WO2023284159A1 - 一种含磺酰胺结构的化合物及其制备方法和应用、一种药物组合物及应用 - Google Patents

一种含磺酰胺结构的化合物及其制备方法和应用、一种药物组合物及应用 Download PDF

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WO2023284159A1
WO2023284159A1 PCT/CN2021/126527 CN2021126527W WO2023284159A1 WO 2023284159 A1 WO2023284159 A1 WO 2023284159A1 CN 2021126527 W CN2021126527 W CN 2021126527W WO 2023284159 A1 WO2023284159 A1 WO 2023284159A1
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substituted
preparation
compound
phenyl
methyl
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PCT/CN2021/126527
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English (en)
French (fr)
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黄伟
杨光富
陈涛
赵树立
龚溢
王明书
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南京烁慧医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the invention relates to the field of medicine, in particular to a compound containing a sulfonamide structure, a preparation method and application thereof, a pharmaceutical composition and application thereof.
  • Proton pump inhibitors represented by omeprazole strongly and persistently inhibit gastric acid secretion by inhibiting H+/K+-ATPase on gastric parietal cells.
  • PPIs proto pump inhibitors
  • P-CABs Potassium-Competitive Acid Blockers
  • P-CABs Potassium-Competitive Acid Blockers
  • P-CABs Potassium-Competitive Acid Blockers
  • P-CAB Compared with proton pump inhibitors (PPI), P-CAB is a kind of lipophilic weak base, which has faster onset of acid suppression and long-lasting effect, and is not easy to produce nocturnal acid breakthrough phenomenon; and P-CAB drugs have good stability and do not require It is made into enteric spray type and is not affected by genetic polymorphism. .
  • the object of the present invention is to provide a class of new compounds with the efficacy of potassium-competitive acid blockers in order to overcome the aforementioned defects of the prior art.
  • the first aspect of the present invention provides a compound containing a sulfonamide structure or its tautomer, mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a pharmaceutically acceptable salt, the compound has a structure shown in formula (I),
  • X is CH2 or CH( CH3 );
  • R 1 is H, a substituted or unsubstituted C 1 -C 4 alkyl group, a C 1 -C 3 alkoxy group, a saturated three-membered ring group containing a heteroatom of S, a saturated three-membered ring group containing a heteroatom of O or S A four-membered ring group, a saturated five-membered ring group containing O or S heteroatoms, a six-membered saturated heterocycloalkyl group containing 1-2 oxygen atoms, a substituted or unsubstituted six-membered ring group containing 1-2 nitrogen atoms Saturated heterocycloalkyl, substituted or unsubstituted five-membered unsaturated heterocycloalkyl containing at least one nitrogen atom, substituted or unsubstituted six-membered unsaturated heterocycloalkyl containing at least one nitrogen atom, -C 1 - C 4 alkylene-OC 1 -C 3
  • R 2 is 3-pyridyl, substituted or unsubstituted phenyl; optional substituents in R 2 are selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -OC 1 -C 4 alkylene-OC 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by 1-6 halogen, C 1 -C 3 alkyl substituted by 1-6 halogen At least one of oxy, cyano, -OC 1 -C 4 alkylene -C 3 -C 6 cycloalkyl;
  • R 3 is C 1 -C 3 alkyl
  • R 4 is H, C 1 -C 3 alkoxy, halogen
  • R 5 and R 6 is H, and the other is selected from F, C 1 -C 3 alkyl.
  • a second aspect of the present invention provides the preparation of compounds containing sulfonamide structures or tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, Or the method of pharmaceutically acceptable salt, this compound has the structure shown in formula (I),
  • the method comprises: carrying out a contact reaction between a compound represented by formula (II) and a compound represented by formula (III);
  • the third aspect of the present invention provides a pharmaceutical composition containing a therapeutically effective amount of the compound described in the aforementioned first aspect or its tautomer, mesoform, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, and the pharmaceutical composition also contains pharmaceutically acceptable carriers, excipients or diluents.
  • a fourth aspect of the present invention provides the compound described in the first aspect or its tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof , or a pharmaceutically acceptable salt, or the pharmaceutical composition described in the third aspect, the application in the preparation of H+/K+-ATPase inhibitor medicine and/or the preparation of potassium ion competitive acid blocker medicine.
  • a fifth aspect of the present invention provides the compound described in the first aspect or its tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof , or a pharmaceutically acceptable salt, or the pharmaceutical composition described in the third aspect, in preparation for the treatment or prevention of peptic ulcer, Zoller-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis , symptomatic gastroesophageal reflux disease, Barrett's esophagitis, functional dyspepsia, H. Drug application for multiple or ulcers.
  • the aforementioned compounds provided by the present invention can be used as therapeutic agents, especially as gastric acid secretion inhibitors and potassium ion-competitive acid blockers (P-CABs).
  • P-CABs potassium ion-competitive acid blockers
  • C 1 -C 6 alkyl refers to a saturated alkyl group, including straight or branched chain alkyl groups of 1 to 6 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and the like.
  • C 1 -C 4 alkyl has a similar definition, only the total number of carbon atoms is different, and the present invention will not repeat them.
  • C 1 -C 6 alkoxy refers to a saturated alkoxy group, including straight or branched chain alkoxy groups of 1 to 6 carbon atoms. For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, n-hexyloxy and the like.
  • C 1 -C 4 alkoxy and “C 1 -C 3 alkoxy” have similar definitions, only the total number of carbon atoms is different, and the present invention will not repeat them.
  • “Six-membered saturated heterocycloalkyl group containing 1-2 oxygen atoms” means that 1-2 ring atoms in the six-membered saturated heterocycloalkyl group are oxygen atoms, such as tetrahydropyranyl, dioxane Base etc.
  • Substituted or unsubstituted C 3 -C 6 cycloalkyl means that the number of ring atoms is 3-6, such as 3, 4, 5 or 6, and the ring atoms are all C atoms.
  • the substituted positions may be substituted by groups defined in the present invention.
  • Substituted or unsubstituted piperidinyl means that any position in the piperidine ring that can be substituted can be substituted by a group as defined in the present invention.
  • -OC 1 -C 4 alkylene-OC 1 -C 2 alkyl means that the group is connected to the core structure through O, and the terminal alkyl group is methyl or ethyl.
  • C 1 -C 3 alkyl substituted by 1-3 halogens means that any position that can be substituted in the C 1 -C 3 alkyl is substituted by 1-3 halogens.
  • -OC 1 -C 4 alkylene group-C 3 -C 6 cycloalkyl group means that the group is connected to the core structure through O, and the terminal alkyl group is a C 3 -C 6 cycloalkyl group.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • the "saturated three-membered heteroatom ring containing S” means a group formed by replacing at least one carbon atom forming the ring with S, based on the "saturated three-membered carbocycle”.
  • a saturated four-membered ring containing a heteroatom of O or S means that the number of atoms forming the ring is 4, at least one of which is O or S, and the remaining atoms are C atoms, and the group is a saturated ring group .
  • a saturated five-membered ring containing a heteroatom of O or S means that the number of atoms forming the ring is five, at least one of which is O or S, and the remaining atoms are C atoms, and the group is a saturated ring group .
  • Substituted unsaturated five-membered ring containing at least one N atom means that the number of atoms forming the ring is 5, at least one of which is N, and the remaining atoms are C atoms, and the group is an unsaturated ring group, There is at least one substituent at any position capable of being substituted in the group.
  • Substituted unsaturated six-membered ring containing at least one N atom means that the number of atoms forming the ring is 6, at least one of which is N, and the remaining atoms are C atoms, and the group is an unsaturated ring group, There is at least one substituent at any position capable of being substituted in the group.
  • “Pharmaceutically acceptable salts” means those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
  • Salt formation with acid obtained by reacting the free base of the parent compound with inorganic or organic acids.
  • Inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid, etc.
  • organic acids include acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid
  • malic acid fumaric acid, maleic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid
  • the acidic proton present in the parent compound is replaced by a metal ion or a salt formed by coordination with an organic base, such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, and an organic base such as ethanolamine, diethanolamine, three Ethanolamine, tromethamine, N-methylglucamine, etc.
  • an organic base such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion
  • an organic base such as ethanolamine, diethanolamine, three Ethanolamine, tromethamine, N-methylglucamine, etc.
  • “Pharmaceutical composition” refers to mixing one or more of the compounds of the present invention or their pharmaceutically acceptable salts, solvates, hydrates or prodrugs with other chemical ingredients, such as pharmaceutically acceptable carriers. .
  • the purpose of the pharmaceutical composition is to facilitate the process of administration to animals.
  • “Pharmaceutically acceptable carrier” refers to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to the 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 Sugar (such as lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic acid polymer or methacrylic acid polymer, gel, water, polyethylene glycol, propylene glycol, ethylene glycol Glycols, castor oil or hydrogenated castor oil or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil, etc.
  • the first aspect of the present invention provides a compound containing a sulfonamide structure or its tautomer, mesoform, racemate, enantiomer, diastereoisomer body, or a mixture thereof, or a pharmaceutically acceptable salt, the compound has a structure shown in formula (I), in formula (I),
  • X is CH2 or CH( CH3 );
  • R 1 is H, a substituted or unsubstituted C 1 -C 4 alkyl group, a C 1 -C 3 alkoxy group, a saturated three-membered ring group containing a heteroatom of S, a saturated three-membered ring group containing a heteroatom of O or S A four-membered ring group, a saturated five-membered ring group containing O or S heteroatoms, a six-membered saturated heterocycloalkyl group containing 1-2 oxygen atoms, a substituted or unsubstituted six-membered ring group containing 1-2 nitrogen atoms Saturated heterocycloalkyl, substituted or unsubstituted five-membered unsaturated heterocycloalkyl containing at least one nitrogen atom, substituted or unsubstituted six-membered unsaturated heterocycloalkyl containing at least one nitrogen atom, -C 1 - C 4 alkylene-OC 1 -C 3
  • R 2 is 3-pyridyl, substituted or unsubstituted phenyl; optional substituents in R 2 are selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -OC 1 -C 4 alkylene-OC 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by 1-6 halogen, C 1 -C 3 alkyl substituted by 1-6 halogen At least one of oxy, cyano, -OC 1 -C 4 alkylene -C 3 -C 6 cycloalkyl;
  • R 3 is C 1 -C 3 alkyl
  • R 4 is H, C 1 -C 3 alkoxy, halogen
  • R 5 and R 6 is H, and the other is selected from F, C 1 -C 3 alkyl.
  • X is CH2 or CH( CH3 );
  • R 1 is H, substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 3 alkoxy, six-membered saturated heterocycloalkyl containing 1-2 oxygen atoms, substituted or unsubstituted Six-membered saturated heterocycloalkyl containing at least 1 nitrogen atom, -C 1 -C 4 alkylene -OC 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 6 saturated cycloalkyl , Oxiranyl group, saturated four-membered ring group containing O atom, saturated five-membered ring group containing O atom, substituted five-membered unsaturated heterocycloalkyl group containing at least one nitrogen atom, substituted five-membered unsaturated heterocycloalkyl group containing at least one nitrogen atom Atomic six-membered unsaturated heterocycloalkyl, phenyl substituted by at least two halogens, phen
  • R 2 is 3-pyridyl, substituted or unsubstituted phenyl; optional substituents in R 2 are selected from fluorine, chlorine, bromine, iodine, C 1 -C 6 alkyl, C 1 -C 6 Alkoxy, -OC 1 -C 4 alkylene -OC 1 -C 2 alkyl, C 1 -C 3 alkyl substituted by 1-3 halogens, C substituted by 1-3 halogens At least one of 1 -C 3 alkoxy, cyano, -OC 1 -C 4 alkylene-C 3 -C 6 cycloalkyl;
  • R 3 is methyl, ethyl, n-propyl or isopropyl
  • R is H, methoxy, ethoxy, n - propoxy, isopropoxy, fluorine, chlorine or bromine;
  • R and R is H, and the other is selected from F, methyl, ethyl, n - propyl, isopropyl.
  • X is CH2 or CH( CH3 );
  • R 1 is H, substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 3 alkoxy, six-membered saturated heterocycloalkyl containing 1-2 oxygen atoms, substituted or unsubstituted Six-membered saturated heterocycloalkyl containing 1-2 nitrogen atoms, -C 1 -C 4 alkylene -OC 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 6 saturated cycloalkane group, oxiranyl group, saturated four-membered ring group containing O atom, saturated five-membered ring group containing O atom, substituted unsaturated five-membered ring group containing at least one N atom, substituted unsaturated five-membered ring group containing at least one N atom Unsaturated six-membered ring; containing at least two halogen-substituted phenyl, difluoromethoxy-substitute
  • R 2 is 3-pyridyl, substituted or unsubstituted phenyl; optional substituents in R 2 are selected from fluorine, chlorine, bromine, C 1 -C 6 alkyl, C 1 -C 6 alkoxy -OC 1 -C 4 alkylene -OC 1 -C 2 alkyl, C 1 -C 3 alkyl substituted by 1-3 halogens, C 1 - At least one of C 3 alkoxy, cyano, -OC 1 -C 4 alkylene -C 3 -C 6 cycloalkyl;
  • R 3 is methyl or ethyl
  • R 4 is H, methoxy or fluorine
  • R and R is H, and the other is selected from F, methyl, ethyl, n - propyl, isopropyl.
  • X is CH2 or CH( CH3 );
  • R 1 is H, methyl, isopropyl, tert-butyl, hydroxy-substituted tert-butyl, difluoromethyl, methoxy, dioxane, substituted or unsubstituted piperidinyl, -C 1 -C 4 alkylene group-OC 1 -C 3 alkyl group, substituted or unsubstituted C 3 -C 6 saturated cycloalkyl group, oxirane group, saturated four-membered ring group containing O atom, containing A saturated five-membered ring group with an O atom, a substituted unsaturated five-membered ring group containing at least one N atom, a substituted unsaturated six-membered ring group containing at least one N atom, a phenyl group substituted by at least two halogens, a bis Fluoromethoxy-substituted phenyl, trifluoromethoxy-substituted
  • R 2 is 3-pyridyl, substituted or unsubstituted phenyl; optional substituents in R 2 are selected from fluorine, chlorine, bromine, C 1 -C 6 alkyl, C 1 -C 6 alkoxy -OC 1 -C 4 alkylene -OC 1 -C 2 alkyl, C 1 -C 3 alkyl substituted by 1-3 halogens, C 1 - At least one of C 3 alkoxy, cyano, -OC 1 -C 4 alkylene -C 3 -C 6 cycloalkyl;
  • R 3 is methyl or ethyl
  • R 4 is H, methoxy or fluorine
  • R and R is H, and the other is selected from F, methyl, ethyl, n - propyl, isopropyl.
  • the compound represented by formula (I) is selected from any one of the following:
  • the pharmaceutically acceptable salts of the structure represented by the formula (I) of the present invention include but not limited to the hydrochloride salt form.
  • the present invention has no special requirements on the specific method for preparing the compound described in the aforementioned first aspect. Those skilled in the art can easily determine the appropriate preparation method according to the characteristics of the structural formula provided by the present invention in combination with known technical means in the field of organic synthesis. method. Moreover, the examples of the present invention exemplarily list the preparation methods of some specific compounds, and those skilled in the art can determine the specific preparation methods of the remaining compounds according to these exemplified preparation methods.
  • the present invention provides the method described in the second aspect to prepare a compound containing a sulfonamide structure or its tautomer, mesomer, racemate Rotary body, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt, the compound has the structure shown in formula (I),
  • the method comprises: carrying out a contact reaction between a compound represented by formula (II) and a compound represented by formula (III);
  • the compound of the present invention is obtained by the method shown in the following synthetic route, and the conditions of the substituents involved in the synthetic route are consistent with those described above.
  • the present invention has no particular limitation on the parameter conditions in the aforementioned synthetic route, those skilled in the art can use the parameters known in the art to carry out, and the synthesis parameter conditions of some specific compounds are exemplarily given in the following text of the present invention, those skilled in the art It should not be understood by the skilled person as a limitation of the present invention.
  • the third aspect of the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of the compound described in the aforementioned first aspect or its tautomer, mesomer, Racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt, and the pharmaceutical composition also contains a pharmaceutically acceptable carrier, excipient or diluent agent.
  • the present invention has no special requirements to the pharmaceutically acceptable carrier, excipient or diluent, and can be various substances known in the art, and the present invention will not repeat them here, and those skilled in the art should not be understood as the definition of the present invention limit.
  • the fourth aspect of the present invention provides the compound involved in the aforementioned first aspect or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof form, or a pharmaceutically acceptable salt, or the pharmaceutical composition involved in the third aspect, in the preparation of H+/K+-ATPase inhibitor medicine and/or the application of potassium ion competitive acid blocker medicine.
  • the fifth aspect of the present invention provides the compound involved in the aforementioned first aspect or its tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof form, or a pharmaceutically acceptable salt, or the pharmaceutical composition involved in the aforementioned third aspect, used in the preparation for the treatment or prevention of peptic ulcer, Zoller-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagus pylori infection, gastric cancer, gastric MALT lymphoma, ulcers due to NSAIDs, or stomach acid due to postoperative stress Excessive or ulcerative drug application.
