d,J＝1.8Hz,1H),7.37(t,J＝7.8Hz,1H),7.17(dd,J＝8.4,2.4Hz,1H),7.09(d,J＝7.8Hz,1H),6.94(t,J＝8.4Hz,1H),6.80(t,J＝2.4Hz,1H),6.70(dd,J＝8.4,2.4Hz,1H),6.62(dd,J＝11.4,2.4Hz,1H),6.33(d,J＝1.8Hz,1H),4.08(s,2H),3.85(t,J＝6.6Hz,2H),3.81(d,J＝6.0Hz,2H),2.70(s,3H),1.94–1.86(m,2H),1.86–1.68(m,6H),1.50–1.20(m,7H),1.18–1.07(m,2H),0.97(t,J＝7.0Hz,3H).

Preparation example 37: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 37

ethylene glycol methyl ether in step 4) was replaced with an equimolar amount of 3-methoxy-1-propanol as a yellow solid with a yield of 61%.

Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of 1- (5-bromo-1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine as a yellow solid in 61% yield.

Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 37 as a white solid in 44% yield in step 7).

¹H NMR(400MHz,Methanol-d₄)δ7.73(d,J＝1.8Hz,1H),7.38(t,J＝8.4Hz,1H),7.19(dd,J＝8.4,2.4Hz,1H),7.12–7.07(m,1H),6.96(t,J＝8.4Hz,1H),6.87(t,J＝2.4Hz,1H),6.72(dd,J＝8.4,2.4Hz,1H),6.66(dd,J＝11.4,2.4Hz,1H),6.34(d,J＝1.8Hz,1H),4.36–4.27(m,1H),4.08(s,2H),4.04–3.94(m,4H),3.55(t,J＝6.0Hz,2H),3.50–3.41(m,2H),3.35(s,3H),2.70(s,3H),2.06–1.97(m,2H),1.93–1.82(m,2H),1.70–1.62(m,1H),1.59–1.41(m,2H),1.31(d,J＝6.0Hz,3H).

Preparation example 38: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 38

replacing ethylene glycol methyl ether in the step 4) with an equimolar amount of-methoxy-1-butanol as a yellow solid with a yield of 58%.

Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of 1- (5-bromo-1- ((3- (4-methoxybutoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine as a yellow solid in 61% yield.

Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 38 as a yellow solid in 20% yield in step 7).

¹H NMR(400MHz,Methanol-d₄)δ7.67(d,J＝1.8Hz,1H),7.35(t,J＝8.4Hz,1H),7.16(dd,J＝8.4,2.4Hz,1H),7.09–7.05(m,1H),6.94(t,J＝8.4Hz,1H),6.84(t,J＝2.4Hz,1H),6.69(dd,J＝8.4,2.4Hz,1H),6.63(dd,J＝11.4,2.4Hz,1H),6.31(d,J＝1.8Hz,1H),4.34–4.23(m,1H),4.04–3.95(m,4H),3.91(t,J＝6.0Hz,2H),3.48–3.41(m,4H),3.33(s,3H),2.62(s,3H),1.87–1.76(m,4H),1.75–1.67(m,2H),1.67–1.60(m,1H),1.56–1.41(m,4H),1.29(d,J＝6.0Hz,3H).

Preparation example 39: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 39

pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-trifluoromethylbenzenesulfonyl chloride as a yellow solid in 68% yield.

Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-trifluoromethylbenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 65% yield.

The (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give the hydrochloride of compound 39 as a white solid in 54% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.99(d,J＝7.8Hz,1H),7.86–7.68(m,3H),7.56(s,1H),6.97(t,J＝8.4Hz,1H),6.73(dd,J＝8.4,2.4Hz,1H),6.62(dd,J＝11.4,2.4Hz,1H),6.37(d,J＝1.8Hz,1H),4.09(s,2H),4.00(dd,J＝10.8,4.2Hz,2H),3.88(d,J＝6.6Hz,2H),3.49(td,J＝12.0,2.4Hz,2H),2.70(s,3H),2.15–2.05(m,1H),1.83–1.73(m,2H),1.53–1.42(m,2H).

Preparation example 40: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 40

the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of methanol to give the hydrochloride of compound 40 as a white solid in a one-step yield of 46% in step 6).

¹H NMR(600MHz,Methanol-d₄)δ9.01(d,J＝5.4Hz,1H),8.81(s,1H),8.35(d,J＝8.4Hz,1H),7.96(dd,J＝8.4,5.4Hz,1H),7.89–7.82(m,1H),7.04(t,J＝8.4Hz,1H),6.78(dd,J＝8.4,2.4Hz,1H),6.71(dd,J＝11.4,2.4Hz,1H),6.47(d,J＝1.8Hz,1H),4.12(s,2H),3.87(s,3H),2.72(s,3H).

Preparation example 41: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 41

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of ethanol to give the hydrochloride salt of compound 41 as a white solid in 53% yield in one step in step 6).

¹H NMR(600MHz,DMSO-d₆)δ8.86(s,1H),8.56(s,1H),7.86(d,J＝7.8Hz,1H),7.66–7.49(m,2H),7.04–6.93(m,1H),6.88–6.71(m,2H),6.34(s,1H),4.19–3.97(m,2H),3.61(s,2H),2.30(s,3H),1.30–1.22(m,3H).

Preparation example 42: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 42

the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2, 2-difluoroethanol to give the hydrochloride of compound 42 as a white solid in a one-step yield of 47% in step 6).

¹H NMR(600MHz,DMSO-d₆)δ8.86(d,J＝4.8Hz,1H),8.57(d,J＝2.4Hz,1H),7.87(d,J＝8.4Hz,1H),7.61(dd,J＝8.4,4.8Hz,1H),7.48(s,1H),7.04(t,J＝8.4Hz,1H),6.97(d,J＝11.4Hz,1H),6.86(dd,J＝8.4,2.4Hz,1H),6.43(t,J＝55.2Hz,1H),6.32(s,1H),4.46–4.35(m,2H),3.51(s,2H),2.24(s,3H).

Preparation example 43: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 43

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 3-methoxypropanol to give the hydrochloride salt of compound 43 as a yellow solid in 51% yield in step 6).

¹H NMR(600MHz,DMSO-d₆)δ8.86(d,J＝4.8Hz,1H),8.56(s,1H),7.87(d,J＝8.4Hz,1H),7.61(t,J＝6.6Hz,1H),7.45(s,1H),6.99(t,J＝8.4Hz,1H),6.83(d,J＝11.4Hz,1H),6.77(d,J＝8.4Hz,1H),6.30(s,1H),4.12–4.03(m,2H),3.49(d,J＝6.0Hz,4H),3.26(s,3H),2.24(s,3H),2.02–1.93(m,2H).

Preparation example 44: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 44

the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of isopropanol to give the hydrochloride salt of compound 44 as a white solid in 50% yield in one step in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.81(d,J＝4.8Hz,1H),8.55(s,1H),7.90(d,J＝8.4Hz,1H),7.78(s,1H),7.59–7.52(m,1H),6.99(t,J＝8.4Hz,1H),6.75(d,J＝8.4Hz,1H),6.65(d,J＝11.4Hz,1H),6.38(s,1H),4.09(s,2H),3.80(d,J＝6.6Hz,2H),2.71(s,3H),2.15–2.04(m,1H),1.06(dd,J＝6.7,2.4Hz,6H).

Preparation example 45: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 45

the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of neopentyl alcohol to give the hydrochloride salt of compound 45 as a white solid in one step yield of 38% in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.85(d,J＝4.8Hz,1H),8.65–8.58(m,1H),8.01(d,J＝8.4Hz,1H),7.79(s,1H),7.65(dd,J＝8.4,4.8Hz,1H),6.99(t,J＝8.4Hz,1H),6.77(d,J＝8.4Hz,1H),6.71–6.64(m,1H),6.44–6.35(m,1H),4.09(s,2H),3.69(s,2H),2.71(s,3H),1.07(s,9H).

Preparation example 46: this preparation is illustrative of the procedure for the synthesis of compound 46

the 33% methylamine methanol solution in step 2) was replaced with an equimolar amount of ethylamine methanol, a brown oily liquid, yield 70%.

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give compound 46 as a white solid in 48% yield in step 6).

¹H NMR(600MHz,Chloroform-d)δ8.75(dd,J＝4.8,1.8Hz,1H),8.60(d,J＝2.4Hz,1H),7.81–7.71(m,1H),7.47(s,1H),7.34(dd,J＝8.4,4.8Hz,1H),7.01(t,J＝8.4Hz,1H),6.65(dd,J＝8.4,2.4Hz,1H),6.55(dd,J＝11.4,2.4Hz,1H),6.30(d,J＝1.8Hz,1H),4.08–3.99(m,2H),3.81(d,J＝6.6Hz,2H),3.76(s,2H),3.52–3.41(m,3H),2.81–2.72(m,2H),2.13–2.04(m,1H),1.81–1.72(m,2H),1.53–1.42(m,2H),1.21(t,J＝7.2Hz,3H).