  • the peptic ulcer includes at least one of gastric ulcer, duodenal ulcer and anastomotic ulcer;
  • the symptomatic gastroesophageal reflux disease includes non-erosive reflux disease and anesophageal At least one of the inflammatory gastroesophageal reflux diseases.
  • the aforementioned pharmaceutical composition and the aforementioned compound of the present invention can be used to prepare a gastric acid secretion inhibitor.
  • the present invention provides a method for inhibiting gastric acid secretion, the method comprising administering an effective dose of the aforementioned compound or its tautomer, mesoform, racemate, enantiomer to a patient in need of treatment , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable carrier in addition to the pharmaceutically acceptable carrier, it can also include adjuvants commonly used in medicine (pharmaceuticals), such as: antibacterial agents, antifungal agents, antimicrobial agents, preservatives, toners, enhancers, etc. Solvents, thickeners, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, sweeteners, pigments, flavors or their combinations, etc.
  • adjuvants commonly used in medicine (pharmaceuticals), such as: antibacterial agents, antifungal agents, antimicrobial agents, preservatives, toners, enhancers, etc.
  • Solvents thickeners, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, sweeteners, pigments, flavors or their combinations, etc.
  • preparation examples of the present invention for compound A1 to compound A15 are respectively named as preparation example A1 to preparation example A15.
  • preparation examples for compound 1 to compound 100 in the present invention are named as preparation example 1 to preparation example 100 respectively.
  • Step 2 Preparation of tert-butyl ((5-bromo-1H-pyrrol-3-yl)methyl)(methyl)carbamate
  • Brown-yellow oil the above product was dissolved in acetonitrile (30mL), di-tert-butyl dicarbonate (20.6mmol) was added dropwise, stirred at room temperature for 30min, TLC monitored the complete reaction of raw materials, and the reaction system was transferred in batches with ethyl acetate (300mL) Put it into a separatory funnel, wash with saturated brine (150mL ⁇ 3), dry the organic phase over anhydrous sodium sulfate, concentrate and mix the sample under reduced pressure, purify by column chromatography, and concentrate under reduced pressure to obtain a brown oily liquid with a yield of 79.5%.
  • Step 3 Preparation of tert-butyl ((5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate
  • reaction system was transferred to a separatory funnel with ethyl acetate (150 mL), washed with saturated brine (100 mL ⁇ 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a light yellow solid. Yield 69.8%.
  • Step 6 1-(5-(4-(Benzyloxy)-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylformazan Amine hydrochloride
  • the preparation method of this preparation example is similar to preparation example A1, and difference is:
  • the preparation method of this preparation example is similar to preparation example A1, and difference is:
  • the preparation method of this preparation example is similar to preparation example A1, and difference is:
  • the preparation method of this preparation example is similar to preparation example A1, and difference is:
  • step 6 The 3-hydroxymethyl-2-fluoropyridine in step 6) is replaced by 2-fluoro-6-hydroxymethylpyridine in an equimolar amount to obtain the hydrochloride salt of compound A5, a white solid, a step in step 6) Yield 46%.
  • the preparation method of this preparation example is similar to preparation example A1, and difference is:
  • step 6 The 3-hydroxymethyl-2-fluoropyridine in step 6) was replaced by equimolar amounts of 3-fluoro-2-hydroxymethylpyridine to obtain the hydrochloride salt of compound A6, a yellow solid, a step in step 6) Yield 49%.
  • the preparation method of this preparation example is similar to preparation example A1, and difference is:
  • step 6 The 3-hydroxymethyl-2-fluoropyridine in step 6) was replaced by an equimolar amount of 3-hydroxymethylpyridazine to obtain the hydrochloride salt of compound A7, a yellow solid, and the one-step yield in step 6) was 41 %.
  • the preparation method of this preparation example is similar to preparation example A1, and difference is:
  • step 6 The 3-hydroxymethyl-2-fluoropyridine in step 6) is replaced by an equimolar amount of 3-hydroxymethyl-1-methylpyrazole to obtain the hydrochloride salt of compound A8, a white solid, in step 6)
  • the one-step yield is 38%.
  • the preparation method of this preparation example is similar to preparation example A1, and difference is:
  • step 6 The 3-hydroxymethyl-2-fluoropyridine in step 6) was replaced by an equimolar amount of cyclopropylmethanol to obtain the hydrochloride salt of compound A9, a white solid, and the one-step yield in step 6) was 48%.
  • the preparation method of this preparation example is similar to preparation example A1, and difference is:
  • step 6 The 3-hydroxymethyl-2-fluoropyridine in step 6) was replaced by (2,2-difluorocyclopropyl)methanol in an equimolar amount to obtain the hydrochloride salt of compound A10, a white solid, in step 6)
  • the one-step yield is 36%.
  • the preparation method of this preparation example is similar to preparation example A1, and difference is:
  • step 6 The 3-hydroxymethyl-2-fluoropyridine in step 6) was replaced by an equimolar amount of oxirane-2-ylmethanol to obtain the hydrochloride salt of compound A11, a white solid, and one step in step 6). Rate 60%.
  • the preparation method of this preparation example is similar to preparation example A1, and difference is:
  • step 6 The 3-hydroxymethyl-2-fluoropyridine in step 6) was replaced by an equimolar amount of oxetan-3-ylmethanol to obtain the hydrochloride salt of compound A12, a white solid, a step in step 6) Yield 44%.
  • the preparation method of this preparation example is similar to preparation example A1, and difference is:
  • step 6 The 3-hydroxymethyl-2-fluoropyridine in step 6) was replaced by an equimolar amount of tetrahydrofuran-3-ylmethanol to obtain the hydrochloride salt of compound A13, a white solid, and the one-step yield in step 6) was 40% .
  • the preparation method of this preparation example is similar to preparation example A1, and difference is:
  • step 6 The 3-hydroxymethyl-2-fluoropyridine in step 6) was replaced by an equimolar amount of tetrahydrofuran-2-ylmethanol to obtain the hydrochloride salt of compound A14, a white solid, and the one-step yield in step 6) was 46% .
  • the preparation method of this preparation example is similar to preparation example A1, and difference is:
  • step 6 The 3-hydroxymethyl-2-fluoropyridine in step 6) was replaced by an equimolar amount of oxetan-2-ylmethanol to obtain the hydrochloride salt of compound A15, a yellow solid, a step in step 6) Yield 52%.
  • Step 2 Preparation of tert-butyl ((5-bromo-1H-pyrrol-3-yl)methyl)(methyl)carbamate
  • Brown-yellow oil the above product was dissolved in acetonitrile (30mL), di-tert-butyl dicarbonate (20.6mmol) was added dropwise, stirred at room temperature for 30min, TLC monitored the complete reaction of raw materials, and the reaction system was transferred in batches with ethyl acetate (300mL) Put it into a separatory funnel, wash with saturated brine (150mL ⁇ 3), dry the organic phase over anhydrous sodium sulfate, concentrate and mix the sample under reduced pressure, purify by column chromatography, and concentrate under reduced pressure to obtain a brown oily liquid with a yield of 79.5%.
  • Step 3 Preparation of tert-butyl ((5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate
  • reaction system was transferred to a separatory funnel with ethyl acetate (150 mL), washed with saturated brine (100 mL ⁇ 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a light yellow solid. Yield 69.8%.
  • Step 6 (S)-1-(5-(4-((1,4-dioxan-2-yl)methoxy)-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl Acyl)-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 Replace the (2S)-1,4-dioxane-2-methanol in step 6) with an equimolar amount of cyclobutylmethanol to obtain the hydrochloride salt of compound 2, a white solid, the one-step yield in step 6). rate 24%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 The (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of cyclopentylmethanol to obtain the hydrochloride salt of compound 3, a white solid, the one-step yield in step 6). rate 31%.
  • the preparation method of this preparation example is similar to that of preparation example 1, except that the (2S)-1,4-dioxane-2-methanol in step 6) is replaced by an equimolar amount of cyclohexylmethanol to obtain the compound
  • the hydrochloride salt of 4, white solid, the one-step yield in step 6) is 35%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 4,4-difluoro-cyclohexanemethanol to obtain the hydrochloride salt of compound 5, a white solid,
  • the one-step yield in step 6) was 37%.
  • the preparation method of this preparation example is similar to that of preparation example 1, and the difference is that (2S)-1,4-dioxane-2-methanol in step 6) is replaced by an equimolar amount of 4-hydroxymethyl tetra Hydropyran, compound 6 was obtained as a white solid, the one-step yield in step 6) was 34%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of tetrahydropyran-2-methanol to obtain the hydrochloride salt of compound 7, a white solid, step 6)
  • the yield in one step is 40%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • (2S)-1,4-dioxane-2-methanol in step 6) is replaced by equimolar amounts of 1-(tetrahydro-2H-pyran-4-yl)ethanol to obtain the hydrochloric acid of compound 8 Salt, white solid, one step yield 25% in step 6).
  • the preparation method of this preparation example is similar to that of preparation example 1, the difference is: replace the pyridine-3-sulfonyl chloride in step 3) with 3,5-difluorobenzenesulfonyl chloride in an equimolar amount, yellow solid, yield 70%.
  • (2S)-1,4-dioxane-2-methanol in step 6) is replaced by equimolar amounts of 1-(tetrahydro-2H-pyran-4-yl)ethanol to obtain the hydrochloric acid of compound 9 Salt, white solid, 28% one-step yield in step 6).
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • (2S)-1,4-dioxane-2-methanol in step 6) is replaced by equimolar amounts of 1-(tetrahydro-2H-pyran-4-yl)ethanol to obtain the hydrochloric acid of compound 10 Salt, white solid, one step yield in step 6) 35%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • (2S)-1,4-dioxane-2-methanol in step 6) is replaced by equimolar amounts of 1-(tetrahydro-2H-pyran-4-yl)ethanol to obtain the hydrochloric acid of compound 11 Salt, white solid, 31% one-step yield in step 6).
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • (2S)-1,4-dioxane-2-methanol in step 6) is replaced by equimolar amounts of 1-(tetrahydro-2H-pyran-4-yl)ethanol to obtain the hydrochloric acid of compound 12 Salt, white solid, 40% one-step yield in step 6).
  • the preparation method of this preparation example is similar to that of preparation example 1, the difference is: the pyridine-3-sulfonyl chloride in step 3) is replaced by an equimolar amount of 3-cyanobenzenesulfonyl chloride, yellow solid, yield 71% .
  • (2S)-1,4-dioxane-2-methanol in step 6) is replaced by an equimolar amount of 1-(tetrahydro-2H-pyran-4-yl)ethanol to obtain the hydrochloric acid of compound 13 Salt, white solid, 36% one-step yield in step 6).
  • Step 3 Preparation of tert-butyl ((5-bromo-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate
  • Step 6 tert-Butyl((1-((3-(2-methoxyethoxy)phenyl)sulfonyl)-5-(2-fluoro-4-hydroxyphenyl)-1H-pyrrole-3 Preparation of -yl)methyl)(methyl)carbamate
  • reaction system was transferred to a separatory funnel with ethyl acetate (150 mL), washed with saturated brine (100 mL ⁇ 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a light yellow solid. Yield 69.3%.
  • Step 7 1-(5-(2-fluoro-4-(1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)-1-((3-(2-methoxy (ethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine – hydrochloride
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 The pyridine-3-sulfonyl chloride in step 3) was replaced by an equimolar amount of 3-methoxybenzenesulfonyl chloride, a yellow solid with a yield of 69%.
  • (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 1-(tetrahydro-2H-pyran-4-yl)ethanol to obtain the hydrochloric acid of compound 15 Salt, gray solid, 45% one-step yield in step 6).
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • (2S)-1,4-dioxane-2-methanol in step 6) is replaced by an equimolar amount of 1-(tetrahydro-2H-pyran-4-yl)ethanol to obtain the hydrochloric acid of compound 16 Salt, white solid, 41% one-step yield in step 6).
  • the preparation method of this preparation example is similar to that of preparation example 1, except that the pyridine-3-sulfonyl chloride in step 3) is replaced by 2,4-difluorobenzenesulfonyl chloride in an equimolar amount, yellow solid, yield 68%.
  • (2S)-1,4-dioxane-2-methanol in step 6) is replaced by equimolar amounts of 1-(tetrahydro-2H-pyran-4-yl)ethanol to obtain the hydrochloric acid of compound 17 Salt, white solid, 42% one-step yield in step 6).
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 The pyridine-3-sulfonyl chloride in step 3) was replaced by an equimolar amount of 4-cyanobenzenesulfonyl chloride, a yellow solid with a yield of 66%.
  • (2S)-1,4-dioxane-2-methanol in step 6) is replaced by equimolar amounts of 1-(tetrahydro-2H-pyran-4-yl)ethanol to obtain the hydrochloric acid of compound 18 Salt, white solid, 43% one-step yield in step 6).
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 Replace the (2S)-1,4-dioxane-2-methanol in step 6) with an equimolar amount of 1-cyclohexyl ethanol to obtain the hydrochloride salt of compound 20, a white solid, a step in step 6) Yield 49%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 1-methyl-4-piperidinemethanol to obtain the hydrochloride salt of compound 22, gray solid, step 6)
  • the one-step yield in 6) is 40%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 1-(4-(hydroxymethyl)piperidin-1-yl)ethanone to obtain compound 23
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 4-hydroxymethyltetrahydropyran to obtain the hydrochloride salt of compound 24, a white solid, step 6 ) in one step yield 45%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 4-hydroxymethyltetrahydropyran to obtain the hydrochloride salt of compound 25, a white solid, step 6 ) in one step yield 42%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 4-hydroxymethyltetrahydropyran to obtain the hydrochloride salt of compound 26, a white solid, step 6 ) in one step yield 44%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 4-hydroxymethyltetrahydropyran to obtain the hydrochloride salt of compound 27, a white solid, step 6 ) in one step yield 49%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 The pyridine-3-sulfonyl chloride in step 3) was replaced by an equimolar amount of 3-cyanobenzenesulfonyl chloride, a yellow solid with a yield of 70%.
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 4-hydroxymethyltetrahydropyran to obtain the hydrochloride salt of compound 28, a white solid, step 6 ) in one step yield 51%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 The pyridine-3-sulfonyl chloride in step 3) was replaced by an equimolar amount of 4-cyanobenzenesulfonyl chloride, a yellow solid with a yield of 68%.
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 4-hydroxymethyltetrahydropyran to obtain the hydrochloride salt of compound 29, a white solid, step 6 ) in one step yield 42%.
  • the preparation method of this preparation example is similar to preparation example 14, and difference is:
  • step 4 The ethylene glycol methyl ether in step 4) was replaced by an equimolar amount of 2-fluoroethanol, resulting in a yellow solid with a yield of 60%.
  • step 7 The 1-(tetrahydro-2H-pyran-4-yl) ethanol in step 7) was replaced by an equimolar amount of 4-hydroxymethyltetrahydropyran to obtain the hydrochloride salt of compound 30, a white solid, step 7)
  • the one-step yield in 7) is 43%.
  • the preparation method of this preparation example is similar to preparation example 14, and difference is:
  • step 4 The ethylene glycol methyl ether in step 4) was replaced by an equimolar amount of n-amyl alcohol, resulting in a yellow solid with a yield of 62%.
  • step 7 Replace the 1-(tetrahydro-2H-pyran-4-yl)ethanol in step 7) with an equimolar amount of 4-hydroxymethyltetrahydropyran to obtain the hydrochloride salt of compound 31, a white solid, step 7)
  • the one-step yield in 7) is 20%.
  • the preparation method of this preparation example is similar to preparation example 14, and difference is:
  • step 4 The ethylene glycol methyl ether in step 4) was replaced by an equimolar amount of 3-methoxy-1-propanol, resulting in a yellow solid with a yield of 64%.
  • step 7) The 1-(tetrahydro-2H-pyran-4-yl)ethanol in step 7) was replaced by an equimolar amount of 4-hydroxymethyltetrahydropyran to obtain the hydrochloride salt of compound 32, a white solid, step 7)
  • the one-step yield in 7) is 25%.
  • the preparation method of this preparation example is similar to preparation example 14, and difference is:
  • step 4 The ethylene glycol methyl ether in step 4) was replaced by an equimolar amount of cyclopropylmethanol, resulting in a yellow solid with a yield of 61%.
  • step 7 Replace the 1-(tetrahydro-2H-pyran-4-yl)ethanol in step 7) with an equimolar amount of 1-(tetrahydro-2H-pyran-4-yl)ethanol to obtain the salt of compound 33 Acid salt, white solid, one-step yield in step 7) 34%.
  • the preparation method of this preparation example is similar to preparation example 14, and difference is:
  • step 4 The ethylene glycol methyl ether in step 4) was replaced by an equimolar amount of cyclopentylmethanol, resulting in a yellow solid with a yield of 61%.
  • step 7) The 1-(tetrahydro-2H-pyran-4-yl)ethanol in step 7) was replaced by an equimolar amount of 4-hydroxymethyltetrahydropyran to obtain the hydrochloride salt of compound 34, a white solid, step 7)
  • the one-step yield in 7) is 46%.
  • the preparation method of this preparation example is similar to preparation example 14, and difference is:
  • step 4 The ethylene glycol methyl ether in step 4) was replaced by an equimolar amount of 2-fluoroethanol, resulting in a yellow solid with a yield of 62%.
  • step 7 The 1-(tetrahydro-2H-pyran-4-yl)ethanol in step 7) was replaced by an equimolar amount of cyclohexylmethanol to obtain the hydrochloride salt of compound 35, a white solid, the one-step yield in step 7). Rate 45%.
  • the preparation method of this preparation example is similar to preparation example 14, and difference is:
  • step 4 The ethylene glycol methyl ether in step 4) was replaced by an equimolar amount of n-amyl alcohol, resulting in a yellow solid with a yield of 64%.
  • step 7 The 1-(tetrahydro-2H-pyran-4-yl)ethanol in step 7) was replaced by an equimolar amount of cyclohexylmethanol to obtain the hydrochloride salt of compound 36, a white solid, the one-step yield in step 7). rate 19%.
  • the preparation method of this preparation example is similar to preparation example 14, and difference is:
  • step 4 The ethylene glycol methyl ether in step 4) was replaced by an equimolar amount of 3-methoxy-1-propanol, resulting in a yellow solid with a yield of 61%.
  • step 7 Replace the 1-(tetrahydro-2H-pyran-4-yl)ethanol in step 7) with an equimolar amount of 1-(tetrahydro-2H-pyran-4-yl)ethanol to obtain the salt of compound 37 Acid salt, white solid, one-step yield in step 7) 44%.
  • Preparation 38 This preparation is used to illustrate the synthesis process of the hydrochloride salt of compound 38
  • the preparation method of this preparation example is similar to preparation example 14, and difference is:
  • step 4 The ethylene glycol methyl ether in step 4) was replaced by an equimolar amount of -methoxy-1-butanol, a yellow solid with a yield of 58%.
  • step 7 Replace the 1-(tetrahydro-2H-pyran-4-yl)ethanol in step 7) with an equimolar amount of 1-(tetrahydro-2H-pyran-4-yl)ethanol to obtain the salt of compound 38 Acid salt, yellow solid, one-step yield in step 7) 20%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 The pyridine-3-sulfonyl chloride in step 3) was replaced by an equimolar amount of 3-trifluoromethylbenzenesulfonyl chloride, a yellow solid with a yield of 68%.
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 4-hydroxymethyltetrahydropyran to obtain the hydrochloride salt of compound 39, a white solid, step 6 ) in one step yield 54%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 The (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of methanol to obtain the hydrochloride salt of compound 40, a white solid, and the one-step yield in step 6) was 46% .
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 The (2S)-1,4-dioxane-2-methanol in step 6) was replaced by ethanol in an equimolar amount to obtain the hydrochloride salt of compound 41, a white solid, and the one-step yield in step 6) was 53% .
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 Replace the (2S)-1,4-dioxane-2-methanol in step 6) with an equimolar amount of 2,2-difluoroethanol to obtain the hydrochloride salt of compound 42, a white solid, in step 6)
  • the one-step yield is 47%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by isopropanol in an equimolar amount to obtain the hydrochloride salt of compound 44, a white solid, and the one-step yield in step 6) 50%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 The (2S)-1,4-dioxane-2-methanol in step 6) was replaced by neopentyl alcohol in an equimolar amount to obtain the hydrochloride salt of compound 45, a white solid, and the one-step yield in step 6) 38%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 2 The 33% methylamine-methanol solution in step 2) was replaced by an equimolar amount of ethylamine-methanol, resulting in a brown oily liquid with a yield of 70%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • TLC detection post-treatment after disappearance of raw materials: drop water 500mL to quench, extract with MTBE (200mL ⁇ 3), combine organic phases, wash with 300mL saturated brine ⁇ 2, dry over anhydrous sodium sulfate, filter and rotary evaporate under reduced pressure to remove the solvent to obtain Yellow semi-solid.
  • Step 4 Preparation of methyl 5-(4-(cyclopropylmethoxy)-2-fluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylate
  • Step 6 (5-(4-(Cyclopropylmethoxy)-2-fluorophenyl)-4-methoxy-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl ) Preparation of Methanol
  • Step 7 5-(4-(Cyclopropylmethoxy)-2-fluorophenyl)-4-methoxy-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde preparation
  • Step 8 1-(5-(4-(Cyclopropylmethoxy)-2-fluorophenyl)-4-methoxy-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 - Preparation of -N-methylmethylamine
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 Replace the (2S)-1,4-dioxane-2-methanol in step 6) with (S)-glycidol in an equimolar amount to obtain the hydrochloride salt of compound 49, gray solid, the Yield of 45% in one step.
  • Preparation 50 This preparation is used to illustrate the synthesis process of the hydrochloride salt of compound 50
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • preparation method of this preparation example is similar to preparation example 48, the difference is:
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 2-methylpropane-1,2-diol to obtain the hydrochloride salt of compound 52, a brown solid , step 6) in one step yield 46%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of cis-2-fluorocyclopropyl)methanol to obtain the hydrochloride salt of compound 53 as a white solid,
  • the one-step yield in step 6) was 46%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 2,4-difluorobenzyl alcohol to obtain the hydrochloride salt of compound 55, yellow oil, step 6 ) in one step yield 45%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 2,6-difluorobenzyl alcohol to obtain the hydrochloride salt of compound 56 as a white solid, step 6)
  • the yield in one step is 45%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 3,4-difluorobenzyl alcohol to obtain the hydrochloride salt of compound 57, a white solid, step 6)
  • the yield in one step is 56%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 3,5-difluorobenzyl alcohol to obtain the hydrochloride salt of compound 58, a white solid, step 6)
  • the yield in one step is 55%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 2-trifluoromethoxybenzyl alcohol to obtain the hydrochloride salt of compound 60, a white solid, step 6 ) in one step yield 56%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 4-difluoromethoxybenzyl alcohol to obtain the hydrochloride salt of compound 61, a white solid, step 6 ) in one step yield 55%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 Pyridine-3-sulfonyl chloride in step 3) is replaced by 3-cyanobenzenesulfonyl chloride in an equimolar amount, (2S)-1,4-dioxane-2-methanol in step 6) is replaced by molar amount of 1-hydroxymethylnaphthalene, the hydrochloride of compound 63 was obtained, a white solid, and the one-step yield in step 6) was 43%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • Preparation 65 This preparation is used to illustrate the synthesis process of the hydrochloride salt of compound 65
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • Preparation 66 This preparation is used to illustrate the synthesis process of the hydrochloride salt of compound 66
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • Preparation 68 This preparation is used to illustrate the synthesis process of the hydrochloride salt of compound 68
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 Pyridine-3-sulfonyl chloride in step 3) is replaced by 3-cyanobenzenesulfonyl chloride in an equimolar amount, (2S)-1,4-dioxane-2-methanol in step 6) is replaced by molar amount of 1-(2,6-difluorophenyl)ethanol, the hydrochloride salt of compound 69 was obtained as a white solid, and the one-step yield in step 6) was 43%.
  • Preparation 70 This preparation is used to illustrate the synthesis process of the hydrochloride salt of compound 70
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 Pyridine-3-sulfonyl chloride in step 3) is replaced by 3-cyanobenzenesulfonyl chloride in an equimolar amount, (2S)-1,4-dioxane-2-methanol in step 6) is replaced by molar amount of 1-(3,5-difluorophenyl)ethanol, the hydrochloride salt of compound 70 was obtained as a white solid, and the one-step yield in step 6) was 45%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • Preparation 72 This preparation is used to illustrate the synthesis process of the hydrochloride salt of compound 72
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • Pyridine-3-sulfonyl chloride in step 3) is replaced by 3-(cyclopropylmethoxy)benzenesulfonyl chloride in an equimolar amount
  • (2S)-1,4-dioxane- 2-methanol was replaced by an equimolar amount of 1-(2,6-difluorophenyl)ethanol to obtain the hydrochloride salt of compound 72 as a yellow oil
  • the one-step yield in step 6) was 45%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 2,4-dimethylbenzyl alcohol to obtain the hydrochloride salt of compound 73, a white solid, step 6 ) in one step yield 56%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 The (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 4-hydroxymethylpyridine to obtain compound 74 as a white solid, and the one-step yield in step 6) was 57 %.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • Preparation 76 This preparation is used to illustrate the synthesis process of the hydrochloride salt of compound 76
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 The (2S)-1,4-dioxane-2-methanol in step 6) was replaced by an equimolar amount of 3-hydroxymethylthiophene to obtain compound 77, a yellow solid, and the one-step yield in step 6) was 40 %.
  • Preparation 78 This preparation is used to illustrate the synthesis process of the hydrochloride salt of compound 78
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 Replace the pyridine-3-sulfonyl chloride in step 3) with 3-chlorobenzenesulfonyl chloride in an equimolar amount, and replace the (2S)-1,4-dioxane-2-methanol in step 6) with an equimolar amount of 2,5-difluorobenzyl alcohol to obtain the hydrochloride salt of compound 78, a white solid, and the one-step yield in step 6) was 40%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 Pyridine-3-sulfonyl chloride in step 3) is replaced by equimolar 3-fluorobenzenesulfonyl chloride, and (2S)-1,4-dioxane-2-methanol in step 6) is replaced by equimolar amount of 2,5-difluorobenzyl alcohol to obtain the hydrochloride salt of compound 79, a white solid, and the one-step yield in step 6) was 36%.
  • Preparation 80 This preparation is used to illustrate the synthesis process of the hydrochloride salt of compound 80
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 Replace the pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-fluoro-4-methylbenzenesulfonyl chloride, and replace the (2S)-1,4-dioxane-2- Methanol was replaced by an equimolar amount of 2,5-difluorobenzyl alcohol to obtain the hydrochloride salt of compound 81 as a white solid, and the one-step yield in step 6) was 36%.
  • Preparation 82 This preparation is used to illustrate the synthesis process of the hydrochloride salt of compound 82
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • Pyridine-3-sulfonyl chloride in step 3) is replaced by 3-pentyloxybenzenesulfonyl chloride in an equimolar amount
  • (2S)-1,4-dioxane-2-methanol in step 6) is replaced by Equimolar amounts of 2,5-difluorobenzyl alcohol were used to obtain the hydrochloride salt of compound 82 as a white solid, and the one-step yield in step 6) was 36%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • Pyridine-3-sulfonyl chloride in step 3) is replaced by 3-cyclobutylmethoxybenzenesulfonyl chloride in an equimolar amount
  • (2S)-1,4-dioxane-2-methanol in step 6) is replaced Equimolar amount of 1-(2,6-difluorophenyl)-ethanol was used to obtain the hydrochloride salt of compound 83 as a yellow oil, and the one-step yield in step 6) was 41%.
  • Preparation 84 This preparation is used to illustrate the synthesis process of the hydrochloride salt of compound 84
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 Replace the pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-(2-methoxy-ethoxy)benzenesulfonyl chloride, and (2S)-1,4-di Oxane-2-methanol was replaced by an equimolar amount of 2,4-difluorobenzyl alcohol to obtain the hydrochloride salt of compound 86 as a white solid in a one-step yield of 45% in step 6).
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 Replace the pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-(2-methoxy-ethoxy)benzenesulfonyl chloride, and (2S)-1,4-di Oxane-2-methanol was replaced by an equimolar amount of 2-methoxybenzyl alcohol to obtain compound 87 as a white solid in a one-step yield of 39% in step 6).
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 Replace the pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-(3-methoxy-propoxyl)benzenesulfonyl chloride, and (2S)-1,4-di Oxane-2-methanol was replaced by an equimolar amount of 1-(2,6-difluorophenyl)-ethanol to obtain compound 88 as a yellow oil in a one-step yield of 44% in step 6).
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • Preparation 90 This preparation is used to illustrate the synthesis process of the hydrochloride salt of compound 90
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 Replace the pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-(4-methoxy-butoxy)benzenesulfonyl chloride, and (2S)-1,4-di Oxane-2-methanol was replaced by an equimolar amount of 2-hydroxymethylnaphthalene to obtain the hydrochloride salt of compound 90 as a white solid, and the one-step yield in step 6) was 51%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 Replace the pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-(4-methoxy-butoxy)benzenesulfonyl chloride, and (2S)-1,4-di Oxane-2-methanol was replaced by an equimolar amount of 1-(2,6-difluorophenyl)-ethanol to obtain compound 91 as a white solid in a one-step yield of 48% in step 6).
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 Replace the pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-(4-methoxy-butoxy)benzenesulfonyl chloride, and (2S)-1,4-di Oxane-2-methanol was replaced by an equimolar amount of 1-(3,5-difluorophenyl)-ethanol to obtain the hydrochloride salt of compound 92 as a yellow solid, and the one-step yield in step 6) was 41%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 6 (2S)-1,4-dioxane-2-methanol in step 6) was replaced by equimolar amounts of 1,3-benzodioxolane-4-alkylmethanol to obtain the hydrochloric acid of compound 94 Salt, white solid, one step yield in step 6) 50%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • Preparation 96 This preparation is used to illustrate the synthesis process of the hydrochloride salt of compound 96
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • (2S)-1,4-dioxane-2-methanol in step 6) is replaced by an equimolar amount of 2,3-dihydro-1,4-benzodioxin-5-methanol to obtain the compound
  • the hydrochloride salt of 96, white solid, the one-step yield in step 6) is 56%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • step 3 Pyridine-3-sulfonyl chloride in step 3) is replaced by 3-trifluoromethylbenzenesulfonyl chloride in an equimolar amount, and (2S)-1,4-dioxane-2-methanol in step 6) is replaced Equimolar amount of 2,-5-difluorobenzyl alcohol was used to obtain the hydrochloride salt of compound 98 as a white solid, and the one-step yield in step 6) was 52%.
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • Preparation 100 This preparation is used to illustrate the synthesis process of the hydrochloride salt of compound 100
  • the preparation method of this preparation example is similar to preparation example 1, and difference is:
  • Test Example 1 Biological Evaluation of H + /K + -ATPase
  • This test example evaluates the inhibitory effect of the compound of the present invention on H + /K + -ATPase enzyme activity through an in vitro screening test, and is represented by the IC 50 value of the compound (calculated by the inhibition rate at different concentrations).
  • Malachite green solution 0.12wt% malachite green (Bai Lingwei Chemical Technology Co., Ltd., article number: 913120) was dissolved in 2.5mol/L sulfuric acid, 7.5wt% ammonium molybdate (Bailingwei Chemical Technology Co., Ltd., article number: 128321) and 11 %Tween 20 (V/V), sulfuric acid, ammonium molybdate, and Tween 20 are mixed in a ratio of 100:25:2 when used;
  • tissue particles After homogenization, if there are larger tissue particles, they can be removed by centrifugation (600g, 10min), then move the supernatant to a clean centrifuge tube and centrifuge at 20,000g for 30min, then move the supernatant to a clean centrifuge tube for further Centrifuge, centrifuge at 100000g for 90min, collect the precipitate; use the homogenate to suspend the precipitate, blow it evenly, use the Bradford method to measure the protein concentration, and adjust the concentration to 10mg/ml; Collect the middle layer (H+/K+-ATPaseenriched gastric membranes) in a clean centrifuge tube, dilute it 4-5 times with the homogenate, continue to centrifuge at 100 000g for 90min, and collect the precipitate; use the homogenate to suspend the sediment, and homogenize with a glass homogenizer The protein concentration was measured by the Bradford method, and the concentration was adjusted to 22.5mg/ml. Freeze at -80°C for later use.
  • Test Example 2 Inhibitory Effects of Compounds on Histamine-Induced Gastric Acid Secretion in Rats
  • the rat was anesthetized with 300mg/kg (1ml/100g) of chloral hydrate, fixed on the rat board, and cut the abdominal wall from the substernal xiphoid process along the midline of the abdomen. , and gently push up with your fingers to expose the stomach to the incision. Thread a thread under the pylorus to ligate the pylorus (other adjacent blood vessels are not ligated), and then suture the abdominal wall incision. Animals were given histamine dihydrochloride (30mg/10ml/kg) subcutaneously 1 hour after intragastric administration of the test compound or normal saline.
  • the rats were killed by asphyxiation with excessive CO 2 , the stomach was taken out, the contents of the stomach were collected, centrifuged at 3000 rpm/min for 10 minutes, the acid solution was titrated to pH 7.0 with 0.1mol/L NaOH, and the total acid and Acid suppression rate.
  • Acid suppression rate (%) (total acid amount of model group-total acid amount of administration group)/total acid amount of model group ⁇ 100%.
  • Test Example 3 Rat Tissue Distribution Test of Compound 48, Compound A9 and Comparative Compound Vonorazan
  • the solvent used for the preparation of drug preparations pure water. Fasting 4 hours before administration. Plasma, liver, and stomach were collected at 1h, 2h, and 4h (the remaining SD rats took blank tissues for the analysis group). The tissue was homogenized, and the corresponding blank tissue was used to prepare standard music and QC quantification. Blood samples should be centrifuged within 1 hour of collection to obtain plasma, and blood samples should be placed on crushed ice before centrifugation. Plasma samples obtained by centrifugation were stored in a freezer until analysis. Centrifugation conditions: 4-10°C, 8000rpm, 6 minutes. The sample concentration was detected by LC-MS-MS (MS03: Shimadzu LC30AD and API 4000)), and the exposure data was calculated by WINNOLIN software. The results are listed in Table 3, Table 4 and Table 5.