Preparation example 47: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 47

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 47 as a white solid in 38% yield in one step in step 6).

Preparation example 48: this preparation is illustrative of the procedure for the synthesis of Compound 48

Step 1: preparation of 4- (cyclopropylmethoxy) -2-fluorobenzaldehyde

A single neck round bottom flask was charged with 2-fluoro-4-hydroxybenzaldehyde (14.2mmol), (bromomethyl) cyclopropane (20.7mmol), potassium carbonate (42.7mmol), DMF (40mL), stirred overnight at 60 deg.C, TLC monitored the starting material reaction to completion. Purification by column chromatography gave 2.7g of a white oily liquid in 99% yield.

Step 2: preparation of N- ((4- (cyclopropylmethoxy) -2-fluorophenyl) (tosyl) methyl) carboxamide

A round bottom flask was charged with a reaction mixture of sodium 4-methylbenzenesulfonate (32.0mmol), (15) - (+) -10-camphorsulfonic acid (, 0.320mmol), 4- (cyclopropylmethoxy) -2-fluorobenzaldehyde (35.2mmol) and formamide (160mmol) which was solidified overnight at about 65 deg.C for about 16 h. The solids were broken down and suspended in methanol. The solid block was ground to a powder with a spatula, filtered and washed with methanol. The filter cake was dried under vacuum at about 60 ℃ to give a white powder with a yield of 79%.

And step 3: preparation of 4- (cyclopropylmethoxy) -2-fluoro-1- (isocyano (tosyl) methyl) benzene

Dissolving N- ((4- (cyclopropylmethoxy) -2-fluorophenyl) (tosyl) methyl) formamide (105.2mmol) with 500ml of anhydrous tetrahydrofuran, adding phosphorus oxychloride (210.4mmol) into a reaction bottle, reducing the temperature in an ice bath under the protection of nitrogen, dropwise adding triethylamine (631.1mmol) at the temperature of 0-10 ℃, and stirring for 60min after the addition in the ice bath. TLC detection, and after the raw material disappears, processing: quenched by dropping 500mL of water, extracted with MTBE (200 mL. times.3), combined organic phases, washed with 300mL of saturated brine X2, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent to give a yellow semisolid. 120mL of petroleum ether, 6mL of ethyl acetate were added. Stirring at room temperature for 30min, and filtering. And drying the product at room temperature. A pale yellow solid was obtained in a yield of 72%.

And 4, step 4: preparation of methyl 5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1H-pyrrole-3-carboxylate

NaH (67.5mmol), 250mL of diethyl ether, nitrogen protection, ice-bath cooling, 250mL of acetonitrile-dissolved 4- (cyclopropylmethoxy) -2-fluoro-1- (isocyano (tosyl) methyl) benzene (225.0mmol) and dimethyl 2- (methoxymethylene) malonate (13.5mmol) were added dropwise at-10 deg.C, after the addition, the temperature was raised to 40 deg.C and stirred for 48 h. After the reaction is finished, 500mL of water is added, 100mL of MTBE is used for extraction for three times, organic phases are combined, 300mL of saturated saline solution is used for washing, anhydrous sodium sulfate is used for drying, filtration and reduced pressure rotary evaporation are carried out to remove the solvent, an oily substance is obtained, 1.5 times of weight of 100-fold silica gel and 200-fold silica gel are added for mixing sample preparation and sand preparation, 4 times of weight of 200-fold silica gel and 300-fold silica gel are used for packing a column and column chromatography, a product point is collected, 50mL of n-heptane is added after reduced pressure concentration and drying, 2mL of ethyl acetate is used for pulping at room temperature for 1h, and yellow powdery solid is obtained through filtration, wherein the yield is 45%.

And 5: preparation of methyl 5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carboxylate

Adding 60mL of ultra-dry tetrahydrofuran into a single-neck round-bottom flask, cooling to 0 ℃, adding sodium hydride (60% in kerosene and 47.2mmol), slowly dropwise adding 5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1H-pyrrole-3-carboxylic acid methyl ester (13.5mmol) dissolved in 10mL of N, N-dimethylformamide, stirring at 0 ℃ for 30min, dropwise adding 15 crown 5(40.5mmol), dropwise adding pyridine-3-sulfonyl chloride (20.2mmol), continuously stirring at 0 ℃ for 30min after dropwise adding is finished, stirring at room temperature for 30min, detecting the completion of the reaction of raw materials by TLC, pouring the system into ethyl acetate (200mL multiplied by 2) in ice water for extraction, washing with saturated saline (150mL multiplied by 2), combining organic phases, drying with anhydrous sodium sulfate, concentrating the organic phases under reduced pressure, purifying by column chromatography to obtain a light yellow solid, the yield thereof was found to be 71.5%.

Step 6: preparation of (5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methanol

Methyl 5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carboxylate (60.8mmol) was dissolved in tetrahydrofuran. To the resulting solution was added diisobutylaluminum hydride (1.0M n-hexane solution) (182.2mmol) at 0 ℃ and then stirred at room temperature for 1 h. Water was added to the reaction mixture at 0 ℃ and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane ═ 1:4(v/v)) to obtain a yellow compound in a yield of 50%.

And 7: preparation of 5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde

(5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methanol (50.0mmol) was dissolved in dichloromethane. To the resulting solution was added pyridinium chlorochromate (150.0mmol), stirred at room temperature for 30min, and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a yellow compound in a yield of 63.5%.

And 8: preparation of 1- (5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine

5- (4- (Cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde (0.23mmol), methylamine (33 wt% in methanol, 2.3mmol), and methanol (3mL) were added to a single-neck round-bottom flask in an ice-water bath and stirred for 30 min. The ice bath was removed and the temperature was raised naturally to ambient temperature and stirred overnight. The next day sodium borohydride (1.2mmol) was added and the reaction was continued at room temperature (25 ℃ C.) for 3 h. TLC monitored the starting material reaction was complete. The system was added to ice water, extracted with dichloromethane (50mL × 4), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and purified by column chromatography to give a white solid with a one-step yield of 33%.

¹H NMR(600MHz,Methanol-d₄)δ8.89(d,J＝4.8Hz,1H),8.60(s,1H),8.07(d,J＝7.8Hz,1H),7.80–7.67(m,2H),7.02(t,J＝8.4Hz,1H),6.76(dd,J＝8.4,2.4Hz,1H),6.63(dd,J＝11.4,2.4Hz,1H),4.08(s,2H),3.88(d,J＝6.6Hz,2H),3.44(s,3H),2.72(s,3H),1.32–1.28(m,1H),0.69–0.61(m,2H),0.46–0.31(m,2H).

Preparation example 49: this preparation serves to illustrate the synthesis of the hydrochloride salt of compound 49:

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of (S) -glycidol to give the hydrochloride salt of compound 49 as a gray solid in 45% yield in step 6).

¹H NMR(400MHz,Methanol-d₄)δ8.82(d,J＝4.8Hz,1H),8.57(s,1H),7.92(d,J＝8.0Hz,1H),7.79(s,1H),7.59(dd,J＝8.4,4.8Hz,1H),7.02(t,J＝8.4Hz,1H),6.85–6.77(m,1H),6.72(dd,J＝11.6,2.4Hz,1H),6.40(d,J＝2.0Hz,1H),4.20–4.06(m,5H),3.82–3.75(m,1H),3.75–3.67(m,1H),2.71(s,3H).

Preparation example 50: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 50

replacement of (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of (R) -glycidol provided the hydrochloride salt of compound 50 as a grey solid in 46% yield in step 6).

¹H NMR(400MHz,Methanol-d₄)δ8.89(d,J＝5.2Hz,1H),8.67(s,1H),8.13–8.05(m,1H),7.82(d,J＝2.0Hz,1H),7.72(dd,J＝8.4,5.2Hz,1H),7.04(t,J＝8.4Hz,1H),6.82(dd,J＝8.4,2.4Hz,1H),6.74(dd,J＝11.2,2.4Hz,1H),6.43(d,J＝1.6Hz,1H),4.20–4.07(m,5H),3.78(dd,J＝11.2,4.8Hz,1H),3.71(dd,J＝11.2,5.2Hz,1H),2.71(s,3H).