  • Table 3 Tissue distribution of Compound 48 in rats at an oral dose of 4 mg/kg
  • Table 4 Tissue distribution of Compound A9 in rats at an oral dose of 4 mg/kg
  • Table 5 Comparison of hepatic drug concentrations between compound A9 and the comparative compound Vonorazan at an oral dose of 4 mg/kg
  • the compound of the present invention is expected to improve the therapeutic effect while reducing the safety risks such as liver toxicity of the marketed drug Vonorazan.

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Abstract

本发明涉及药物领域，公开了一种含磺酰胺结构的化合物及其制备方法和应用、一种药物组合物及应用，该化合物具有式(I)所示的结构，本发明提供的化合物能够作为治疗剂，特别是作为胃酸分泌抑制剂和钾离子竞争性酸阻滞剂(P-CABs)。

Description

一种含磺酰胺结构的化合物及其制备方法和应用、一种药物组合物及应用
相关申请的交叉引用
本申请要求2021年07月12日提交的中国专利申请202110786023.X的权益，该申请的内容通过引用被合并于本文。
技术领域
本发明涉及药物领域，具体涉及一种含磺酰胺结构的化合物及其制备方法和应用、一种药物组合物及应用。
背景技术
以奥美拉唑为代表的质子泵抑制剂(proton pump inhibitor，PPI)通过抑制胃壁细胞上的H+/K+-ATP酶，强而持久地抑制胃酸分泌，目前PPI广泛用于治疗胃食管反流病、消化性溃疡、幽门螺杆菌感染、上消化道出血、卓-艾综合征等酸相关性疾病。
自1988年以来，长期的临床应用发现，PPI由于存在不稳定、半衰期短、受CYP2C19基因多态性影响、服药时间受限制、起效慢等缺点，临床上需要起效更快，抑酸作用更强，pH维持时间更长的抗酸药物。
钾竞争性酸阻滞剂(Potassium-Competitive Acid Blockers，P-CABs)钾离子竞争性酸阻滞剂(P-CAB)作为一种新型抑酸药物，通过离子形式直接与K+竞争H+/K+-ATP酶上的结合位点，同时抑制静止和激活状态的H+/K+-ATP酶，从而有效抑制胃酸分泌。与传统质子泵抑制剂相比，P-CABs具有亲脂性、弱碱性、解离常数高和在低pH条件下稳定的特点。
相比质子泵抑制剂(PPI)，P-CAB是一类亲脂性弱碱，抑酸起效更快、作用持久，且不易产生夜间酸突破现象；且P-CAB类药物稳定性好，无需制成肠溶剂型，且不受基因多态性影响。。
然而，已上市的代表性P-CABs沃诺拉赞的在临床应用中也表现出一定的安全性风险，如肝毒性等。因此，尽管目前已公开了一系列钾竞争性酸阻滞剂，但仍需要开发结构类型更丰富的，新的可能具有更好的组织分布等成药性质的化合物。
发明内容
本发明的目的是为了克服现有技术的前述缺陷，提供一类具有钾竞争性酸阻滞剂功效的新化合物。
为了实现上述目的，本发明的第一方面提供一种含磺酰胺结构的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐，该化合物具有式(I)所示的结构，
Figure PCTCN2021126527-appb-000001
在式(I)中，
X为CH 2或CH(CH 3)；
R 1为H、取代或未取代的C 1-C 4的烷基、C 1-C 3的烷氧基、含有S的杂原子的饱和三元环基、含有O或S的杂原子的饱和四元环基、含有O或S的杂原子的饱和五元环基、含有1-2个氧原子的六元饱和杂环烷基、取代或未取代的含有1-2个氮原子的六元饱和杂环烷基、取代或未取代的含有至少一个氮原子的五元不饱和杂环烷基、 取代或未取代的含有至少一个氮原子的六元不饱和杂环烷基、-C 1-C 4的亚烷基-O-C 1-C 3的烷基、取代或未取代的C 3-C 6的饱和环烷基、环氧乙烷基、含有至少两个卤素取代的苯基、二氟甲氧基取代的苯基、三氟甲氧基取代的苯基、羧基取代的苯基、萘基、含有至少两个甲基取代的苯基、吡啶-4-基、甲氧基取代的苯基、噻吩-3-基、苯并二氧戊环基、苯并二氧己环基、-CH 2-含有至少两个卤素取代的苯基、呋喃-3-基；R 1中任选存在的取代基选自卤素、氰基、硝基、羟基、C 1-C 6的烷基、C 1-C 6的烷氧基、C 1-C 3的醛基中的至少一种；
R 2为3-吡啶基、取代或未取代的苯基；R 2中任选存在的取代基选自卤素、C 1-C 6的烷基、C 1-C 6的烷氧基、-O-C 1-C 4的亚烷基-O-C 1-C 3的烷基、由1-6个卤素取代的C 1-C 3的烷基、由1-6个卤素取代的C 1-C 3的烷氧基、氰基、-O-C 1-C 4的亚烷基-C 3-C 6的环烷基中的至少一种；
R 3为C 1-C 3的烷基；
R 4为H、C 1-C 3的烷氧基、卤素；
R 5和R 6中的一者为H，另一者选自F、C 1-C 3的烷基。
本发明的第二方面提供制备含磺酰胺结构的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐的方法，该化合物具有式(I)所示的结构，
该方法包括：将式(II)所示的化合物与式(III)所示的化合物进行接触反应；
Figure PCTCN2021126527-appb-000002
其中，在式(I)、式(II)和式(III)中，各基团的定义与第一方面中所述的定义相同。
本发明的第三方面提供一种药物组合物，该药物组合物含有治疗有效量的前述第一方面中所述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐，以及该药物组合物中还含有药物可接受的载体、赋形剂或稀释剂。
本发明的第四方面提供第一方面中所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐，或者第三方面中所述的药物组合物，在制备H+/K+-ATPase抑制剂药物和/或制备钾离子竞争性酸阻滞剂药物中的应用。
本发明的第五方面提供第一方面中所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐，或者第三方面中所述的药物组合物，在制备用于治疗或预防消化性溃疡、卓-艾综合症、胃炎、糜烂性食管炎、反流性食管炎、症状性胃食管反流疾病、巴雷特食管炎、功能性消化不良、幽门螺旋杆菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡或手术后应激导致的胃酸过多或溃疡的药物中的应用。
本发明提供的前述化合物能够作为治疗剂，特别是作为胃酸分泌抑制剂和钾离子竞争性酸阻滞剂(P-CABs)。
具体实施方式
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值，这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说，各个范围的端点值之间、各个范围的端点值和单独的点值之间，以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围，这些数值范围应被视为在本文中具体公开。
除非有相反陈述，下列用在本文中的术语具有下述含义。
“C 1-C 6的烷基”指饱和的烷基基团，包括1至6个碳原子的直链或支链烷基基团。例如甲基、乙基、正丙基、 异丙基、正丁基、异丁基、叔丁基、正戊基、正己基等。针对“C 1-C 4的烷基”等具有与此类似的定义，仅是碳原子总数不同，本发明不再赘述。
“C 1-C 6的烷氧基”指饱和的烷氧基基团，包括1至6个碳原子的直链或支链烷氧基基团。例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基、正己氧基等。针对“C 1-C 4的烷氧基”、“C 1-C 3的烷氧基”等具有与此类似的定义，仅是碳原子总数不同，本发明不再赘述。
“含有1-2个氧原子的六元饱和杂环烷基”指六元饱和杂环烷基中的1-2个成环原子为氧原子，例如四氢吡喃环基、二氧六环基等。
“取代或未取代的C 3-C 6的环烷基”指成环原子数为3-6，例如3、4、5或6，且成环原子均为C原子，环烷基中任意能够被取代的位置可以由本发明定义的基团取代。
“取代或未取代的哌啶基”指哌啶环中任意能够被取代的位置可以由本发明定义的基团取代。
“-O-C 1-C 4的亚烷基-O-C 1-C 2的烷基”指该基团通过O与母核结构连接，且末端烷基为甲基或乙基。
“由1-3个卤素取代的C 1-C 3的烷基”指C 1-C 3的烷基中的任意能够被取代的位置由1-3个卤素取代。
“-O-C 1-C 4的亚烷基-C 3-C 6的环烷基”指该基团通过O与母核结构连接，且末端烷基为C 3-C 6的环烷基。
“卤素”表示氟、氯、溴或碘。
“含有S的杂原子的饱和三元环”表示在“饱和三元碳环”的基础上，成环的至少一个碳原子被S替换而形成的基团。
“含有O或S的杂原子的饱和四元环”表示成环的原子数为4个，且其中至少一个为O或S，且剩余的原子为C原子，以及该基团为饱和环基团。
“含有O或S的杂原子的饱和五元环”表示成环的原子数为5个，且其中至少一个为O或S，且剩余的原子为C原子，以及该基团为饱和环基团。
“取代的含有至少一个N原子的不饱和五元环”表示成环的原子数为5个，且其中至少一个为N，剩余的原子为C原子，以及该基团为不饱和环基团，在该基团中任意能够被取代的位置上含有至少一个取代基。
“取代的含有至少一个N原子的不饱和六元环”表示成环的原子数为6个，且其中至少一个为N，剩余的原子为C原子，以及该基团为不饱和环基团，在该基团中任意能够被取代的位置上含有至少一个取代基。
本发明“任选存在的”的意思是指后续描述的事件或情形可能会也可能不会发生，并且该描述包括事物或情形可能会也可能不会发生，并且该描述包括事物或情形发生和不发生两种情况。
“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括：
(1)与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸包括盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸包括乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属例子例如碱金属离子、碱土金属离子或铝离子，有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。
“药物组合物”指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂化物、水合物或前药与别的化学成分，例如药学上可接受的载体，混合。药物组合物的目的是促进给药给动物的过程。
“药用载体”指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的药物组合物中的非活性成分，例如但不限于：碳酸钙、磷酸钙、各种糖(例如乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镁、纤维素、碳酸镁、丙烯酸聚合物或甲基丙烯酸聚合物、凝胶、水、聚乙二醇、丙二醇、乙二醇、蓖麻油或氢化蓖麻油或多乙氧基氢化蓖麻油、芝麻油、玉米油、花生油等。
如前所述，本发明的第一方面提供了一种含磺酰胺结构的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐，该化合物具有式(I)所示的结构，在式(I)中，
X为CH 2或CH(CH 3)；
R 1为H、取代或未取代的C 1-C 4的烷基、C 1-C 3的烷氧基、含有S的杂原子的饱和三元环基、含有O或S的杂原子的饱和四元环基、含有O或S的杂原子的饱和五元环基、含有1-2个氧原子的六元饱和杂环烷基、取代或未取代的含有1-2个氮原子的六元饱和杂环烷基、取代或未取代的含有至少一个氮原子的五元不饱和杂环烷基、取代或未取代的含有至少一个氮原子的六元不饱和杂环烷基、-C 1-C 4的亚烷基-O-C 1-C 3的烷基、取代或未取代的C 3-C 6的饱和环烷基、环氧乙烷基、含有至少两个卤素取代的苯基、二氟甲氧基取代的苯基、三氟甲氧基取代的苯基、羧基取代的苯基、萘基、含有至少两个甲基取代的苯基、吡啶-4-基、甲氧基取代的苯基、噻吩-3-基、苯并二氧戊环基、苯并二氧己环基、-CH 2-含有至少两个卤素取代的苯基、呋喃-3-基；R 1中任选存在的取代基选自卤素、氰基、硝基、羟基、C 1-C 6的烷基、C 1-C 6的烷氧基、C 1-C 3的醛基中的至少一种；
R 2为3-吡啶基、取代或未取代的苯基；R 2中任选存在的取代基选自卤素、C 1-C 6的烷基、C 1-C 6的烷氧基、-O-C 1-C 4的亚烷基-O-C 1-C 3的烷基、由1-6个卤素取代的C 1-C 3的烷基、由1-6个卤素取代的C 1-C 3的烷氧基、氰基、-O-C 1-C 4的亚烷基-C 3-C 6的环烷基中的至少一种；
R 3为C 1-C 3的烷基；
R 4为H、C 1-C 3的烷氧基、卤素；
R 5和R 6中的一者为H，另一者选自F、C 1-C 3的烷基。
根据一种优选的具体实施方式，在式(I)中，
X为CH 2或CH(CH 3)；
R 1为H、取代或未取代的C 1-C 4的烷基、C 1-C 3的烷氧基、含有1-2个氧原子的六元饱和杂环烷基、取代或未取代的含有至少1个氮原子的六元饱和杂环烷基、-C 1-C 4的亚烷基-O-C 1-C 3的烷基、取代或未取代的C 3-C 6的饱和环烷基、环氧乙烷基、含有O原子的饱和四元环基、含有O原子的饱和五元环基、取代的含有至少一个氮原子的五元不饱和杂环烷基、取代的含有至少一个氮原子的六元不饱和杂环烷基、含有至少两个卤素取代的苯基、二氟甲氧基取代的苯基、三氟甲氧基取代的苯基、羧基取代的苯基、萘基、含有至少两个甲基取代的苯基、吡啶-4-基、甲氧基取代的苯基、噻吩-3-基、苯并二氧戊环基、苯并二氧己环基、-CH 2-含有至少两个卤素取代的苯基、呋喃-3-基；R 1中任选存在的取代基选自氟、氯、溴、羟基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 2的醛基、氰基、硝基中的至少一种；
R 2为3-吡啶基、取代或未取代的苯基；R 2中任选存在的取代基选自氟、氯、溴、碘、C 1-C 6的烷基、C 1-C 6的烷氧基、-O-C 1-C 4的亚烷基-O-C 1-C 2的烷基、由1-3个卤素取代的C 1-C 3的烷基、由1-3个卤素取代的C 1-C 3的烷氧基、氰基、-O-C 1-C 4的亚烷基-C 3-C 6的环烷基中的至少一种；
R 3为甲基、乙基、正丙基或异丙基；
R 4为H、甲氧基、乙氧基、正丙氧基、异丙氧基、氟、氯或溴；
R 5和R 6中的一者为H，另一者选自F、甲基、乙基、正丙基、异丙基。
根据另一种优选的具体实施方式，在式(I)中，
X为CH 2或CH(CH 3)；
R 1为H、取代或未取代的C 1-C 4的烷基、C 1-C 3的烷氧基、含有1-2个氧原子的六元饱和杂环烷基、取代或未取代的含有1-2个氮原子的六元饱和杂环烷基、-C 1-C 4的亚烷基-O-C 1-C 3的烷基、取代或未取代的C 3-C 6的饱和环烷基、环氧乙烷基、含有O原子的饱和四元环基、含有O原子的饱和五元环基、取代的含有至少一个N原 子的不饱和五元环、取代的含有至少一个N原子的不饱和六元环；含有至少两个卤素取代的苯基、二氟甲氧基取代的苯基、三氟甲氧基取代的苯基、羧基取代的苯基、萘基、含有至少两个甲基取代的苯基、吡啶-4-基、甲氧基取代的苯基、噻吩-3-基、苯并二氧戊环基、苯并二氧己环基、-CH 2-含有至少两个卤素取代的苯基、呋喃-3-基；R 1中任选存在的取代基选自氟、氯、溴、羟基、C 1-C 4烷基、C 1-C 4烷氧基、乙醛基中的至少一种；
R 2为3-吡啶基、取代或未取代的苯基；R 2中任选存在的取代基选自氟、氯、溴、C 1-C 6的烷基、C 1-C 6的烷氧基、-O-C 1-C 4的亚烷基-O-C 1-C 2的烷基、由1-3个卤素取代的C 1-C 3的烷基、由1-3个卤素取代的C 1-C 3的烷氧基、氰基、-O-C 1-C 4的亚烷基-C 3-C 6的环烷基中的至少一种；
R 3为甲基或乙基；
R 4为H、甲氧基或氟；
R 5和R 6中的一者为H，另一者选自F、甲基、乙基、正丙基、异丙基。
根据还有一种优选的具体实施方式，在式(I)中，
X为CH 2或CH(CH 3)；
R 1为H、甲基、异丙基、叔丁基、羟基取代的叔丁基、二氟甲基、甲氧基、二氧六环基、取代或未取代的哌啶基、-C 1-C 4的亚烷基-O-C 1-C 3的烷基、取代或未取代的C 3-C 6的饱和环烷基、环氧乙烷基、含有O原子的饱和四元环基、含有O原子的饱和五元环基、取代的含有至少一个N原子的不饱和五元环基、取代的含有至少一个N原子的不饱和六元环基、含有至少两个卤素取代的苯基、二氟甲氧基取代的苯基、三氟甲氧基取代的苯基、羧基取代的苯基、萘基、含有至少两个甲基取代的苯基、吡啶-4-基、甲氧基取代的苯基、噻吩-3-基、苯并二氧戊环基、苯并二氧己环基、-CH 2-含有至少两个卤素取代的苯基、呋喃-3-基；R 1中任选存在的取代基选自氟、氯、溴、羟基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、乙醛基中的至少一种；
R 2为3-吡啶基、取代或未取代的苯基；R 2中任选存在的取代基选自氟、氯、溴、C 1-C 6的烷基、C 1-C 6的烷氧基、-O-C 1-C 4的亚烷基-O-C 1-C 2的烷基、由1-3个卤素取代的C 1-C 3的烷基、由1-3个卤素取代的C 1-C 3的烷氧基、氰基、-O-C 1-C 4的亚烷基-C 3-C 6的环烷基中的至少一种；
R 3为甲基或乙基；
R 4为H、甲氧基或氟；
R 5和R 6中的一者为H，另一者选自F、甲基、乙基、正丙基、异丙基。
根据一种特别优选的具体实施方式，式(I)所示的化合物选自以下中的任意一种：
化合物A1：
Figure PCTCN2021126527-appb-000003
化合物A2：
Figure PCTCN2021126527-appb-000004
化合物A3：
Figure PCTCN2021126527-appb-000005
化合物A4：
Figure PCTCN2021126527-appb-000006
化合物A5：
Figure PCTCN2021126527-appb-000007
化合物A6：
Figure PCTCN2021126527-appb-000008
化合物A7：
Figure PCTCN2021126527-appb-000009
化合物A8：
Figure PCTCN2021126527-appb-000010
化合物A9：
Figure PCTCN2021126527-appb-000011
化合物A10：
Figure PCTCN2021126527-appb-000012
化合物A11：
Figure PCTCN2021126527-appb-000013
化合物A12：
Figure PCTCN2021126527-appb-000014
化合物A13：
Figure PCTCN2021126527-appb-000015
化合物A14：
Figure PCTCN2021126527-appb-000016
化合物A15：
Figure PCTCN2021126527-appb-000017
Figure PCTCN2021126527-appb-000018
Figure PCTCN2021126527-appb-000019
Figure PCTCN2021126527-appb-000020
Figure PCTCN2021126527-appb-000021
Figure PCTCN2021126527-appb-000022
本发明的所述式(I)所示的结构的药学上可接受的盐包括但不限于盐酸盐形式。
本发明对制备前述第一方面中所述化合物的具体方法没有特别的要求，本领域技术人员能够根据本发明提供的结构式的特点，结合有机合成领域内的已知技术手段容易地确定合适的制备方法。并且，本发明的实例部分示例性地列举了部分具体化合物的制备方法，本领域技术人员根据这些示例性提供的制备方法能够确定其余化合物的具体制备方法。
并且，优选情况下，为了获得收率和纯度更高的化合物，本发明提供第二方面中所述的方法制备含磺酰胺结构的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐，该化合物具有式(I)所示的结构，
该方法包括：将式(II)所示的化合物与式(III)所示的化合物进行接触反应；
其中，在式(I)、式(II)和式(III)中，各基团的定义与第一方面所述的定义相同。
根据一种特别优选的具体实施方式，本发明所述化合物采用如下合成路线所示的方法获得，合成路线中涉及的取代基的情况与前文中所述对应一致。
Figure PCTCN2021126527-appb-000023
本发明对前述合成路线中的参数条件没有特别的限制，本领域技术人员可以采用本领域已知的参数进行，本 发明的后文中示例性地给出了一些具体化合物的合成参数条件，本领域技术人员不应理解为对本发明的限制。
如前所述，本发明的第三方面提供了一种药物组合物，该药物组合物含有治疗有效量的前述第一方面中所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐，以及该药物组合物中还含有药物可接受的载体、赋形剂或稀释剂。
本发明对药物可接受的载体、赋形剂或稀释剂没有特别的要求，可以为本领域内已知的各种物质，本发明在此不作赘述，本领域技术人员不应理解为对本发明的限制。
本发明的第四方面提供了前述第一方面中涉及的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐，或者第三方面中涉及的药物组合物，在制备H+/K+-ATPase抑制剂药物和/或制备钾离子竞争性酸阻滞剂药物中的应用。
本发明的第五方面提供了前述第一方面中涉及的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐，或者前述第三方面中涉及的药物组合物，在制备用于治疗或预防消化性溃疡、卓-艾综合症、胃炎、糜烂性食管炎、反流性食管炎、症状性胃食管反流疾病、巴雷特食管炎、功能性消化不良、幽门螺旋杆菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡或手术后应激导致的胃酸过多或溃疡的药物中的应用。
特别优选情况下，所述消化性溃疡包括胃溃疡、十二指肠溃疡和吻合口溃疡中的至少一种；所述症状性胃食管反流疾病包括非糜烂性的反流性疾病和无食管炎的胃食管反流疾病中的至少一种。
优选情况下，本发明的前述药物组合物和前述化合物能够用于制备胃酸分泌抑制剂。
优选地，本发明提供一种抑制胃酸分泌的方法，该方法包括给予需要治疗的患者有效剂量的前述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐。
前文中，除了包括药学上可接受的载体外，还可以包括在药(剂)学上常用的辅剂，例如：抗细菌剂、抗真菌剂、抗微生物剂、保质剂、调色剂、增溶剂、增稠剂、表面活性剂、络合剂、蛋白质、氨基酸、脂肪、糖类、维生素、矿物质、微量元素、甜味剂、色素、香精或它们的结合等。
以下将通过实例对本发明进行详细描述。以下实例中，在没有特别说明的情况下，以下使用的原料均为普通市售品。
本发明针对化合物A1至化合物A15的制备例分别对应命名为制备例A1至制备例A15。
本发明针对化合物1至化合物100的制备例分别对应命名为制备例1至制备例100。
制备例A1：该制备例用于说明化合物A1的盐酸盐的合成过程：
Figure PCTCN2021126527-appb-000024
步骤1：5-溴-1H-吡咯-3-甲醛的制备
在双口圆底烧瓶中加入购买的吡咯-3-甲醛(52.6mmol)和四氢呋喃(THF,100mL)并置于低温磁力搅拌器中冷却至-78℃，将溶解在N,N-二甲基甲酰胺(DMF,30mL)中的溴代丁二酰亚胺(NBS,52.6mmol)滴加入反应体系中。滴加完毕继续反应1h后，升温至-10℃继续反应1h。TLC监测原料反应完全。向体系中加入冰水，乙酸 乙酯萃取(200mL×2)，饱和食盐水洗涤(150mL×2)，合并有机相，无水硫酸钠干燥，减压浓缩后得棕色固体，然后用异丙醚洗涤，抽滤得白色固体，收率49.4％。
步骤2：((5-溴-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯的制备
在单口圆底烧瓶中加入5-溴-1H-吡咯-3-甲醛(17.2mmol)，33％甲胺甲醇溶液(34.4mmol)和甲醇(40mL)室温搅拌1h，冰浴下分批加入硼氢化钠(25.8mmol)继续搅拌1h。TLC监测原料反应完全。向体系中加入50mL水，搅拌10min，用乙酸乙酯(300mL)将反应体系分批转移至分液漏斗中，饱和食盐水(150mL×3)洗涤，无水硫酸钠干燥，减压浓缩后的棕黄色油状物，将上述产物用乙腈(30mL)溶解，滴加二碳酸二叔丁酯(20.6mmol)，室温搅拌30min，TLC监测原料反应完全用乙酸乙酯(300mL)将反应体系分批转移至分液漏斗中，饱和食盐水(150mL×3)洗涤，有机相无水硫酸钠干燥，减压浓缩拌样，柱层析纯化，减压浓缩，得棕色油状液体，收率79.5％。
步骤3：叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯的制备
在单口圆底烧瓶中加入超干四氢呋喃60mL，冷却到0℃，加入氢化钠(47.2mmol)，缓慢滴加溶解在10mL N,N-二甲基甲酰胺中的((5-溴-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯(13.5mmol)，0℃下搅拌30min后滴加15-冠醚-5(40.5mmol)，然后滴加吡啶-3-磺酰氯(20.2mmol)，滴加完毕0℃下继续搅拌30min，然后室温搅拌30min，TLC监测原料反应完全，将体系倒入冰水中乙酸乙酯(200mL×2)萃取，饱和食盐水(150mL×2)洗涤，合并有机相，无水硫酸钠干燥，有机相减压浓缩后经柱层析纯化，得淡黄色固体，收率82.1％。
步骤4：3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯酚的制备
在反应管中加入4-溴-3-氟-苯酚(262mmol)，联硼酸频那醇酯(314mmol)，四三苯基膦钯(13.1mmol)，醋酸钾(524mmol)。抽充氮气3次后加入1,4-二氧六环400mL，130℃下搅拌器12h，TLC监测原料反应完全。向体系中加入冰水，萃取，有机相用无水硫酸钠干燥，减压浓缩后经柱层析纯化得白色固体，收率51.5％。
步骤5：叔丁基((5-(2-氟-4-羟基苯基)-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯的制备
在反应管中加入叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(2.3mmol)，3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯酚(3.49mmol)，四三苯基膦钯(0.233mmol)，碳酸氢钠(6.96mmol)，抽充氮气3次，氮气保护下加入DME(20mL),H 2O(5mL)，100℃下反应2h。TLC监测原料反应完全。用乙酸乙酯(150mL)将反应体系转移至分液漏斗中，饱和食盐水(100mL×3)洗涤，无水硫酸钠干燥，减压浓缩后，残余物经柱层析纯化得淡黄色固体，收率69.8％。
步骤6：1-(5-(4-(苄氧基)-2-氟苯基)-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐
搅拌器设定80℃预热，在单口圆底烧瓶中加入叔丁基((5-(2-氟-4-羟基苯基)-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(0.43mmol,1.0eq)，三苯基膦(0.866mmol,2.0eq)，3-羟甲基-2-氟吡啶(0.866mmol,2.0eq)，甲苯10mL，加热搅拌溶解。当温度升到80℃时滴加偶氮二甲酸二异丙酯(0.866mmol,2.0eq)，80℃下搅拌30min，TLC监测原料反应完全。将体系直接减压浓缩后，加入2mL氯化氢的乙酸乙酯溶液，乙酸乙酯2mL，室温搅拌12h，TLC监测原料反应完全。抽滤得到化合物A1的盐酸盐，白色固体，收率40％。 1H NMR(600MHz,Methanol-d 4)δ8.85(d,J＝5.4Hz,1H),8.64(s,1H),8.15(d,J＝3.6Hz,1H),8.11–8.02(m,2H),7.76(s,1H),7.74–7.68(m,1H),7.37–7.28(m,1H),7.04–6.96(m,1H),6.82(d,J＝9.0Hz,1H),6.77(d,J＝12.0Hz,1H),6.38(s,1H),5.16(s,2H),4.03(s,2H),2.64(s,3H).
制备例A2：该制备例用于说明化合物A2的盐酸盐的合成过程：
该制备例的制备方法与制备例A1相似，不同之处在于：
将步骤6)中的3-羟甲基-2-氟吡啶替换为等摩尔量的3-羟甲基-2-甲基吡啶，得到化合物A2的盐酸盐，黄色 固体，步骤6)中的一步收率36％。 1H NMR(600MHz,Methanol-d 4)δ8.84(d,J＝3.6Hz,1H),8.70–8.61(m,2H),8.57(s,1H),8.10(d,J＝8.4Hz,1H),7.98–7.88(m,1H),7.76(s,1H),7.74–7.68(m,1H),7.09–7.00(m,1H),6.91(d,J＝8.4Hz,1H),6.87(d,J＝10.8Hz,1H),6.39(s,1H),5.35(s,2H),4.03(s,2H),2.80(s,3H),2.64(s,3H).
制备例A3：该制备例用于说明化合物A3的盐酸盐的合成过程：
该制备例的制备方法与制备例A1相似，不同之处在于：
将步骤6)中的3-羟甲基-2-氟吡啶替换为等摩尔量的4-羟甲基-1-甲基-吡唑，得到化合物A3的盐酸盐，白色固体，步骤6)中的一步收率24％。 1H NMR(600MHz,Methanol-d 4)δ8.79(s,1H),8.51(s,1H),7.92–7.69(m,3H),7.62–7.44(m,2H),6.99(s,1H),6.86–6.62(m,4H),6.38(s,1H),5.05(s,2H),4.08(s,2H),3.90(s,3H),2.70(s,3H).
制备例A4：该制备例用于说明化合物A4的盐酸盐的合成过程：
该制备例的制备方法与制备例A1相似，不同之处在于：
将步骤6)中的3-羟甲基-2-氟吡啶替换为等摩尔量的5-羟甲基-2甲氧基吡啶，得到化合物A4的盐酸盐，黄色固体，步骤6)中的一步收率45％。 1H NMR(600MHz,Methanol-d 4)δ8.76(d,J＝5.4Hz,1H),8.50(d,J＝2.4Hz,1H),8.21(d,J＝2.4Hz,1H),7.83(d,J＝8.4Hz,1H),7.79(dd,J＝8.4,2.4Hz,1H),7.67(s,1H),7.49(dd,J＝8.4,4.8Hz,1H),6.99(t,J＝8.4Hz,1H),6.86–6.79(m,2H),6.74(dd,J＝11.4,2.4Hz,1H),6.33(s,1H),5.07(s,2H),3.92(s,2H),3.90(s,3H),2.58(s,3H).
制备例A5：该制备例用于说明化合物A5的盐酸盐的合成过程：
该制备例的制备方法与制备例A1相似，不同之处在于：
将步骤6)中的3-羟甲基-2-氟吡啶替换为等摩尔量的2-氟-6-羟甲基吡啶，得到化合物A5的盐酸盐，白色固体，步骤6)中的一步收率46％。 1H NMR(600MHz,Methanol-d 4)δ8.85(s,1H),8.63(s,1H),8.05(d,J＝8.4Hz,1H),7.98–7.90(m,1H),7.77(d,J＝1.8Hz,1H),7.71–7.64(m,1H),7.46(d,J＝7.8Hz,1H),7.02–6.93(m,2H),6.83(dd,J＝8.4,2.4Hz,1H),6.78–6.70(m,1H),6.38(d,J＝1.8Hz,1H),5.14(s,2H),4.05(s,2H),2.66(s,3H).
制备例A6：该制备例用于说明化合物A6的盐酸盐的合成过程：
该制备例的制备方法与制备例A1相似，不同之处在于：
将步骤6)中的3-羟甲基-2-氟吡啶替换为等摩尔量的3-氟-2-羟甲基吡啶，得到化合物A6的盐酸盐，黄色固体，步骤6)中的一步收率49％。 1H NMR(600MHz,Methanol-d 4)δ8.82(d,J＝4.8Hz,1H),8.70(d,J＝5.4Hz,1H),8.58(s,1H),8.43(t,J＝8.4Hz,1H),8.10(d,J＝7.8Hz,1H),8.05–8.00(m,1H),7.75–7.68(m,2H),7.04(t,J＝8.4Hz,1H),6.97–6.87(m,2H),6.39–6.34(m,1H),5.55(s,2H),3.99(s,2H),2.59(s,3H).
制备例A7：该制备例用于说明化合物A7的盐酸盐的合成过程：
该制备例的制备方法与制备例A1相似，不同之处在于：
将步骤6)中的3-羟甲基-2-氟吡啶替换为等摩尔量的3-羟甲基哒嗪，得到化合物A7的盐酸盐，黄色固体，步骤6)中的一步收率41％。 1H NMR(600MHz,Methanol-d 4)δ9.68–9.59(m,1H),8.85(s,1H),8.76(d,J＝8.4Hz,1H),8.66–8.50(m,2H),8.03(d,J＝8.4Hz,1H),7.82(s,1H),7.65(t,J＝6.6Hz,1H),7.11(t,J＝8.4Hz,1H),7.03–6.88(m,2H),6.45(s,1H),5.66(s,2H),4.10(s,2H),2.71(s,3H).
制备例A8：该制备例用于说明化合物A8的盐酸盐的合成过程：
该制备例的制备方法与制备例A1相似，不同之处在于：
将步骤6)中的3-羟甲基-2-氟吡啶替换为等摩尔量的3-羟甲基-1-甲基吡唑，得到化合物A8的盐酸盐，白色固体，步骤6)中的一步收率38％。 1H NMR(600MHz,Methanol-d 4)δ8.85(s,1H),8.58(s,1H),7.98(d,J＝6.0Hz,1H),7.84–7.78(m,2H),7.66–7.60(m,1H),7.04(t,J＝8.4Hz,1H),6.90–6.85(m,1H),6.79(d,J＝11.4Hz,1H),6.54(s,1H),6.41(s,1H),5.20(s,2H),4.10(s,2H),4.00(s,3H),2.71(s,3H).
制备例A9：该制备例用于说明化合物A9的盐酸盐的合成过程：
该制备例的制备方法与制备例A1相似，不同之处在于：
将步骤6)中的3-羟甲基-2-氟吡啶替换为等摩尔量的环丙基甲醇，得到化合物A9的盐酸盐，白色固体，步骤6)中的一步收率48％。 1H NMR(600MHz,Chloroform-d)δ8.77–8.71(m,1H),8.62(d,J＝2.4Hz,1H),7.72(dt,J＝8.4,1.8Hz,1H),7.40(s,1H),7.33(dd,J＝8.4,4.8Hz,1H),7.02(t,J＝8.4Hz,1H),6.66(dd,J＝8.4,2.4Hz,1H),6.56(dd,J＝11.4,2.4Hz,1H),6.23(d,J＝1.8Hz,1H),3.81(d,J＝7.2Hz,2H),3.66(s,2H),2.45(s,3H),1.32–1.28(m,1H),0.72–0.62(m,2H),0.40–0.33(m,2H).