Preparation example 51: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 51

The preparation of this preparation is similar to that of preparation 48, except that:

the methyl 5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1H-pyrrole-3-carboxylate in step 4) was replaced with an equimolar amount of methyl 5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-fluoro-1H-pyrrole-3-carboxylate to give the hydrochloride salt of compound 51 as a brown solid in 46% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.90(d,J＝5.4Hz,1H),8.70(d,J＝2.4Hz,1H),8.20(d,J＝9.0Hz,1H),7.85–7.79(m,2H),7.04(t,J＝8.4Hz,1H),6.82–6.78(m,1H),6.49–6.44(m,1H),4.10(s,2H),3.84(s,2H),2.73(s,3H),1.33(s,6H).

Preparation example 52: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 52

the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2-methylpropane-1, 2-diol to give the hydrochloride of compound 52 as a brown solid in a one-step yield of 46% in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.94(d,J＝5.4Hz,1H),8.72(d,J＝2.4Hz,1H),8.20(d,J＝9.0Hz,1H),7.89–7.79(m,2H),7.03(t,J＝8.4Hz,1H),6.86–6.79(m,1H),6.77–6.70(m,1H),6.48–6.42(m,1H),4.11(s,2H),3.86(s,2H),2.72(s,3H),1.34(s,6H).

Preparation example 53: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 53

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of cis-2-fluorocyclopropyl) methanol to give the hydrochloride salt of compound 53 as a white solid in 46% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.93(d,J＝5.2Hz,1H),8.75–8.66(m,1H),8.16(d,J＝7.8Hz,1H),7.88–7.75(m,2H),7.03(dd,J＝9.5,7.6Hz,1H),6.81(dd,J＝8.6,2.5Hz,1H),6.72(dd,J＝11.4,2.5Hz,1H),6.44(d,J＝2.1Hz,1H),4.34–4.25(m,1H),4.17–4.02(m,3H),2.74(s,3H),1.05–0.97(m,1H),0.95–0.81(m,1H).

Preparation example 54: this preparation is illustrative of the procedure for the synthesis of compound 54

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2, 5-difluorobenzyl alcohol to give compound 54 as a white solid in 48% yield in step 6).

¹H NMR(600MHz,Chloroform-d)δ8.74(d,J＝4.8Hz,1H),8.63(s,1H),7.71(d,J＝8.4Hz,1H),7.38(s,1H),7.32(dd,J＝8.4,4.8Hz,1H),7.25–7.21(m,1H),7.10–7.05(m,2H),7.04–6.98(m,1H),6.75(d,J＝8.4Hz,1H),6.66(d,J＝11.4Hz,1H),6.24(s,1H),5.12(s,2H),3.63(s,2H),2.45(s,3H).

Preparation example 55: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 55

the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2, 4-difluorobenzyl alcohol to give the hydrochloride of compound 55 as a yellow oil in 45% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.85–8.79(m,1H),8.57(s,1H),7.91(d,J＝8.4Hz,1H),7.80(s,1H),7.64–7.53(m,2H),7.10–7.00(m,3H),6.86(d,J＝8.4Hz,1H),6.79(d,J＝11.4Hz,1H),6.40(d,J＝2.4Hz,1H),5.18(s,2H),4.10(s,2H),2.72(s,3H).

Preparation example 56: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 56

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2, 6-difluorobenzyl alcohol to give the hydrochloride salt of compound 56 as a white solid in 45% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.85(d,J＝4.8Hz,1H),8.63(s,1H),7.97(d,J＝8.4Hz,1H),7.81(s,1H),7.62(t,J＝6.6Hz,1H),7.54–7.43(m,1H),7.15–6.98(m,3H),6.87(d,J＝8.4Hz,1H),6.81(d,J＝11.4Hz,1H),6.42(s,1H),5.21(s,2H),4.10(s,2H),2.72(s,3H).

Preparation example 57: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 57

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 3, 4-difluorobenzyl alcohol to give the hydrochloride salt of compound 57 as a white solid in 56% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.85(d,J＝4.8Hz,1H),8.60(d,J＝2.4Hz,1H),7.99(d,J＝8.4Hz,1H),7.81(s,1H),7.67–7.60(m,1H),7.43(t,J＝9.6Hz,1H),7.31(m,2H),7.04(t,J＝8.4Hz,1H),6.86(d,J＝9.0Hz,1H),6.78(d,J＝11.4Hz,1H),6.42(d,J＝2.1Hz,1H),5.14(s,2H),4.10(s,2H),2.71(s,4H).

Preparation example 58: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 58

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 3, 5-difluorobenzyl alcohol to give the hydrochloride of compound 58 as a white solid in 55% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.84(d,J＝4.8Hz,1H),8.59(s,1H),7.94(d,J＝8.4Hz,1H),7.82(s,1H),7.64–7.55(m,1H),7.16–7.10(m,2H),7.06(t,J＝8.4Hz,1H),6.99–6.93(m,1H),6.88(d,J＝8.4Hz,1H),6.81(d,J＝11.4Hz,1H),6.43(d,J＝2.4Hz,1H),5.21(s,2H),4.12(s,2H),2.73(s,3H).

Preparation example 59: this preparation serves to illustrate the synthesis of compound 59:

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2-difluoromethoxybenzyl alcohol to give compound 59 as a yellow powder in 49% yield in one step in step 6).

¹H NMR(400MHz,Methanol-d₄)δ8.75(dd,J＝4.8,1.6Hz,1H),8.53(d,J＝2.4Hz,1H),7.87–7.81(m,1H),7.58(dd,J＝7.6,1.6Hz,1H),7.51(d,J＝1.8Hz,1H),7.50–7.46(m,1H),7.42(td,J＝7.6,1.6Hz,1H),7.34–7.22(m,2H),7.01(t,J＝8.4Hz,1H),6.88(t,J＝73.6Hz,1H),6.81(dd,J＝8.4,2.4Hz,1H),6.74(dd,J＝11.2,2.4Hz,1H),6.29(d,J＝1.6Hz,1H),5.19(s,2H),3.63(s,2H),2.39(s,3H).

Preparation example 60: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 60

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2-trifluoromethoxy benzyl alcohol to give the hydrochloride salt of compound 60 as a white solid in 56% yield in step 6).

¹H NMR(400MHz,Methanol-d₄)δ8.88(d,J＝5.2Hz,1H),8.67(s,1H),8.04(ddd,J＝8.4,2.4,1.6Hz,1H),7.82(d,J＝2.0Hz,1H),7.71–7.63(m,2H),7.52–7.46(m,1H),7.45–7.36(m,2H),7.05(t,J＝8.4Hz,1H),6.85(dd,J＝8.4,2.4Hz,1H),6.77(dd,J＝11.2,2.4Hz,1H),6.44(d,J＝2.0Hz,1H),5.23(s,2H),4.11(s,2H),2.72(s,3H).

Preparation example 61: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 61

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-difluoromethoxybenzyl alcohol to give the hydrochloride of compound 61 as a white solid in 55% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.87–8.80(m,1H),8.60(d,J＝2.4Hz,1H),7.96(d,J＝7.8Hz,1H),7.81(s,1H),7.64–7.57(m,1H),7.56–7.51(m,2H),7.24–7.18(m,2H),7.02(t,J＝8.4Hz,1H),6.86(t,J＝66.0Hz,1H),6.86–6.84(m,1H),6.79–6.75(m,1H),6.41(d,J＝2.4Hz,1H),5.16(s,2H),4.10(s,2H),2.72(s,3H).

Preparation example 62: this preparation is illustrative of the procedure for the synthesis of hydrochloride salt of compound 62

the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1-hydroxymethylnaphthalene to give the hydrochloride of compound 62 as a white solid in 53% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.83–8.78(m,1H),8.61(s,1H),8.13(d,J＝8.4Hz,1H),7.98–7.84(m,3H),7.80(s,1H),7.67(d,J＝6.6Hz,1H),7.64–7.46(m,3H),7.04(t,J＝8.4Hz,1H),6.92(d,J＝8.4Hz,1H),6.85(d,J＝11.4Hz,1H),6.41(s,1H),5.62(s,2H),4.10(s,2H),2.72(s,3H).

Preparation example 63: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 63

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-cyanobenzenesulfonyl chloride and replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1-hydroxymethylnaphthalene gave the hydrochloride salt of compound 63 as a white solid in 43% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.19–8.12(m,1H),8.05–8.00(m,1H),7.94(dd,J＝12.6,8.4Hz,2H),7.84–7.73(m,2H),7.72–7.66(m,2H),7.65–7.48(m,4H),7.09–7.01(m,1H),6.98–6.91(m,1H),6.89–6.83(m,1H),6.41(s,1H),5.63(s,2H),4.11(s,2H),2.73(s,3H).

Preparation example 64: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 64

the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethylbenzoic acid to give the hydrochloride salt of compound 64 as a white solid in a one-step yield of 25% in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.85(d,J＝5.4Hz,1H),8.63(s,1H),8.07(d,J＝7.8Hz,2H),8.00(d,J＝7.2Hz,1H),7.80(s,1H),7.68–7.52(m,3H),7.08–6.97(m,1H),6.86(d,J＝8.4Hz,1H),6.78(d,J＝11.4Hz,1H),6.41(s,1H),5.25(s,2H),4.09(s,2H),2.71(s,3H).

Preparation example 65: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 65

replacing the (2S) -1, 4-dioxane-2-methanol of step 6) with an equimolar amount of 1- (2, 5-difluorophenyl) ethanol gave the hydrochloride salt of compound 65 as a white solid in 48% yield in one step of step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.84(d,J＝4.8Hz,1H),8.61(d,J＝2.4Hz,1H),7.93(d,J＝8.4Hz,1H),7.79(s,1H),7.63–7.56(m,1H),7.23–7.16(m,2H),7.11–7.05(m,1H),6.98(t,J＝8.4Hz,1H),6.73(dd,J＝8.4,2.4Hz,1H),6.63(dd,J＝11.4,2.4Hz,1H),6.39(s,1H),5.76(q,J＝6.4Hz,1H),4.08(s,2H),2.70(s,3H),1.68(d,J＝6.4Hz,3H).

Preparation example 66: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 66

(2S) -1, 4-Dioxane-2-methanol in step 6) was replaced with an equimolar amount of (S) -1- (2, 6-dichloro-3-fluorophenyl) ethanol to give the hydrochloride salt of compound 66 as a white solid in 56% yield in one step in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.89(dd,J＝5.4,1.8Hz,1H),8.65(d,J＝2.4Hz,1H),8.02–7.97(m,1H),7.81(d,J＝1.8Hz,1H),7.70–7.65(m,1H),7.50–7.45(m,1H),7.28(t,J＝8.4Hz,1H),6.98(t,J＝8.4Hz,1H),6.69(dd,J＝8.4,2.4Hz,1H),6.59(dd,J＝11.4,2.4Hz,1H),6.40(d,J＝1.8Hz,1H),6.16(q,J＝6.6Hz,1H),4.10(s,2H),2.71(s,3H),1.84(d,J＝6.6Hz,3H).

Preparation example 67: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 67

replacing the (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (2, 6-difluorophenyl) ethanol gave the hydrochloride salt of compound 67 as a white solid in 53% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.92–8.88(m,1H),8.68(d,J＝2.4Hz,1H),8.04–7.97(m,1H),7.82(d,J＝1.8Hz,1H),7.67(dd,J＝8.4,5.4Hz,1H),7.45–7.32(m,1H),7.02(t,J＝8.4Hz,2H),6.98(t,J＝8.4Hz,1H),6.76(dd,J＝8.4,2.4Hz,1H),6.65(dd,J＝11.4,2.4Hz,1H),6.40(d,J＝2.4Hz,1H),5.88(q,J＝6.6Hz,1H),4.10(s,2H),2.72(s,3H),1.81(d,J＝6.6Hz,3H).

Preparation example 68: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 68

replacing the (2S) -1, 4-dioxane-2-methanol of step 6) with an equimolar amount of 1- (3, 5-difluorophenyl) ethanol gave the hydrochloride salt of compound 68 as a white solid in 55% yield in one step of step 6).

¹H NMR(400MHz,Methanol-d₄)δ8.84(dd,J＝4.8,1.6Hz,1H),8.60(d,J＝2.4Hz,1H),7.93(dt,J＝8.4,2.0Hz,1H),7.79(d,J＝1.6Hz,1H),7.59(dd,J＝8.4,4.8Hz,1H),7.10–7.01(m,2H),6.96(t,J＝8.4Hz,1H),6.87(tt,J＝9.2,2.4Hz,1H),6.74(dd,J＝8.4,2.4Hz,1H),6.65(dd,J＝11.2,2.4Hz,1H),6.38(d,J＝2.0Hz,1H),5.54(q,J＝6.4Hz,1H),4.08(s,2H),2.70(s,3H),1.64(d,J＝6.4Hz,3H).

Preparation example 69: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 69

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-cyanobenzenesulfonyl chloride and replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (2, 6-difluorophenyl) ethanol gave the hydrochloride salt of compound 69 as a white solid in 43% yield in step 6).

¹H NMR(400MHz,Methanol-d₄)δ8.00(dt,J＝7.6,1.6Hz,1H),7.76(d,J＝2.0Hz,1H),7.70–7.65(m,1H),7.64–7.53(m,2H),7.42–7.32(m,1H),7.00(t,J＝8.4Hz,2H),6.93(t,J＝8.4Hz,1H),6.74(dd,J＝8.8,2.4Hz,1H),6.60(dd,J＝11.2,2.4Hz,1H),6.35(d,J＝2.0Hz,1H),5.87(q,J＝6.4Hz,1H),4.07(s,2H),2.70(s,3H),1.80(d,J＝6.4Hz,3H).

Preparation example 70: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 70

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-cyanobenzenesulfonyl chloride and replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (3, 5-difluorophenyl) ethanol gave the hydrochloride salt of compound 70 as a white solid in 45% yield in step 6).

¹H NMR(400MHz,Methanol-d₄)δ8.01(dt,J＝7.6,1.2Hz,1H),7.76(d,J＝2.0Hz,1H),7.71–7.67(m,1H),7.64–7.58(m,2H),7.11–7.01(m,2H),6.94(t,J＝8.4Hz,1H),6.86(tt,J＝9.2,2.4Hz,1H),6.74(dd,J＝8.4,2.4Hz,1H),6.63(dd,J＝11.2,2.4Hz,1H),6.35(d,J＝2.0Hz,1H),5.54(q,J＝6.4Hz,1H),4.07(s,2H),2.69(s,3H),1.64(d,J＝6.4Hz,3H).

Preparation example 71: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 71

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (cyclopropylmethoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (3, 5-difluorophenyl) ethanol gave the hydrochloride salt of compound 71 as a white solid in 47% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.71(d,J＝1.8Hz,1H),7.34–7.24(m,1H),7.15(dd,J＝8.4,2.4Hz,1H),7.09–7.04(m,2H),6.98–6.94(m,1H),6.94–6.85(m,2H),6.81(t,J＝2.4Hz,1H),6.70(dd,J＝8.4,2.4Hz,1H),6.63(dd,J＝11.4,2.4Hz,1H),6.31(d,J＝2.4Hz,1H),5.53(q,J＝6.6Hz,1H),4.06(s,2H),3.81–3.65(m,2H),2.68(s,3H),1.64(d,J＝6.6Hz,3H),1.26–1.17(m,1H),0.67–0.59(m,2H),0.39–0.32(m,2H).

Preparation example 72: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 72

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (cyclopropylmethoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (2, 6-difluorophenyl) ethanol gave the hydrochloride salt of compound 72 as a yellow oil in 45% yield in step 6).

¹H NMR(400MHz,Methanol-d₄)δ7.67(d,J＝2.0Hz,1H),7.44–7.31(m,1H),7.24(t,J＝8.0Hz,1H),7.14(dd,J＝8.4,2.4Hz,1H),7.04–6.97(m,2H),6.94–6.85(m,2H),6.81(t,J＝2.0Hz,1H),6.69(dd,J＝8.4,2.4Hz,1H),6.59(dd,J＝11.4,2.4Hz,1H),6.27(d,J＝2.0Hz,1H),5.85(q,J＝6.4Hz,1H),4.00(s,2H),3.73(d,J＝7.2Hz,2H),2.65(s,3H),1.80(d,J＝6.4Hz,3H),1.28–1.11(m,1H),0.71–0.54(m,2H),0.42–0.27(m,2H).

Preparation example 73: this preparation serves to illustrate the synthesis of the hydrochloride salt of compound 73:

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2, 4-dimethylbenzyl alcohol to give the hydrochloride of compound 73 as a white solid in 56% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.89(s,1H),8.69(s,1H),8.05(d,J＝7.8Hz,1H),7.81(s,1H),7.68(s,1H),7.27(d,J＝7.8Hz,1H),7.11–6.96(m,3H),6.84(d,J＝8.4Hz,1H),6.76(d,J＝11.4Hz,1H),6.42(s,1H),5.10(s,2H),4.10(s,2H),2.71(s,3H),2.33(d,J＝26.8Hz,6H).

Preparation example 74: this preparation is illustrative of the procedure for the synthesis of compound 74

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethylpyridine to give compound 74 as a white solid in 57% yield in step 6).