制备例A10：该制备例用于说明化合物A10的盐酸盐的合成过程：
该制备例的制备方法与制备例A1相似，不同之处在于：
将步骤6)中的3-羟甲基-2-氟吡啶替换为等摩尔量的(2,2-二氟环丙基)甲醇，得到化合物A10的盐酸盐，白色固体，步骤6)中的一步收率36％。 1H NMR(600MHz,Methanol-d 4)δ8.90(d,J＝4.8Hz,1H),8.68(s,1H),8.12(d,J＝7.8Hz,1H),7.82(s,1H),7.75(dd,J＝8.4,4.8Hz,1H),7.03(t,J＝8.4Hz,1H),6.84–6.77(m,1H),6.75–6.68(m,1H),6.43(s,1H),4.26–4.18(m,1H),4.10(s,2H),4.07–4.00(m,1H),2.71(s,3H),2.23–2.11(m,1H),1.71–1.61(m,1H),1.44–1.34(m,1H).
制备例A11：
该制备例用于说明化合物A11的盐酸盐的合成过程：
该制备例的制备方法与制备例A1相似，不同之处在于：
将步骤6)中的3-羟甲基-2-氟吡啶替换为等摩尔量的环氧乙烷-2-基甲醇，得到化合物A11的盐酸盐，白色固体，步骤6)中的一步收率60％。 1H NMR(600MHz,Methanol-d 4)δ8.91(d,J＝4.8Hz,1H),8.68(s,1H),8.12(d,J＝8.4Hz,1H),7.82(d,J＝2.4Hz,1H),7.76(dd,J＝8.4,4.8Hz,1H),7.04(t,J＝8.4Hz,1H),6.85–6.79(m,1H),6.74(dd,J＝11.4,3.0Hz,1H),6.43(t,J＝3.0Hz,1H),4.20–4.11(m,2H),4.10(s,2H),3.82–3.76(m,1H),3.73–3.68(m,1H),2.71(s,3H).
制备例A12：该制备例用于说明化合物A12的盐酸盐的合成过程：
该制备例的制备方法与制备例A1相似，不同之处在于：
将步骤6)中的3-羟甲基-2-氟吡啶替换为等摩尔量的氧杂环丁烷-3-基甲醇，得到化合物A12的盐酸盐，白色固体，步骤6)中的一步收率44％。 1H NMR(600MHz,Chloroform-d)δ8.69(d,J＝4.8Hz,1H),8.55(d,J＝2.4Hz,1H),7.69(d,J＝8.4Hz,1H),7.36(s,1H),7.28(dd,J＝8.4,4.8Hz,1H),6.99(t,J＝8.4Hz,1H),6.63(dd,J＝8.4,2.4Hz,1H),6.54(dd,J＝11.4,2.4Hz,1H),6.24–6.17(m,1H),4.88–4.80(m,2H),4.56–4.48(m,2H),4.15(d,J ＝6.6Hz,2H),3.61(s,2H),3.45–3.36(m,1H),2.41(s,3H).
制备例A13：该制备例用于说明化合物A13的盐酸盐的合成过程：
该制备例的制备方法与制备例A1相似，不同之处在于：
将步骤6)中的3-羟甲基-2-氟吡啶替换为等摩尔量的四氢呋喃-3-基甲醇，得到化合物A13的盐酸盐，白色固体，步骤6)中的一步收率40％。 1H NMR(400MHz,Methanol-d 4)δ8.81(d,J＝5.2Hz,1H),8.56(d,J＝2.4Hz,1H),7.91(d,J＝8.4Hz,1H),7.78(s,1H),7.57(dd,J＝8.4,4.8Hz,1H),7.00(t,J＝8.4Hz,1H),6.77(d,J＝8.8Hz,1H),6.69(d,J＝12.8Hz,1H),6.38(d,J＝2.0Hz,1H),4.09(s,2H),4.06–4.00(m,1H),3.99–3.96(m,1H),3.95–3.88(m,2H),3.83–3.75(m,1H),3.74–3.68(m,1H),2.82–2.73(m,1H),2.71(s,3H),2.21–2.10(m,1H),1.85–1.73(m,1H).
制备例A14：该制备例用于说明化合物A14的盐酸盐的合成过程：
该制备例的制备方法与制备例A1相似，不同之处在于：
将步骤6)中的3-羟甲基-2-氟吡啶替换为等摩尔量的四氢呋喃-2-基甲醇，得到化合物A14的盐酸盐，白色固体，步骤6)中的一步收率46％。 1H NMR(600MHz,Methanol-d 4)δ8.92(d,J＝5.4Hz,1H),8.72–8.65(m,1H),8.14(d,J＝8.4Hz,1H),7.86–7.75(m,2H),7.02(t,J＝8.4Hz,1H),6.85–6.77(m,1H),6.75–6.66(m,1H),6.45–6.36(m,1H),4.34–4.25(m,1H),4.14–4.05(m,3H),4.03–3.98(m,1H),3.97–3.89(m,1H),3.88–3.81(m,1H),2.71(s,3H),2.17–2.08(m,1H),2.06–1.92(m,2H),1.87–1.75(m,1H).
制备例A15：该制备例用于说明化合物A15的盐酸盐的合成过程：
该制备例的制备方法与制备例A1相似，不同之处在于：
将步骤6)中的3-羟甲基-2-氟吡啶替换为等摩尔量的氧杂环丁烷-2-基甲醇，得到化合物A15的盐酸盐，黄色固体，步骤6)中的一步收率52％。 1H NMR(600MHz,Methanol-d 4)δ8.95(d,J＝5.4Hz,1H),8.73(t,J＝4.2Hz,1H),8.21(d,J＝8.4Hz,1H),7.89–7.78(m,2H),7.05(t,J＝8.4Hz,1H),6.87–6.80(m,1H),6.77–6.70(m,1H),6.45(d,J＝7.2Hz,1H),4.22–4.15(m,1H),4.15–4.09(m,2H),4.08–3.96(m,2H),3.79(s,2H),2.73(s,3H),2.13–1.99(m,2H).
制备例1：该制备例用于说明化合物1的盐酸盐的合成过程
Figure PCTCN2021126527-appb-000025
步骤1：5-溴-1H-吡咯-3-甲醛的制备
在双口圆底烧瓶中加入吡咯-3-甲醛(52.6mmol)和四氢呋喃(THF,100mL)并置于低温磁力搅拌器中冷却至-78℃，将溶解在N,N-二甲基甲酰胺(DMF,30mL)中的溴代丁二酰亚胺(NBS,52.6mmol)滴加入反应体系中。滴加完毕继续反应1h后，升温至-10℃继续反应1h。TLC监测原料反应完全。向体系中加入冰水，乙酸乙酯萃取(200mL×2)，饱和食盐水洗涤(150mL×2)，合并有机相，无水硫酸钠干燥，减压浓缩后得棕色固体，然后用异 丙醚洗涤，抽滤得白色固体，收率49.4％。
步骤2：((5-溴-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯的制备
在单口圆底烧瓶中加入5-溴-1H-吡咯-3-甲醛(17.2mmol)，33wt％甲胺甲醇溶液(34.4mmol)和甲醇(40mL)室温(25℃，下同)搅拌1h，冰浴下分批加入硼氢化钠(25.8mmol)继续搅拌1h。TLC监测原料反应完全。向体系中加入50mL水，搅拌10min，用乙酸乙酯(300mL)将反应体系分批转移至分液漏斗中，饱和食盐水(150mL×3)洗涤，无水硫酸钠干燥，减压浓缩后的棕黄色油状物，将上述产物用乙腈(30mL)溶解，滴加二碳酸二叔丁酯(20.6mmol)，室温搅拌30min，TLC监测原料反应完全用乙酸乙酯(300mL)将反应体系分批转移至分液漏斗中，饱和食盐水(150mL×3)洗涤，有机相无水硫酸钠干燥，减压浓缩拌样，柱层析纯化，减压浓缩，得棕色油状液体，收率79.5％。
步骤3：叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯的制备
在单口圆底烧瓶中加入超干四氢呋喃60mL，冷却到0℃，加入氢化钠(47.2mmol)，缓慢滴加溶解在10mL的N,N-二甲基甲酰胺中的((5-溴-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯(13.5mmol)，0℃下搅拌30min后滴加15-冠醚-5(40.5mmol)，然后滴加吡啶-3-磺酰氯(20.2mmol)，滴加完毕0℃下继续搅拌30min，然后室温搅拌30min，TLC监测原料反应完全，将体系倒入冰水中乙酸乙酯(200mL×2)萃取，饱和食盐水(150mL×2)洗涤，合并有机相，无水硫酸钠干燥，有机相减压浓缩后经柱层析纯化，得淡黄色固体，收率82.1％。
步骤4：3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯酚的制备
在反应管中加入4-溴-3-氟-苯酚(262mmol)，联硼酸频那醇酯(314mmol)，四三苯基膦钯(13.1mmol)，醋酸钾(524mmol)。抽充氮气3次后加入1,4-二氧六环400mL，130℃下搅拌器12h，TLC监测原料反应完全。向体系中加入冰水，萃取，有机相用无水硫酸钠干燥，减压浓缩后经柱层析纯化得白色固体，收率51.5％。
步骤5：叔丁基((5-(2-氟-4-羟基苯基)-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯的制备
在反应管中加入叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(2.3mmol)，3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯酚(3.49mmol)，四三苯基膦钯(0.233mmol)，碳酸氢钠(6.96mmol)，抽充氮气3次，氮气保护下加入DME(20mL),H 2O(5mL)，100℃下反应2h。TLC监测原料反应完全。用乙酸乙酯(150mL)将反应体系转移至分液漏斗中，饱和食盐水(100mL×3)洗涤，无水硫酸钠干燥，减压浓缩后，残余物经柱层析纯化得淡黄色固体，收率69.8％。
步骤6：(S)-1-(5-(4-((1,4-二恶烷-2-基)甲氧基)-2-氟苯基)-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐
搅拌器设定80℃预热，在单口圆底烧瓶中加入叔丁基((5-(2-氟-4-羟基苯基)-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(0.43mmol,1.0eq)，三苯基膦(0.866mmol,2.0eq)，(2S)-1,4-二恶烷-2-甲醇(0.866mmol,2.0eq)，甲苯10mL，加热搅拌溶解。当温度升到80℃时滴加偶氮二甲酸二异丙酯(0.866mmol,2.0eq)，80℃下搅拌30min，TLC监测原料反应完全。将体系直接减压浓缩后，加入2mL氯化氢的乙酸乙酯溶液，乙酸乙酯2mL，室温搅拌12h，TLC监测原料反应完全。抽滤得到化合物1的盐酸盐，黄色固体，收率50％。
1H NMR(600MHz,Methanol-d 4)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).
制备例2：该制备例用于说明化合物2的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的环丁基甲醇，得到化合物2的盐酸盐，白色固体，步骤6)中的一步收率24％。
1H NMR(600MHz,Methanol-d 4)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).
制备例3：该制备例用于说明化合物3的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的环戊基甲醇，得到化合物3的盐酸盐，白色固体，步骤6)中的一步收率31％。
1H NMR(600MHz,Methanol-d 4)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).
制备例4：该制备例用于说明化合物4的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的环己基甲醇，得到化合物4的盐酸盐，白色固体，步骤6)中的一步收率35％。
1H NMR(600MHz,Methanol-d 4)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).
制备例5：该制备例用于说明化合物5的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的4,4-二氟-环己烷甲醇，得到化合物5的盐酸盐，白色固体，步骤6)中的一步收率37％。
1H NMR(600MHz,Methanol-d 4)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).
制备例6：
该制备例用于说明化合物6的合成过程：
该制备例的制备方法与制备例1相似，不同之处在于：将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的4-羟甲基四氢吡喃，得到化合物6，白色固体，步骤6)中的一步收率34％。
1H NMR(400MHz,DMSO-d 6)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).
制备例7：该制备例用于说明化合物7的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的四氢吡喃-2-甲醇，得到化合物7的盐酸盐，白色固体，步骤6)中的一步收率40％。
1H NMR(600MHz,Methanol-d 4)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).
制备例8：该制备例用于说明化合物8的盐酸盐的合成过程：
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(四氢-2H-吡喃-4-基)乙醇，得到化合物8的盐酸盐，白色固体，步骤6)中的一步收率25％。
1H NMR(600MHz,Methanol-d 4)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).
制备例9：该制备例用于说明化合物9的盐酸盐的合成过程
Figure PCTCN2021126527-appb-000026
该制备例的制备方法与制备例1相似，不同之处在于：将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3,5-二氟苯磺酰氯，黄色固体，收率70％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(3，5-二氟苯磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率61％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(四氢-2H-吡喃-4-基)乙醇，得到化合物9的盐酸盐，白色固体，步骤6)中的一步收率28％。
1H NMR(600MHz,Methanol-d 4)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).
制备例10：该制备例用于说明化合物10的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-三氟甲基苯磺酰氯，黄色固体，收率70％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(3-三氟甲基苯磺酰)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率60％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(四氢-2H-吡喃-4-基)乙醇，得到化合物10的盐酸盐，白色固体，步骤6)中的一步收率35％。
1H NMR(600MHz,Methanol-d 4)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).
制备例11：该制备例用于说明化合物11的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-氟-4-甲基苯磺酰氯，黄色固体，收率73％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(3-氟-4-甲基苯磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率63％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(四氢-2H-吡喃-4-基)乙醇，得到化合物11的盐酸盐，白色固体，步骤6)中的一步收率31％。
1H NMR(600MHz,Methanol-d 4)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).
制备例12：该制备例用于说明化合物12的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的2,5-二氟苯磺酰氯，黄色固体，收率72％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(2，5-二氟苯磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率61％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(四氢-2H-吡喃-4-基)乙醇，得到化合物12的盐酸盐，白色固体，步骤6)中的一步收率40％。
1H NMR(600MHz,Methanol-d 4)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).
制备例13：该制备例用于说明化合物13的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-氰基苯磺酰氯，黄色固体，收率71％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(3-氰基苯磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率60％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(四氢-2H-吡喃-4-基)乙醇，得到化合物13的盐酸盐，白色固体，步骤6)中的一步收率36％。
1H NMR(600MHz,Methanol-d 4)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).
制备例14：该制备例用于说明化合物14的盐酸盐的合成过程
Figure PCTCN2021126527-appb-000027
步骤1：5-溴-1-((3-甲氧基苯基)磺酰基)-1H-吡咯-3-甲醛的制备
在单口圆底烧瓶中加入吡咯-3-甲醛(11.5mmol)溶解在25mL超干四氢呋喃中，冷却到0℃，缓慢加入氢化钠(1.61g，煤油中60％，40.0mmol)，然后滴加3-甲氧基苯磺酰氯(17.2mmol)，滴加完毕0℃下继续搅拌30min，然后室温搅拌30min，TLC监测原料反应完全，将体系倒入冰水中乙酸乙酯(200mL×2)萃取，饱和食盐水(150×2)洗涤，合并有机相，无水硫酸钠干燥，有机相减压浓缩后经柱层析纯化得淡黄色固体，收率90.0％。
步骤2：5-溴-1-((3-羟基苯基)磺酰基)-1H-吡咯-3-甲醛的制备
在三口圆底烧瓶中加入5-溴-1-((3-甲氧基苯基)磺酰基)-1H-吡咯-3-甲醛(10.3mmol)和超干二氯甲烷(CH 2Cl 2，50mL)中并置于低温磁力搅拌器中冷却至-78℃，然后将BBr 3(51.7mmol)滴入反应体系中。滴加完毕后转移至冰浴条件下搅拌30min。TLC监测原料反应完全。将体系中加入冰水，EA萃取(200mL×2)，饱和食盐水洗涤(150mL×2)，合并有机相，无水硫酸钠干燥，减压浓缩拌样，柱层析纯化，减压浓缩，得黄色固体，收率58.0％。
步骤3：叔丁基((5-溴-1-((3-羟基苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯的制备
在单口圆底烧瓶中加入甲氨盐酸盐(15.2mmol)和甲醇(CH 3OH，50mL)并置于低温磁力搅拌器中冷却至-40℃，然后加入5-溴-1-((3-羟基苯基)磺酰基)-1H-吡咯-3-甲醛(15.1mmol)和氰基硼氢化钠(52.5mmol)，自然升温至室温。TLC监测原料反应完全，用乙酸乙酯(300mL)将反应体系分批转移至分液漏斗中，饱和食盐水(150mL×3)洗涤，无水硫酸钠干燥，减压浓缩后的棕黄色油状物，将上述产物用乙腈(30mL)溶解，加入二碳酸二叔丁酯(17.3mmol)和碳酸氢钠(42.8mmol)，在油浴50℃下搅拌过夜，TLC监测原料反应完全用乙酸乙酯(300mL)将反应体系分批转移至分液漏斗中，饱和食盐水(150mL×3洗涤，)有机相无水硫酸 钠干燥，减压浓缩拌样，柱层析纯化，减压浓缩，得棕色油状液体，收率44.0％。
步骤4：叔丁基((5-溴-1-((3-(2-甲氧基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯的制备
搅拌器设定80℃预热，在单口圆底烧瓶中加入叔丁基((5-溴-1-((3-羟基苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(0.89mmol)，三苯基膦(1.79mmol)，乙二醇甲醚(1.79mmol)，甲苯10mL，加热搅拌溶解。当温度升到80℃时滴加偶氮二甲酸二异丙酯(1.79mmol)，80℃下搅拌10min，TLC监测原料反应完全。将体系直接减压浓缩，二氯甲烷2mL湿法上样，柱层析纯化得白色固体，收率70.0％。
步骤5：3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯酚的制备
在反应管中加入4-溴-3-氟-苯酚(262mmol)，联硼酸频那醇酯(314mmol)，四三苯基膦钯(13.1mmol)，醋酸钾(524mmol)。抽充氮气3次后加入1,4-二氧六环400mL，130℃下搅拌器12h，TLC监测原料反应完全。向体系中加入冰水，萃取，有机相用无水硫酸钠干燥，减压浓缩后经柱层析纯化得白色固体，收率51.5％。
步骤6：叔丁基((1-((3-(2-甲氧基乙氧基)苯基)磺酰基)-5-(2-氟-4-羟基苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯的制备
在反应管中加入叔丁基((5-溴-1-((3-(2-甲氧基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(2.0mmol)，3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯酚(3.0mmol)，四三苯基膦钯(0.1mmol)，碳酸氢钠(6.10mmol)，抽充氮气3次，氮气保护下加入加入DME(20mL)，H 2O(5mL)，100℃下反应2h。TLC监测原料反应完全。用乙酸乙酯(150mL)将反应体系转移至分液漏斗中，饱和食盐水(100mL×3)洗涤，无水硫酸钠干燥，减压浓缩后，残余物经柱层析纯化得到淡黄色固体，收率69.3％。
步骤7：1-(5-(2-氟-4-(1-(四氢-2H-吡喃-4-基)乙氧基)苯基)-1-((3-(2-甲氧基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺–盐酸盐
搅拌器设定90℃预热，在单口圆底烧瓶中加入叔丁基((1-((3-(2-甲氧基乙氧基)苯基)磺酰基)-5-(2-氟-4-羟基苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(0.64mmol)，三苯基膦(1.28mmol)，1-(四氢-2H-吡喃-4-基)乙醇(1.12mmol)，甲苯10mL，加热搅拌溶解。当温度升到80℃时滴加偶氮二甲酸二异丙酯(1.28mmol)，80℃下搅拌5min，TLC监测原料反应完全。将体系直接减压浓缩，得到粗产物，加入盐酸的乙酸乙酯溶液2mL，乙酸乙酯2mL，室温搅拌12h，TLC监测原料反应完全。抽滤得黄色油状，收率29％。
1H NMR(600MHz,Methanol-d 4)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).