¹H NMR(400MHz,DMSO-d₆)δ8.87–8.84(m,1H),8.64–8.59(m,2H),8.56(d,J＝2.4Hz,1H),7.88–7.82(m,1H),7.59(dd,J＝8.4,4.8Hz,1H),7.49–7.43(m,3H),7.04(t,J＝8.4Hz,1H),6.96(dd,J＝11.2,2.4Hz,1H),6.88(dd,J＝8.4,2.4Hz,1H),6.31(d,J＝2.0Hz,1H),5.27(s,2H),3.48(s,2H),2.23(s,3H).

Preparation example 75: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 75

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2-methoxybenzyl alcohol to give the hydrochloride salt of compound 75 as a white solid in 49% yield in one step in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.89(d,J＝4.8Hz,1H),8.70(s,1H),8.07(d,J＝5.4Hz,1H),7.83(s,1H),7.70(dd,J＝8.4,4.8Hz,1H),7.46–7.40(m,1H),7.38–7.32(m,1H),7.09–6.95(m,3H),6.77(dd,J＝8.4,2.4Hz,1H),6.68(dd,J＝11.4,2.4Hz,1H),6.43(s,1H),5.17(s,2H),4.11(s,2H),3.90(s,3H),2.72(s,3H).

Preparation example 76: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 76

(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of (R) -1- (2, 6-dichloro-3-fluorophenyl) ethanol to give the hydrochloride salt of compound 76 as a white solid in 44% yield in one step in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.85(d,J＝4.8Hz,1H),8.62(d,J＝2.4Hz,1H),7.97(d,J＝8.4Hz,1H),7.77(s,1H),7.68–7.62(m,1H),7.46–7.41(m,1H),7.24(t,J＝8.5Hz,1H),6.94(t,J＝8.4Hz,1H),6.65(dd,J＝8.4,2.4Hz,1H),6.55(dd,J＝11.4,2.4Hz,1H),6.36(d,J＝1.8Hz,1H),6.12(q,J＝6.6Hz,1H),4.05(s,2H),2.67(s,3H),1.79(d,J＝6.6Hz,3H).

Preparation example 77: this preparation is illustrative of the procedure for the synthesis of Compound 77

the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 3-hydroxymethylthiophene to give compound 77 as a yellow solid in 40% yield in step 6).

¹H NMR(600MHz,DMSO-d₆)δ8.86(d,J＝4.8Hz,1H),8.57(s,1H),7.85(d,J＝8.4Hz,1H),7.66–7.46(m,4H),7.22(d,J＝4.8Hz,1H),7.00(t,J＝8.4Hz,1H),6.93(dd,J＝11.4,2.4Hz,1H),6.85(dd,J＝8.4,2.4Hz,1H),6.32(s,1H),5.16(s,2H),3.55(s,2H),2.27(s,3H).

Preparation example 78: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 78

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-chlorobenzenesulfonyl chloride and replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 5-difluorobenzyl alcohol gave the hydrochloride salt of compound 78 as a white solid in 40% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.75(s,1H),7.68(d,J＝8.4Hz,1H),7.52–7.45(m,1H),7.43(d,J＝8.4Hz,1H),7.33–7.30(m,2H),7.24–7.17(m,1H),7.17–7.12(m,1H),7.05–7.00(m,1H),6.87(d,J＝9.0Hz,1H),6.78(d,J＝10.8Hz,1H),6.37(s,1H),5.21(s,2H),4.09(s,2H),2.71(s,3H).

Preparation example 79: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 79

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-fluorobenzenesulfonyl chloride and replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 5-difluorobenzyl alcohol gave the hydrochloride salt of compound 79 as a white solid in a one-step yield of 36% in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.75(s,1H),7.54–7.48(m,1H),7.47–7.41(m,1H),7.35–7.28(m,2H),7.23–7.11(m,3H),7.02(t,J＝8.4Hz,1H),6.85(dd,J＝8.4,2.4Hz,1H),6.81–6.76(m,1H),6.38(s,1H),5.20(s,2H),4.09(s,2H),2.71(s,3H).

Preparation example 80: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 80

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3, 5-difluorobenzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 5-difluorobenzyl alcohol gave the hydrochloride salt of compound 80 as a white solid in 44% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.76(s,1H),7.41–7.36(m,1H),7.33–7.29(m,1H),7.22–7.17(m,1H),7.16–7.11(m,1H),7.10–7.04(m,3H),6.88(d,J＝8.4Hz,1H),6.81(d,J＝10.8Hz,1H),6.42(s,1H),5.20(s,2H),4.10(s,2H),2.71(s,3H).

Preparation example 81: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 81

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-fluoro-4-methylbenzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 5-difluorobenzyl alcohol gave the hydrochloride salt of compound 81 as a white solid in 36% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.73(s,1H),7.37–7.29(m,2H),7.25–7.12(m,3H),7.09(d,J＝9.0Hz,1H),7.06–7.00(m,1H),6.87–6.84(m,1H),6.79(dd,J＝11.4,2.4Hz,1H),6.36(s,1H),5.20(s,2H),4.08(s,2H),2.70(s,3H),2.31(s,3H).

Preparation example 82: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 82

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-pentyloxybenzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 5-difluorobenzyl alcohol gave the hydrochloride salt of compound 82 as a white solid in 36% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ7.74(s,1H),7.40–7.29(m,2H),7.24–7.12(m,3H),7.06(d,J＝7.8Hz,1H),7.03–6.98(m,1H),6.89–6.75(m,3H),6.35(s,1H),5.19(s,2H),4.08(s,2H),3.91–3.81(m,2H),2.70(s,3H),1.82–1.62(m,2H),1.51–1.28(m,4H),0.97–0.87(m,3H).

Preparation example 83: this preparation serves to illustrate the synthesis of the hydrochloride salt of compound 83:

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-cyclobutylmethoxybenzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (2, 6-difluorophenyl) -ethanol gave the hydrochloride salt of compound 83 as a yellow oil in 41% yield in step 6).

¹H NMR(400MHz,Methanol-d₄)δ7.60(d,J＝2.0Hz,1H),7.29–7.19(m,1H),7.13(t,J＝8.4Hz,1H),7.01(dd,J＝8.4,2.4Hz,1H),6.92–6.75(m,4H),6.72(t,J＝2.4Hz,1H),6.57(dd,J＝8.4,2.4Hz,1H),6.49(dd,J＝11.4,2.4Hz,1H),6.21(d,J＝1.8Hz,1H),5.71(q,J＝6.4Hz,1H),3.91(s,2H),3.72(d,J＝6.4Hz,2H),2.54(s,3H),2.07–1.95(m,3H),1.92–1.71(m,4H),1.66(d,J＝6.4Hz,3H).

Preparation example 84: this preparation is illustrative of the synthesis of the hydrochloride salt of compound 84

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-cyclopentylmethoxybenzenesulfonyl chloride and replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 4-difluorobenzyl alcohol gave the hydrochloride salt of compound 84 as a white solid in 40% yield in step 6).

¹H NMR(400MHz,Methanol-d₄)δ7.75(d,J＝1.6Hz,1H),7.40–7.28(m,2H),7.24–7.10(m,3H),7.10–7.06(m,1H),7.01(t,J＝8.4Hz,1H),6.86–6.81(m,2H),6.78(dd,J＝11.2,2.4Hz,1H),6.36(d,J＝1.6Hz,1H),5.19(s,2H),4.09(s,2H),3.75(d,J＝6.8Hz,2H),2.70(s,3H),2.40–2.22(m,1H),1.90–1.74(m,2H),1.69–1.51(m,4H),1.42–1.27(m,2H).

Preparation example 85: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 85

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-cyclopentylmethoxybenzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (2, 6-difluorophenyl) -ethanol gave the hydrochloride salt of compound 85 as a yellow oil in 23% yield in step 6).

¹H NMR(400MHz,Methanol-d₄)δ7.67(d,J＝2.0Hz,1H),7.42–7.31(m,1H),7.25(t,J＝8.0Hz,1H),7.14(dd,J＝8.4,2.4Hz,1H),7.05–6.95(m,2H),6.94–6.87(m,2H),6.80(t,J＝2.0Hz,1H),6.69(dd,J＝8.4,2.4Hz,1H),6.59(dd,J＝11.2,2.4Hz,1H),6.26(d,J＝2.0Hz,1H),5.84(q,J＝6.4Hz,1H),4.01(s,2H),3.75(d,J＝6.8Hz,2H),2.65(s,3H),2.37–2.25(m,1H),1.90–1.75(m,5H),1.72–1.58(m,4H),1.42–1.32(m,2H).

Preparation example 86: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 86

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (2-methoxy-ethoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 4-difluorobenzyl alcohol gave the hydrochloride salt of compound 86 as a white solid in 45% yield in step 6).

¹H NMR(400MHz,Methanol-d₄)δ7.75(d,J＝2.0Hz,1H),7.41–7.29(m,2H),7.25–7.11(m,3H),7.12–7.05(m,1H),7.00(t,J＝8.4Hz,1H),6.88(t,J＝2.0Hz,1H),6.84(dd,J＝8.4,2.4Hz,1H),6.78(dd,J＝11.2,2.4Hz,1H),6.36(d,J＝2.0Hz,1H),5.20(s,2H),4.09(s,2H),4.06–4.01(m,2H),3.74–3.67(m,2H),3.38(s,3H),2.70(s,3H).

Preparation example 87: this preparation is illustrative of the procedure for the synthesis of compound 87

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (2-methoxy-ethoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2-methoxybenzyl alcohol gave compound 87 as a white solid in 39% yield in step 6).

¹H NMR(400MHz,Methanol-d₄)δ7.68(d,J＝2.0Hz,1H),7.46–7.40(m,1H),7.38–7.30(m,2H),7.20(dd,J＝8.4,2.4Hz,1H),7.07–7.02(m,2H),7.00–6.92(m,2H),6.87(t,J＝2.0Hz,1H),6.78(dd,J＝8.4,2.4Hz,1H),6.71(dd,J＝11.2,2.4Hz,1H),6.31(d,J＝2.0Hz,1H),5.15(s,2H),4.04–3.98(m,4H),3.89(s,3H),3.71–3.65(m,2H),3.36(s,3H),2.65(s,3H).

Preparation example 88: this preparation is illustrative of the procedure for the synthesis of compound 88

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (3-methoxy-propoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (2, 6-difluorophenyl) -ethanol gave compound 88 as a yellow oil in 44% yield in step 6).

¹H NMR(400MHz,Methanol-d₄)δ7.67(d,J＝2.0Hz,1H),7.42–7.31(m,1H),7.25(t,J＝8.0Hz,1H),7.18–7.12(m,1H),7.04–6.96(m,2H),6.94–6.87(m,2H),6.83(t,J＝2.0Hz,1H),6.70(dd,J＝8.8,2.4Hz,1H),6.60(dd,J＝11.2,2.4Hz,1H),6.27(d,J＝2.0Hz,1H),5.85(q,J＝6.4Hz,1H),4.01(s,2H),3.96(t,J＝6.4Hz,2H),3.54(t,J＝6.0Hz,2H),3.35(s,3H),2.64(s,3H),2.04–1.95(m,2H),1.79(d,J＝6.4Hz,3H).

Preparation example 89: this preparation is illustrative of the procedure for the synthesis of hydrochloride salt of Compound 89

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (3-methoxy-propoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (3, 5-difluorophenyl) -ethanol gave the hydrochloride salt of compound 89 as a white solid in 46% yield in step 6).

¹H NMR(400MHz,Methanol-d₄)δ7.63(d,J＝2.0Hz,1H),7.21(t,J＝8.0Hz,1H),7.08(dd,J＝8.4,2.4Hz,1H),7.01–6.94(m,2H),6.93–6.88(m,1H),6.86–6.74(m,3H),6.62(dd,J＝8.4,2.4Hz,1H),6.55(dd,J＝11.2,2.4Hz,1H),6.23(d,J＝2.0Hz,1H),5.44(q,J＝6.4Hz,1H),3.98(s,2H),3.89(t,J＝6.4Hz,2H),3.46(t,J＝6.0Hz,2H),3.27(s,3H),2.60(s,3H),1.96–1.85(m,2H),1.55(d,J＝6.4Hz,3H).

Preparation example 90: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 90

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (4-methoxy-butoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2-hydroxymethylnaphthalene gave the hydrochloride salt of compound 90 as a white solid in 51% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.08(d,J＝8.4Hz,1H),7.94–7.85(m,2H),7.73–7.69(m,1H),7.64(d,J＝6.6Hz,1H),7.59–7.45(m,3H),7.28(t,J＝7.8Hz,1H),7.13(dd,J＝8.4,2.4Hz,1H),7.03(d,J＝7.8Hz,1H),6.97(t,J＝8.4Hz,1H),6.85(dd,J＝8.4,2.4Hz,1H),6.81(d,J＝11.4Hz,2H),6.32(d,J＝2.4Hz,1H),5.56(s,2H),4.05(s,2H),3.85(t,J＝6.0Hz,2H),3.26(s,3H),3.21–3.18(m,2H),2.67(s,3H),1.75–1.68(m,2H),1.65–1.58(m,2H).

Preparation example 91: this preparation is illustrative of the procedure for the synthesis of Compound 91

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (4-methoxy-butoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (2, 6-difluorophenyl) -ethanol gave compound 91 as a white solid in 48% yield in step 6).

¹H NMR(400MHz,Methanol-d₄)δ7.69(d,J＝2.0Hz,1H),7.42–7.32(m,1H),7.25(t,J＝8.0Hz,1H),7.15(dd,J＝8.4,2.4Hz,1H),7.04–6.96(m,2H),6.95–6.86(m,2H),6.82(t,J＝2.0Hz,1H),6.70(dd,J＝8.4,2.4Hz,1H),6.60(dd,J＝11.4,2.4Hz,1H),6.29(d,J＝2.0Hz,1H),5.84(q,J＝6.4Hz,1H),4.04(s,2H),3.90(t,J＝6.4Hz,2H),3.46(t,J＝6.4Hz,2H),3.34(s,3H),2.66(s,3H),1.88–1.67(m,7H).

Preparation example 92: this preparation serves to illustrate the synthesis of the hydrochloride salt of compound 92:

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (4-methoxy-butoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (3, 5-difluorophenyl) -ethanol gave the hydrochloride salt of compound 92 as a yellow solid in 41% yield in step 6).

¹H NMR(400MHz,Methanol-d₄)δ7.71(d,J＝2.0Hz,1H),7.29(t,J＝8.0Hz,1H),7.16(dd,J＝8.4,2.54Hz,1H),7.09–7.02(m,2H),7.01–6.96(m,1H),6.95–6.84(m,2H),6.82(t,J＝2.0Hz,1H),6.70(dd,J＝8.4,2.4Hz,1H),6.63(dd,J＝11.2,2.4Hz,1H),6.31(d,J＝2.0Hz,1H),5.52(q,J＝6.4Hz,1H),4.06(s,2H),3.91(t,J＝6.4Hz,2H),3.45(t,J＝6.4Hz,2H),3.34(s,3H),2.68(s,3H),1.85–1.76(m,2H),1.76–1.68(m,2H),1.63(d,J＝6.3Hz,3H).

Preparation example 93: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 93

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (4-methoxy-butoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1, 3-benzodioxolane-4-alkylmethanol gave the hydrochloride salt of compound 93 as a white solid in 40% yield in one step in step 6).

¹H NMR(400MHz,Methanol-d₄)δ7.73(d,J＝2.0Hz,1H),7.33(t,J＝8.0Hz,1H),7.17(dd,J＝8.4,2.4Hz,1H),7.04(d,J＝8.0Hz,1H),7.00–6.94(m,2H),6.92–6.77(m,4H),6.73(dd,J＝11.2,2.4Hz,1H),6.34(d,J＝2.0Hz,1H),6.01(s,2H),5.11(s,2H),4.08(s,2H),3.90(t,J＝6.4Hz,2H),3.41(t,J＝6.4Hz,2H),3.30(s,3H),2.70(s,3H),1.86–1.75(m,2H),1.74–1.63(m,2H).

Preparation 94: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 94

replacing the (2S) -1, 4-dioxane-2-methanol of step 6) with an equimolar amount of 1, 3-benzodioxol-4-alkylmethanol gave the hydrochloride salt of compound 94 as a white solid in 50% yield in one step of step 6).

¹H NMR(600MHz,DMSO-d₆)δ9.14(s,2H),8.89(d,J＝3.6Hz,1H),8.59(s,1H),7.89(d,J＝8.4Hz,1H),7.81(s,1H),7.63–7.59(m,1H),7.01–6.94(m,4H),6.91–6.85(m,2H),6.52(s,1H),6.08(s,2H),5.11(s,2H),3.98(s,3H).

Preparation example 95: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 95

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-cyanobenzenesulfonyl chloride and replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1, 3-benzodioxolane-4-alkylmethanol gave the hydrochloride salt of compound 95 as a white solid in 44% yield in step 6).

Preparation example 96: this preparation is illustrative of the procedure for the synthesis of hydrochloride salt of compound 96

replacing the (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 3-dihydro-1, 4-benzodioxin-5-methanol gave the hydrochloride salt of compound 96 as a white solid in 56% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.96–8.86(m,1H),8.71(d,J＝2.4Hz,1H),8.15–8.01(m,1H),7.82(d,J＝2.4Hz,1H),7.71(dd,J＝8.4,4.8Hz,1H),7.06–6.97(m,2H),6.87–6.80(m,3H),6.75(dd,J＝11.4,2.4Hz,1H),6.43(d,J＝2.4Hz,1H),5.13(s,2H),4.37–4.24(m,4H),4.11(s,2H),2.72(s,3H).