制备例15：该制备例用于说明化合物15的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-甲氧基苯磺酰氯，黄色固体，收率69％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(3-甲氧基苯磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率55％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(四氢-2H-吡喃-4-基)乙醇，得到化合物15的盐酸盐，灰色固体，步骤6)中的一步收率45％。
1H NMR(600MHz,Methanol-d 4)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).
制备例16：该制备例用于说明化合物16的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的2，6-二氟苯磺酰氯，黄色固体，收率67％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(2，6-二氟苯磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率63％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(四氢-2H-吡喃-4-基)乙醇，得到化合物16的盐酸盐，白色固体，步骤6)中的一步收率41％。
1H NMR(600MHz,Methanol-d 4)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).
制备例17：该制备例用于说明化合物17的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的2，4-二氟苯磺酰氯，黄色固体，收率68％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(2，4-二氟苯磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率65％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(四氢-2H-吡喃-4-基)乙醇，得到化合物17的盐酸盐，白色固体，步骤6)中的一步收率42％。
1H NMR(600MHz,Methanol-d 4)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).
制备例18：该制备例用于说明化合物18的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的4-氰基苯磺酰氯，黄色固体，收率66％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(4-氰基苯磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率63％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(四氢-2H-吡喃-4-基)乙醇，得到化合物18的盐酸盐，白色固体，步骤6)中的一步收率43％。
1H NMR(600MHz,Methanol-d 4)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).
制备例19：该制备例用于说明化合物19的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-氟苯磺酰氯，黄色固体，收率68％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(3-氟苯磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率61％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(四氢-2H-吡喃-4-基)乙醇，得到化合物19的盐酸盐，白色固体，步骤6)中的一步收率48％。
1H NMR(600MHz,Methanol-d 4)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).
制备例20：该制备例用于说明化合物20的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-环己基乙醇，得到化合物20的盐酸盐，白色固体，步骤6)中的一步收率49％。
1H NMR(600MHz,Methanol-d 4)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).
制备例21：该制备例用于说明化合物21的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的4-羟甲基哌啶，得到化合物21的盐酸盐，黄色固体，步骤6)中的一步收率33％。
1H NMR(600MHz,Methanol-d 4)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).
制备例22：该制备例用于说明化合物22的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-甲基-4-哌啶甲醇，得到化合物22的盐酸盐，灰色固体，步骤6)中的一步收率40％。
1H NMR(600MHz,Methanol-d 4)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).
制备例23：
该制备例用于说明化合物23的盐酸盐的合成过程：
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(4-(羟基甲基)哌啶-1-基)乙酮，得到化合物23的盐酸盐，白色固体，步骤6)中的一步收率20％。
1H NMR(400MHz,Methanol-d 4)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).
制备例24：该制备例用于说明化合物24的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-氟苯磺酰氯，黄色固体，收率71％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(3-氟苯磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率68％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的4-羟甲基四氢吡喃，得到化合物24的盐酸盐，白色固体，步骤6)中的一步收率45％。
1H NMR(600MHz,Methanol-d 4)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).
制备例25：该制备例用于说明化合物25的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-氯苯磺酰氯，黄色固体，收率72％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(3-氯苯磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率63％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的4-羟甲基四氢吡喃，得到化合物25的盐酸盐，白色固体，步骤6)中的一步收率42％。
1H NMR(600MHz,Methanol-d 4)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).
制备例26：该制备例用于说明化合物26的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-氟-4-甲基苯磺酰氯，黄色固体，收率72％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(3-氟-4-甲基苯磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率65％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的4-羟甲基四氢吡喃，得到化合物26的盐酸盐，白色固体，步骤6)中的一步收率44％。
1H NMR(600MHz,Methanol-d 4)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).
制备例27：该制备例用于说明化合物27的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3,5-二氟苯磺酰氯，黄色固体，收率71％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(3，5-二氟苯磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率61％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的4-羟甲基四氢吡喃，得到化合物27的盐酸盐，白色固体，步骤6)中的一步收率49％。
1H NMR(600MHz,Methanol-d 4)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).
制备例28：该制备例用于说明化合物28的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-氰基苯磺酰氯，黄色固体，收率70％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(3-氰基苯磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率63％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的4-羟甲基四氢吡喃，得到化合物28的盐酸盐，白色固体，步骤6)中的一步收率51％。
1H NMR(600MHz,Methanol-d 4)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).
制备例29：该制备例用于说明化合物29的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的4-氰基苯磺酰氯，黄色固体，收率68％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(4-氰基苯磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率59％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的4-羟甲基四氢吡喃，得到化合物29的盐酸盐，白色固体，步骤6)中的一步收率42％。
1H NMR(600MHz,Methanol-d 4)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).
制备例30：该制备例用于说明化合物30的盐酸盐的合成过程
该制备例的制备方法与制备例14相似，不同之处在于：
将步骤4)中的乙二醇甲醚替换为等摩尔量的2-氟乙醇，黄色固体，收率60％。
将步骤6)中的叔丁基((5-溴-1-((3-(2-甲氧基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-((3-(2-氟乙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率60％。
将步骤7)中的1-(四氢-2H-吡喃-4-基)乙醇替换为等摩尔量的4-羟甲基四氢吡喃，得到化合物30的盐酸盐，白色固体，步骤7)中的一步收率43％。
1H NMR(600MHz,Methanol-d 4)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).
制备例31：该制备例用于说明化合物31的盐酸盐的合成过程
该制备例的制备方法与制备例14相似，不同之处在于：
将步骤4)中的乙二醇甲醚替换为等摩尔量的正戊醇，黄色固体，收率62％。
将步骤6)中的叔丁基((5-溴-1-((3-(2-甲氧基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-((3-(戊氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率62％。
将步骤7)中的1-(四氢-2H-吡喃-4-基)乙醇替换为等摩尔量的4-羟甲基四氢吡喃，得到化合物31的盐酸盐，白色固体，步骤7)中的一步收率20％。
1H NMR(600MHz,Methanol-d 4)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).
制备例32：该制备例用于说明化合物32的盐酸盐的合成过程
该制备例的制备方法与制备例14相似，不同之处在于：
将步骤4)中的乙二醇甲醚替换为等摩尔量的3-甲氧基-1-丙醇，黄色固体，收率64％。
将步骤6)中的叔丁基((5-溴-1-((3-(2-甲氧基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的1-(5-溴-1-((3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺，黄色固体，收率64％。
将步骤7)中的1-(四氢-2H-吡喃-4-基)乙醇替换为等摩尔量的4-羟甲基四氢吡喃，得到化合物32的盐酸盐，白色固体，步骤7)中的一步收率25％。
1H NMR(600MHz,Methanol-d 4)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).
制备例33：该制备例用于说明化合物33的盐酸盐的合成过程
该制备例的制备方法与制备例14相似，不同之处在于：
将步骤4)中的乙二醇甲醚替换为等摩尔量的环丙基甲醇，黄色固体，收率61％。
将步骤6)中的叔丁基((5-溴-1-((3-(2-甲氧基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的1-(5-溴-1-((3-(环丁基甲氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺，黄色固体，收率62％。
将步骤7)中的1-(四氢-2H-吡喃-4-基)乙醇替换为等摩尔量的1-(四氢-2H-吡喃-4-基)乙醇，得到化合物33的盐酸盐，白色固体，步骤7)中的一步收率34％。
1H NMR(400MHz,Methanol-d 4)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).
制备例34：该制备例用于说明化合物34的盐酸盐的合成过程
该制备例的制备方法与制备例14相似，不同之处在于：
将步骤4)中的乙二醇甲醚替换为等摩尔量的环戊基甲醇，黄色固体，收率61％。
将步骤6)中的叔丁基((5-溴-1-((3-(2-甲氧基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的1-(5-溴-1-((3-(环戊基甲氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺，黄色固体，收率62％。
将步骤7)中的1-(四氢-2H-吡喃-4-基)乙醇替换为等摩尔量的4-羟甲基四氢吡喃，得到化合物34的盐酸盐，白色固体，步骤7)中的一步收率46％。
1H NMR(400MHz,Methanol-d 4)δ7.72(d,J＝2.0Hz,1H),7.37(t,J＝8.4Hz,1H),7.17(dd,J＝8.4,2.4Hz,1 H),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).
制备例35：该制备例用于说明化合物35的盐酸盐的合成过程
该制备例的制备方法与制备例14相似，不同之处在于：
将步骤4)中的乙二醇甲醚替换为等摩尔量的2-氟乙醇，黄色固体，收率62％。
将步骤6)中的叔丁基((5-溴-1-((3-(2-甲氧基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的1-(5-溴-1-((3-(2-氟乙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺，黄色固体，收率61％。
将步骤7)中的1-(四氢-2H-吡喃-4-基)乙醇替换为等摩尔量的环己基甲醇，得到化合物35的盐酸盐，白色固体，步骤7)中的一步收率45％。
1H NMR(600MHz,Methanol-d 4)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).
制备例36：该制备例用于说明化合物36的盐酸盐的合成过程
该制备例的制备方法与制备例14相似，不同之处在于：
将步骤4)中的乙二醇甲醚替换为等摩尔量的正戊醇，黄色固体，收率64％。
将步骤6)中的叔丁基((5-溴-1-((3-(2-甲氧基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的1-(5-溴-1-((3-(戊氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺，黄色固体，收率60％。
将步骤7)中的1-(四氢-2H-吡喃-4-基)乙醇替换为等摩尔量的环己基甲醇，得到化合物36的盐酸盐，白色固体，步骤7)中的一步收率19％。
1H NMR(600MHz,Methanol-d 4)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).
制备例37：该制备例用于说明化合物37的盐酸盐的合成过程
该制备例的制备方法与制备例14相似，不同之处在于：
将步骤4)中的乙二醇甲醚替换为等摩尔量的3-甲氧基-1-丙醇，黄色固体，收率61％。
将步骤6)中的叔丁基((5-溴-1-((3-(2-甲氧基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的1-(5-溴-1-((3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺，黄色固体，收率61％。
将步骤7)中的1-(四氢-2H-吡喃-4-基)乙醇替换为等摩尔量的1-(四氢-2H-吡喃-4-基)乙醇，得到化合物37的盐酸盐，白色固体，步骤7)中的一步收率44％。
1H NMR(400MHz,Methanol-d 4)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).
制备例38：该制备例用于说明化合物38的盐酸盐的合成过程
该制备例的制备方法与制备例14相似，不同之处在于：
将步骤4)中的乙二醇甲醚替换为等摩尔量的-甲氧基-1-丁醇，黄色固体，收率58％。
将步骤6)中的叔丁基((5-溴-1-((3-(2-甲氧基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的1-(5-溴-1-((3-(4-甲氧基丁氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺，黄色固体，收率61％。
将步骤7)中的1-(四氢-2H-吡喃-4-基)乙醇替换为等摩尔量的1-(四氢-2H-吡喃-4-基)乙醇，得到化合物38的盐酸盐，黄色固体，步骤7)中的一步收率20％。
1H NMR(400MHz,Methanol-d 4)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).
制备例39：该制备例用于说明化合物39的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-三氟甲基苯磺酰氯，黄色固体，收率68％。
将步骤5)中的叔丁基((5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯替换为等摩尔量的叔丁基((5-溴-1-(3-三氟甲基苯磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯，黄色固体，收率65％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的4-羟甲基四氢吡喃，得到化合物39的盐酸盐，白色固体，步骤6)中的一步收率54％。
1H NMR(600MHz,Methanol-d 4)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).
制备例40：该制备例用于说明化合物40的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的甲醇，得到化合物40的盐酸盐，白色固体，步骤6)中的一步收率46％。
1H NMR(600MHz,Methanol-d 4)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＝11.4,2.4 Hz,1H),6.47(d,J＝1.8Hz,1H),4.12(s,2H),3.87(s,3H),2.72(s,3H).
制备例41：该制备例用于说明化合物41的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的乙醇，得到化合物41的盐酸盐，白色固体，步骤6)中的一步收率53％。
1H NMR(600MHz,DMSO-d 6)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).
制备例42：该制备例用于说明化合物42的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2，2-二氟乙醇，得到化合物42的盐酸盐，白色固体，步骤6)中的一步收率47％。
1H NMR(600MHz,DMSO-d 6)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).
制备例43：该制备例用于说明化合物43的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的3-甲氧基丙醇，得到化合物43的盐酸盐，黄色固体，步骤6)中的一步收率51％。
1H NMR(600MHz,DMSO-d 6)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).
制备例44：该制备例用于说明化合物44的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的异丙醇，得到化合物44的盐酸盐，白色固体，步骤6)中的一步收率50％。
1H NMR(600MHz,Methanol-d 4)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).
制备例45：该制备例用于说明化合物45的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的新戊醇，得到化合物45的盐酸盐，白色固体，步骤6)中的一步收率38％。
1H NMR(600MHz,Methanol-d 4)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).
制备例46：该制备例用于说明化合物46合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤2)中的33％甲胺甲醇溶液替换为等摩尔量的乙胺甲醇，棕色油状液体，收率70％。
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的4-羟甲基四氢吡喃，得到化合物46，白色固体，步骤6)中的一步收率48％。
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).
制备例47：该制备例用于说明化合物47的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(四氢-2H-吡喃-4-基)乙醇，得到化合物47的盐酸盐，白色固体，步骤6)中的一步收率38％。
1H NMR(600MHz,Methanol-d 4)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).