Preparation example 97: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 97

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-cyanobenzenesulfonyl chloride and replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 3-dihydro-1, 4-benzodioxin-5-methanol gave the hydrochloride salt of compound 97 as a white solid in 43% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.03(d,J＝7.7Hz,1H),7.81–7.60(m,4H),7.00(d,J＝10.4Hz,2H),6.88–6.80(m,3H),6.73(d,J＝11.4Hz,1H),6.40(s,1H),5.15(s,2H),4.37–4.25(m,4H),4.10(s,2H),2.72(s,3H).

Preparation example 98: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 98

replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-trifluoromethylbenzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, -5-difluorobenzyl alcohol gave the hydrochloride salt of compound 98 as a white solid in 52% yield in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.00(d,J＝7.8Hz,1H),7.80(d,J＝5.4Hz,2H),7.76–7.70(m,1H),7.60(s,1H),7.34–7.27(m,1H),7.23–7.17(m,1H),7.17–7.12(m,1H),7.03(t,J＝8.4Hz,1H),6.85(d,J＝8.4Hz,1H),6.75(d,J＝11.4Hz,1H),6.39(s,1H),5.19(s,2H),4.09(s,2H),2.70(s,3H).

Preparation example 99: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 99

replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2- (3, 5-difluorophenyl) -ethanol gave the hydrochloride salt of compound 99 as a white solid in 48% yield in step 6).¹H NMR(600MHz,Methanol-d₄)δ8.80(d,J＝4.8Hz,1H),8.55(d,J＝2.4Hz,1H),7.98–7.92(m,1H),7.76(s,1H),7.59(dd,J＝8.4,4.8Hz,1H),7.00–6.89(m,3H),6.82–6.75(m,1H),6.73(d,J＝8.4Hz,1H),6.64(d,J＝11.4Hz,1H),6.36(t,J＝1.8Hz,1H),4.24(t,J＝6.0Hz,2H),4.06(s,2H),3.10(t,J＝6.0Hz,2H),2.67(s,3H).

Preparation example 100: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 100

replacement of (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 3-hydroxymethylfuran afforded the hydrochloride salt of compound 100 as a grey solid in 51% yield in one step in step 6).

¹H NMR(600MHz,Methanol-d₄)δ8.89(d,J＝4.8Hz,1H),8.67(s,1H),8.07(d,J＝8.4Hz,1H),7.82(s,1H),7.71(dd,J＝8.4,4.8Hz,1H),7.65(s,1H),7.53(s,1H),7.02(t,J＝8.4Hz,1H),6.86–6.81(m,1H),6.75(d,J＝11.4Hz,1H),6.55(s,1H),6.45–6.39(m,1H),5.04(s,2H),4.10(s,2H),2.71(s,3H).

Test example 1: h⁺/K⁺Biological evaluation of ATPases

This test example is to evaluate the compounds of the invention for H by in vitro screening assays⁺/K⁺Inhibition of ATPase enzymatic Activity, with Compound IC₅₀Values (calculated from inhibition at different concentrations) are indicated.

In vitro screening assay:

(1) preparation of reagents:

compound solution: independently dissolving the products (namely the compound or the hydrochloride of the compound) obtained in the preparation examples in DMSO respectively to prepare the products with proper concentration;

buffer I: 50mmol/L HEPES-Tris, pH 6.5, 5mmol/L magnesium chloride, 10. mu. mol/L valinomycin (Bailingwei chemical technology Co., Ltd., product number: 227304);

and (2) buffer solution II: 50mmol/L HEPES-Tris, pH 6.5, 5mmol/L magnesium chloride, 10 μmol/L valinomycin, 5mmol/L potassium chloride;

adenosine 5-triphosphate (ATP, Sigma-Aldrich, cat # A2383) solution: diluting ATP to 5mM with buffer I;

malachite green solution: dissolving 0.12 wt% of malachite green (Bailingwei chemical technology Co., Ltd., product number: 913120) in 2.5mol/L sulfuric acid, 7.5 wt% of ammonium molybdate (Bailingwei chemical technology Co., Ltd., product number: 128321) and 11% of Tween 20(V/V), and mixing the sulfuric acid, the ammonium molybdate and the Tween 20 at a ratio of 100:25:2 when in use;

rabbit gastric mucosa microsomes (rich in H +/K + -ATPase, self-extracted) are extracted by a sucrose gradient centrifugation method: the stomach of the rabbit was washed with tap water and 3M NaCl solution, respectively, and then surface water was removed with filter paper. Add pre-cooled homogenization buffer (4ml/g tissue) and homogenize in tissue homogenizer for 2-5 min. After homogenizing, if larger tissue particles exist, centrifuging (600g for 10min) to remove, then transferring the supernatant into a clean centrifuge tube, centrifuging for 30min at 20000g, then transferring the supernatant into a clean centrifuge tube, further centrifuging, centrifuging for 90min at 100000g, and collecting precipitates; suspending and precipitating by using homogenate, uniformly blowing, measuring the protein concentration by using a Bradford method, and adjusting the concentration to be 10 mg/ml; adding 7.5 wt% of Ficoll layering solution in equal proportion, centrifuging 100000g for 60min, collecting the middle layer (H +/K + -ATPasenered structural membranes) in a clean centrifuge tube, diluting by 4-5 times of homogenate liquid, centrifuging 100000g for 90min, and collecting precipitate; the precipitate was suspended in a homogenate, homogenized in a glass homogenizer, and the protein concentration was measured by the Bradford method to adjust the concentration to 22.5 mg/ml. Freezing at-80 deg.C for use.

(2) The experimental process comprises the following steps:

mu.L of rabbit gastric mucosal microsome (H) was added to 45. mu.L of buffer II⁺/K⁺ATPase), 5. mu.L of the compound solution was added, and 5. mu.L of a 5mM ATP solution was added to start the reaction, followed by pre-reaction at 37 ℃ for 30 min. The reaction was stopped by adding 15. mu.L of malachite green solution, equilibrated at room temperature for 20min and the absorbance read at 620 nm.

At the same time, the same volume reaction was carried out without potassium chloride as background, and subtracted when calculating the enzyme activity, the results are shown in Table 1.

Table 1: compound pair H⁺/K⁺Inhibition of ATPase enzymatic Activity

As can be seen from Table 1, the compounds of the invention are p.H⁺/K⁺Excellent inhibition of the activity of the ATPase enzyme.

Test example 2: inhibitory Effect of Compounds on Histamine-induced gastric acid secretion in rats

70 SPF SD rats (Hangzhou medical school (production)) weighing 180-. Fasting for 24h without water. After 24h, the administration is carried out by gastric lavage, the administration volume is 1ml/100g, each group is administered once, and the negative control group and the model group are administered with physiological saline with the same volume by gastric lavage. Then, after anesthetizing the rat with chloral hydrate at 300mg/kg (1ml/100g), the rat was fixed on a rat plate, the abdominal wall was incised from the lower part of the sternal xiphoid process along the ventral midline for about 2-3 cm, and the left side of the costal margin was gently pushed upward with a finger to expose the stomach to the incision. The pylorus was ligated by threading a line under the pylorus (the other blood vessels in the vicinity were not ligated) and then closing the abdominal wall incision. Animals were administered histamine dihydrochloride (30mg/10ml/kg) subcutaneously 1h after gavage of the test compound or normal saline. 3h after histamine administration with excess CO₂The rats were sacrificed by suffocation, the stomach was taken, the stomach contents were collected, centrifuged at 3000rpm/min for 10min, the acid solution was titrated with 0.1mol/L NaOH to pH7.0, and the total acid and acid inhibitory rate during 3h were calculated.

The acid inhibition rate was calculated as follows, and the results are shown in Table 2:

acid inhibition rate (%) (total acid amount in model group-total acid amount in administration group)/total acid amount in model group × 100%.

Table 2: inhibitory Effect of Compounds on Histamine-induced gastric acid secretion in rats

Compound numbering	Dosage (mg/kg)	Acid inhibitory Rate (%)
			6	2	48
8	2	71
			28	2	71
37	2	56
			48	2	75
48	4	86
			67	2	64

As can be seen from Table 2, the compounds of the present invention have excellent inhibitory effects on gastric acid secretion in rats induced by histamine.

Test example 3: rat tissue distribution assay for Compound 48

Healthy male SD rats 3 (weight range of 220-. Compound 48 was administered orally at a dose of 4 mg/kg.

Vehicle for preparation of drug administration preparation: pure water. Fasting was performed 4h before administration. Plasma, heart (perfusion), liver, stomach were collected at 1h, 2h, 4h (blank tissues were taken from the remaining SD rats to the analysis group). Tissue homogenization, preparation of standard koji with corresponding blank tissue and quantification of QC. Blood samples should be centrifuged to remove plasma within 1 hour after collection and placed on crushed ice prior to centrifugation. Plasma samples obtained by centrifugation were stored in a freezer until assayed. Centrifugation conditions: 4-10 ℃, 8000rpm, 6 minutes. Sample concentrations were measured by LC-MS-MS (MS03: Shimadzu LC30AD and API 4000)) and exposure data were calculated using WINNOLIN software.

Table 3: tissue distribution of Compound 48 rats at an oral dose of 4mg/kg

Tissue of	Exposure (0-4h)/h ng/mL	Ratio of
			Blood plasma	85.8	1
Liver disease	7585.5	88.4
			Stomach (stomach)	14693.7	171.3

As can be seen from Table 3, the compound of the invention has very obvious gastric tissue enrichment effect, has lower exposure in plasma and lower exposure in liver, is expected to reduce the safety risks such as hepatotoxicity and the like existing in marketed drugs such as Vonoprazan and the like while improving the treatment effect by reducing systemic exposure.

The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.

Claims

1. A compound containing a sulfonamide structure or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (I),

in the formula (I), the compound represented by the formula (I),

x is CH₂Or CH (CH)₃)；

R¹Is H, substituted or unsubstituted C₁-C₄Alkyl of (C)₁-C₃Alkoxy of (a), a six-membered saturated heterocycloalkyl group containing 1-2 oxygen atoms, a substituted or unsubstituted six-membered saturated heterocycloalkyl group containing 1-2 nitrogen atoms, -C₁-C₄alkylene-O-C of₁-C₃Alkyl, substituted or unsubstituted C₃-C₆Saturated cycloalkyl groups of (a) a (b) an oxirane group, a phenyl group containing at least two halogen substitutions, a phenyl group substituted with difluoromethoxy, a phenyl group substituted with trifluoromethoxy, a phenyl group substituted with carboxyl, a naphthyl group, a phenyl group containing at least two methyl substitutions, a pyridin-4-yl group, a phenyl group substituted with methoxy, a thiophen-3-yl group, a benzodioxolyl group, -CH₂-phenyl, furan-3-yl containing at least two halogen substitutions; r¹Wherein the optional substituents are selected from halogen, hydroxy, C₁-C₃Alkyl of (C)₁-C₃At least one of aldehyde groups of (a);

R³is C₁-C₃Alkyl groups of (a);

R⁴is H, C₁-C₃Alkoxy, halogen of (a);

2. The compound according to claim 1, wherein, in formula (I),

x is CH₂Or CH (CH)₃)；

R¹Is H, substituted or unsubstituted C₁-C₄Alkyl of (C)₁-C₃Alkoxy, a six-membered saturated heterocycloalkyl group containing 1 to 2 oxygen atoms, a substituted or unsubstituted six-membered saturated heterocycloalkyl group containing 1 to 2 nitrogen atomsSaturated heterocycloalkyl, -C₁-C₄alkylene-O-C of₁-C₃Alkyl, substituted or unsubstituted C₃-C₆Saturated cycloalkyl groups of (a) a (b) an oxirane group, a phenyl group containing at least two halogen substitutions, a phenyl group substituted with difluoromethoxy, a phenyl group substituted with trifluoromethoxy, a phenyl group substituted with carboxyl, a naphthyl group, a phenyl group containing at least two methyl substitutions, a pyridin-4-yl group, a phenyl group substituted with methoxy, a thiophen-3-yl group, a benzodioxolyl group, -CH₂-phenyl, furan-3-yl containing at least two halogen substitutions; r¹Wherein the optional substituents are selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, n-propyl, isopropyl, C₁-C₂At least one of aldehyde groups of (a);

R²is 3-pyridyl, substituted or unsubstituted phenyl; r²Wherein the optional substituents are selected from the group consisting of fluorine, chlorine, bromine, iodine, C₁-C₆Alkyl of (C)₁-C₆Alkoxy of, -O-C₁-C₄alkylene-O-C of₁-C₂Alkyl of (2), C substituted by 1-3 halogens₁-C₃Alkyl of (2), C substituted by 1-3 halogens₁-C₃Alkoxy, cyano, -O-C₁-C₄alkylene-C of₃-C₆At least one of cycloalkyl groups of (a);

R³is methyl, ethyl, n-propyl or isopropyl;

R⁴is H, methoxy, ethoxy, n-propoxy, isopropoxy, fluoro, chloro or bromo;

3. The compound according to claim 2, wherein, in formula (I),

x is CH₂Or CH (CH)₃)；

R¹Is H, substituted or unsubstituted C₁-C₄Alkyl of (C)₁-C₃Alkoxy of (1) to (2)Six-membered saturated heterocycloalkyl group having an oxygen atom, substituted or unsubstituted six-membered saturated heterocycloalkyl group having 1 to 2 nitrogen atoms, -C₁-C₄alkylene-O-C of₁-C₃Alkyl, substituted or unsubstituted C₃-C₆Saturated cycloalkyl groups of (a) a (b) an oxirane group, a phenyl group containing at least two halogen substitutions, a phenyl group substituted with difluoromethoxy, a phenyl group substituted with trifluoromethoxy, a phenyl group substituted with carboxyl, a naphthyl group, a phenyl group containing at least two methyl substitutions, a pyridin-4-yl group, a phenyl group substituted with methoxy, a thiophen-3-yl group, a benzodioxolyl group, -CH₂-phenyl, furan-3-yl containing at least two halogen substitutions; r¹Wherein the optional substituent is at least one of fluorine, chlorine, hydroxyl, methyl, ethyl, n-propyl, isopropyl and glyoxal;

R²is 3-pyridyl, substituted or unsubstituted phenyl; r²Wherein the optional substituents are selected from the group consisting of fluorine, chlorine, bromine, C₁-C₆Alkyl of (C)₁-C₆Alkoxy of, -O-C₁-C₄alkylene-O-C of₁-C₂Alkyl of (2), C substituted by 1-3 halogens₁-C₃Alkyl of (2), C substituted by 1-3 halogens₁-C₃Alkoxy, cyano, -O-C₁-C₄alkylene-C of₃-C₆At least one of cycloalkyl groups of (a);

R³is methyl or ethyl;

R⁴is H, methoxy or fluoro;

4. The compound according to claim 3, wherein, in formula (I),

x is CH₂Or CH (CH)₃)；

R¹Is H, methyl, isopropyl, tert-butyl, hydroxy-substituted tert-butyl, difluoromethyl, methoxy, dioxane, substituted or unsubstituted piperidylC₁-C₄alkylene-O-C of₁-C₃Alkyl, substituted or unsubstituted C₃-C₆Saturated cycloalkyl groups of (a) a (b) an oxirane group, a phenyl group containing at least two halogen substitutions, a phenyl group substituted with difluoromethoxy, a phenyl group substituted with trifluoromethoxy, a phenyl group substituted with carboxyl, a naphthyl group, a phenyl group containing at least two methyl substitutions, a pyridin-4-yl group, a phenyl group substituted with methoxy, a thiophen-3-yl group, a benzodioxolyl group, -CH₂-phenyl, furan-3-yl containing at least two halogen substitutions; r¹Wherein the optional substituent is at least one of fluorine, chlorine, hydroxyl, methyl, ethyl and aldehyde group;

R³is methyl or ethyl;

R⁴is H, methoxy or fluoro;

5. The method according to any one of claims 1 to 4, wherein the compound of formula (I) is selected from any one of the following:

。

6. a process for the preparation of a compound containing a sulfonamide structure, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (I),

wherein, in formula (I), formula (II) and formula (III), the definitions of the respective groups are the same as those described in any one of claims 1 to 5.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

8. The method ofA compound according to any one of claims 1 to 5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, in the preparation of H⁺/K⁺-ATPase inhibitor drugs and/or the use for the preparation of potassium ion competitive acid blocker drugs.

9. Use of a compound according to any one of claims 1 to 5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the treatment or prophylaxis of peptic ulcer, Zollinger-Ellison 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 ulcers caused by post-operative stress.

10. The use according to claim 9, wherein the peptic ulcer comprises at least one of a gastric ulcer, a duodenal ulcer, and a stomal ulcer; the symptomatic gastroesophageal reflux disease includes at least one of non-erosive reflux disease and non-esophagitis gastroesophageal reflux disease.