制备例48：该制备例用于说明化合物48的合成过程
Figure PCTCN2021126527-appb-000028
步骤1：4-(环丙基甲氧基)-2-氟苯甲醛的制备
在单口圆底烧瓶中加入2-氟-4-羟基苯甲醛(14.2mmol)，(溴甲基)环丙烷(20.7mmol)，碳酸钾(42.7mmol)，DMF(40mL)，在60℃搅拌过夜，TLC监测原料反应完全。柱层析纯化，得到2.7g白色油状液体，收率99％。
步骤2：N-((4-(环丙基甲氧基)-2-氟苯基)(甲苯磺酰基)甲基)甲酰胺的制备
在圆底烧瓶中加入4-甲基苯磺酸钠(32.0mmol)、(15)-(+)-10-樟脑磺酸(，0.320mmol)、4-(环丙基甲氧基)-2-氟苯甲醛(35.2mmol)和甲酰胺(160mmol)反应混合物在65℃左右搅拌约16h，反应混合物已在一夜之间固化。固体被分解并悬浮在甲醇中。固体块用铲子磨成粉末，过滤后用甲醇洗涤。滤饼在60℃左右的真空下干燥，得到的化合物为白色粉末，收率79％。
步骤3：4-(环丙基甲氧基)-2-氟-1-(异氰基(甲苯磺酰基)甲基)苯的制备
取N-((4-(环丙基甲氧基)-2-氟苯基)(甲苯磺酰基)甲基)甲酰胺(105.2mmol)用500ml无水四氢呋喃溶解，三氯 氧磷(210.4mmol)加入到反应瓶中，氮气保护，冰浴降温，温度0-10℃滴加三乙胺(631.1mmol)，加料毕冰浴下搅拌60min。TLC检测，原料消失后处理：滴加水500mL淬灭，用MTBE萃取(200mL×3)，合并有机相，用300mL饱和食盐水洗涤×2，无水硫酸钠干燥，过滤减压旋蒸除去溶剂得黄色半固体。加入120mL石油醚，6mL乙酸乙酯。室温搅拌30min，抽滤。产品室温下吹干。得到淡黄色固体，收率72％。
步骤4：5-(4-(环丙基甲氧基)-2-氟苯基)-4-甲氧基-1H-吡咯-3-羧酸甲酯的制备
取NaH(67.5mmol)，250mL乙醚，氮气保护，冰浴降温，在-10℃滴加250mL乙腈溶解的4-(环丙基甲氧基)-2-氟-1-(异氰基(甲苯磺酰基)甲基)苯(225.0mmol)和2-(甲氧基亚甲基)丙二酸二甲酯(13.5mmol)，滴加完毕升至40℃搅拌48h。反应结束后加500mL水，用100ml MTBE萃取三次，合并有机相，用300mL饱和食盐水洗涤，无水硫酸钠干燥，过滤减压旋蒸除去溶剂得油状物，加入1.5倍重量的100-200硅胶拌样制砂，4倍重量的200-300硅胶装柱，柱层析，收集产物点，减压浓缩干后加50mL正庚烷，2mL乙酸乙酯室温打浆1h过滤得黄色粉末状固体，收率45％。
步骤5：5-(4-(环丙基甲氧基)-2-氟苯基)-4-甲氧基-1-(吡啶-3-基磺酰基)-1H-吡咯-3-羧酸甲酯的制备
在单口圆底烧瓶中加入超干四氢呋喃60mL，冷却到0℃，加入氢化钠(煤油中60％，47.2mmol)，缓慢滴加溶解在10mL N,N-二甲基甲酰胺中的5-(4-(环丙基甲氧基)-2-氟苯基)-4-甲氧基-1H-吡咯-3-羧酸甲酯(13.5mmol)，0℃下搅拌30min后滴加15冠5(40.5mmol)，然后滴加吡啶-3-磺酰氯(20.2mmol)，滴加完毕0℃下继续搅拌30min，然后室温搅拌30min，TLC监测原料反应完全，将体系倒入冰水中乙酸乙酯(200mL×2)萃取，饱和食盐水(150mL×2)洗涤，合并有机相，无水硫酸钠干燥，有机相减压浓缩后经柱层析纯化得淡黄色固体，收率71.5％。
步骤6：(5-(4-(环丙基甲氧基)-2-氟苯基)-4-甲氧基-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲醇的制备
5-(4-(环丙基甲氧基)-2-氟苯基)-4-甲氧基-1-(吡啶-3-基磺酰基)-1H-吡咯-3-羧酸甲酯(60.8mmol)溶解到四氢呋喃中。在0℃下向所得溶液中加入二异丁基氢化铝(1.0M正己烷溶液)(182.2mmol)中，然后在室温下搅拌1h。在0℃下将水加入到反应混合物中，然后用乙酸乙酯萃取。萃取液用无水硫酸镁干燥，然后在减压下浓缩。所得残余物用硅胶柱色谱(乙酸乙酯:正己烷＝1:4(v/v))进行纯化，以得到黄色化合物，收率50％。
步骤7：5-(4-(环丙基甲氧基)-2-氟苯基)-4-甲氧基-1-(吡啶-3-基磺酰基)-1H-吡咯-3-甲醛的制备
(5-(4-(环丙基甲氧基)-2-氟苯基)-4-甲氧基-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)甲醇(50.0mmol)溶解到二氯甲烷中。向所得溶液中加入氯铬酸吡啶(150.0mmol)，在室温下搅拌30min，然后通过硅藻土垫过滤。使滤液在减压下浓缩。所得残余物用硅胶柱色谱进行纯化，以得到黄色化合物，收率63.5％。
步骤8：1-(5-(4-(环丙基甲氧基)-2-氟苯基)-4-甲氧基-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)-N-甲基甲胺的制备
冰水浴下，在单口圆底烧瓶中加入5-(4-(环丙基甲氧基)-2-氟苯基)-4-甲氧基-1-(吡啶-3-基磺酰基)-1H-吡咯-3-甲醛(0.23mmol)，甲氨(33重量％的甲醇溶液，2.3mmol)，甲醇(3mL)搅拌30min。撤走冰浴自然升温至环境温度搅拌过夜反应。次日加入硼氢化钠(1.2mmol)继续室温(25℃)反应3h。TLC监测原料反应完全。将体系加入冰水中，二氯甲烷(50mL×4)萃取，无水硫酸钠干燥，减压浓缩有机相后经柱层析纯化得白色固体，一步收率33％。
1H NMR(600MHz,Methanol-d 4)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).
制备例49：该制备例用于说明化合物49的盐酸盐的合成过程：
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的(S)-缩水甘油，得到化合物49的盐酸盐，灰色固体，步骤6)中的一步收率45％。
1H NMR(400MHz,Methanol-d 4)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).
制备例50：该制备例用于说明化合物50的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的(R)-缩水甘油，得到化合物50的盐酸盐，灰色固体，步骤6)中的一步收率46％。
1H NMR(400MHz,Methanol-d 4)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).
制备例51：该制备例用于说明化合物51的盐酸盐的合成过程
该制备例的制备方法与制备例48相似，不同之处在于：
将步骤4)中的5-(4-(环丙基甲氧基)-2-氟苯基)-4-甲氧基-1H-吡咯-3-羧酸甲酯替换为等摩尔量的5-(4-(环丙基甲氧基)-2-氟苯基)-4-氟-1H-吡咯-3-羧酸甲酯，得到化合物51的盐酸盐，棕色固体，步骤6)中的一步收率46％。
1H NMR(600MHz,Methanol-d 4)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).
制备例52：该制备例用于说明化合物52的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2-甲基丙烷-1,2-二醇，得到化合物52的盐酸盐，棕色固体，步骤6)中的一步收率46％。
1H NMR(600MHz,Methanol-d 4)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).
制备例53：该制备例用于说明化合物53的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的顺式-2-氟环丙基)甲醇，得到化合物53的盐酸盐，白色固体，步骤6)中的一步收率46％。
1H NMR(600MHz,Methanol-d 4)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).
制备例54：该制备例用于说明化合物54的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2，5-二氟苄醇，得到化合物54，白色固体，步骤6)中的一步收率48％。
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).
制备例55：该制备例用于说明化合物55的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2，4-二氟苄醇，得到化合物55的盐酸盐，黄色油状物，步骤6)中的一步收率45％。
1H NMR(600MHz,Methanol-d 4)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).
制备例56：该制备例用于说明化合物56的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2,6-二氟苄醇，得到化合物56的盐酸盐，白色固体，步骤6)中的一步收率45％。
1H NMR(600MHz,Methanol-d 4)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).
制备例57：该制备例用于说明化合物57的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的3，4-二氟苄醇，得到化合物57的盐酸盐，白色固体，步骤6)中的一步收率56％。
1H NMR(600MHz,Methanol-d 4)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).
制备例58：该制备例用于说明化合物58的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的3，5-二氟苄醇，得到化合物58的盐酸盐，白色固体，步骤6)中的一步收率55％。
1H NMR(600MHz,Methanol-d 4)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).
制备例59：该制备例用于说明化合物59的合成过程：
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2-二氟甲氧基苄醇，得到化合物59，黄色粉末，步骤6)中的一步收率49％。
1H NMR(400MHz,Methanol-d 4)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).
制备例60：该制备例用于说明化合物60的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2-三氟甲氧基苄醇，得到化合物60的盐酸盐，白色固体，步骤6)中的一步收率56％。
1H NMR(400MHz,Methanol-d 4)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).
制备例61：该制备例用于说明化合物61的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的4-二氟甲氧基苄醇，得到化合物61的盐酸盐，白色固体，步骤6)中的一步收率55％。
1H NMR(600MHz,Methanol-d 4)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).
制备例62：该制备例用于说明化合物62的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-羟甲基萘，得到化合物62的盐酸盐，白色固体，步骤6)中的一步收率53％。
1H NMR(600MHz,Methanol-d 4)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).
制备例63：该制备例用于说明化合物63的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-氰基苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-羟甲基萘，得到化合物63的盐酸盐，白色固体，步骤6)中的一步收率43％。
1H NMR(600MHz,Methanol-d 4)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).
制备例64：该制备例用于说明化合物64的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的4-羟甲基苯甲酸，得到化合物64的盐酸盐，白色固体，步骤6)中的一步收率25％。
1H NMR(600MHz,Methanol-d 4)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).
制备例65：该制备例用于说明化合物65的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(2,5-二氟苯基)乙醇，得到化合物65的盐酸盐，白色固体，步骤6)中的一步收率48％。
1H NMR(600MHz,Methanol-d 4)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).
制备例66：该制备例用于说明化合物66的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的(s)-1-(2,6-二氯-3-氟苯基)乙醇，得到化合物66的盐酸盐，白色固体，步骤6)中的一步收率56％。
1H NMR(600MHz,Methanol-d 4)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).
制备例67：该制备例用于说明化合物67的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(2,6-二氟苯基)乙醇，得到化合物67的盐酸盐，白色固体，步骤6)中的一步收率53％。
1H NMR(600MHz,Methanol-d 4)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).
制备例68：该制备例用于说明化合物68的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(3,5-二氟苯基)乙醇，得到化合物68的盐酸盐，白色固体，步骤6)中的一步收率55％。
1H NMR(400MHz,Methanol-d 4)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).
制备例69：该制备例用于说明化合物69的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-氰基苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(2,6-二氟苯基)乙醇，得到化合物69的盐酸盐，白色固体，步骤6)中的一步收率43％。
1H NMR(400MHz,Methanol-d 4)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).
制备例70：该制备例用于说明化合物70的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-氰基苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(3,5-二氟苯基)乙醇，得到化合物70的盐酸盐，白色固体，步骤6)中的一步收率45％。
1H NMR(400MHz,Methanol-d 4)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).
制备例71：该制备例用于说明化合物71的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-(环丙基甲氧基)苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(3,5-二氟苯基)乙醇，得到化合物71的盐酸盐，白色固体，步骤6)中的一步收率47％。
1H NMR(600MHz,Methanol-d 4)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).
制备例72：该制备例用于说明化合物72的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-(环丙基甲氧基)苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(2,6-二氟苯基)乙醇，得到化合物72的盐酸盐，黄色油状，步骤6)中的一步收率45％。
1H NMR(400MHz,Methanol-d 4)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).
制备例73：该制备例用于说明化合物73的盐酸盐的合成过程：
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2,4-二甲基苄醇，得到化合物73的盐酸盐，白色固体，步骤6)中的一步收率56％。
1H NMR(600MHz,Methanol-d 4)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).
制备例74：该制备例用于说明化合物74的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的4-羟甲基吡啶，得到化合物74，白色固体，步骤6)中的一步收率57％。
1H NMR(400MHz,DMSO-d 6)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).
制备例75：该制备例用于说明化合物75的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2-甲氧基苄醇，得到化合物75的盐酸盐，白色固体，步骤6)中的一步收率49％。
1H NMR(600MHz,Methanol-d 4)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).
制备例76：该制备例用于说明化合物76的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的(R)-1-(2,6-二氯-3-氟苯基)乙醇，得到化合物76的盐酸盐，白色固体，步骤6)中的一步收率44％。
1H NMR(600MHz,Methanol-d 4)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).
制备例77：该制备例用于说明化合物77的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的3-羟甲基噻吩，得到化合物77，黄色固体，步骤6)中的一步收率40％。
1H NMR(600MHz,DMSO-d 6)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).
制备例78：该制备例用于说明化合物78的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-氯苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2,5-二氟苄醇，得到化合物78的盐酸盐，白色固体，步骤6)中的一步收率40％。
1H NMR(600MHz,Methanol-d 4)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).
制备例79：该制备例用于说明化合物79的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-氟苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2,5-二氟苄醇，得到化合物79的盐酸盐，白色固体，步骤6)中的一步收率36％。
1H NMR(600MHz,Methanol-d 4)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).
制备例80：该制备例用于说明化合物80的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3，5-二氟苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2,5-二氟苄醇，得到化合物80的盐酸盐，白色固体，步骤6)中的一步收率44％。
1H NMR(600MHz,Methanol-d 4)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).
制备例81：该制备例用于说明化合物81的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-氟-4-甲基苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2,5-二氟苄醇，得到化合物81的盐酸盐，白色固体，步骤6)中的一步收率36％。
1H NMR(600MHz,Methanol-d 4)δ7.73(s,1H),7.37–7.29(m,2H),7.25–7.12(m,3H),7.09(d,J＝9.0Hz,1 H),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).
制备例82：该制备例用于说明化合物82的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-戊氧基苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2,5-二氟苄醇，得到化合物82的盐酸盐，白色固体，步骤6)中的一步收率36％。
1H NMR(600MHz,Methanol-d 4)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).
制备例83：该制备例用于说明化合物83的盐酸盐的合成过程：
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-环丁基甲氧基苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(2,6-二氟苯基)-乙醇，得到化合物83的盐酸盐，黄色油状，步骤6)中的一步收率41％。
1H NMR(400MHz,Methanol-d 4)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).
制备例84：该制备例用于说明化合物84的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-环戊基甲氧基苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2,4-二氟苄醇，得到化合物84的盐酸盐，白色固体，步骤6)中的一步收率40％。
1H NMR(400MHz,Methanol-d 4)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).
制备例85：该制备例用于说明化合物85的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-环戊基甲氧基苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(2,6-二氟苯基)-乙醇，得到化合物85的盐酸盐，黄色油状，步骤6)中的一步收率23％。
1H NMR(400MHz,Methanol-d 4)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).
制备例86：该制备例用于说明化合物86的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-(2-甲氧基-乙氧基)苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2，4-二氟苄醇，得到化合物86的盐酸盐，白色固体，步骤6)中的一步收率45％。
1H NMR(400MHz,Methanol-d 4)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).
制备例87：该制备例用于说明化合物87的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-(2-甲氧基-乙氧基)苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2-甲氧基苄醇，得到化合物87，白色固体，步骤6)中的一步收率39％。
1H NMR(400MHz,Methanol-d 4)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).
制备例88：该制备例用于说明化合物88的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-(3-甲氧基-丙氧基)苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(2,6-二氟苯基)-乙醇，得到化合物88，黄色油状，步骤6)中的一步收率44％。
1H NMR(400MHz,Methanol-d 4)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).
制备例89：该制备例用于说明化合物89的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-(3-甲氧基-丙氧基)苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(3,5-二氟苯基)-乙醇，得到化合物89的盐酸盐，白色固体，步骤6)中的一步收率46％。
1H NMR(400MHz,Methanol-d 4)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).
制备例90：该制备例用于说明化合物90的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-(4-甲氧基-丁氧基)苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2-羟甲基萘，得到化合物90的盐酸盐，白色固体，步骤6)中的一步收率51％。
1H NMR(600MHz,Methanol-d 4)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).
制备例91：该制备例用于说明化合物91的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-(4-甲氧基-丁氧基)苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(2,6-二氟苯基)-乙醇，得到化合物91，白色固体，步骤6)中的一步收率48％。
1H NMR(400MHz,Methanol-d 4)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).
制备例92：该制备例用于说明化合物92的盐酸盐的合成过程：
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-(4-甲氧基-丁氧基)苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1-(3,5-二氟苯基)-乙醇，得到化合物92的盐酸盐，黄色固体，步骤6)中的一步收率41％。
1H NMR(400MHz,Methanol-d 4)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).
制备例93：该制备例用于说明化合物93的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-(4-甲氧基-丁氧基)苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1,3-苯并二氧戊环-4-烷基甲醇，得到化合物93的盐酸盐，白色固体，步骤6)中的一步收率40％。
1H NMR(400MHz,Methanol-d 4)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＝2.0 Hz,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).
制备例94：该制备例用于说明化合物94的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1,3-苯并二氧戊环-4-烷基甲醇，得到化合物94的盐酸盐，白色固体，步骤6)中的一步收率50％。
1H NMR(600MHz,DMSO-d 6)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).
制备例95：该制备例用于说明化合物95的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-氰基苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的1,3-苯并二氧戊环-4-烷基甲醇，得到化合物95的盐酸盐，白色固体，步骤6)中的一步收率44％。
1H NMR(400MHz,Methanol-d 4)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).
制备例96：该制备例用于说明化合物96的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2,3-二氢-1,4-苯并二噁英-5-甲醇，得到化合物96的盐酸盐，白色固体，步骤6)中的一步收率56％。
1H NMR(600MHz,Methanol-d 4)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).
制备例97：该制备例用于说明化合物97的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-氰基苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2,3-二氢-1,4-苯并二噁英-5-甲醇，得到化合物97的盐酸盐，白色固体，步骤6)中的一步收率43％。
1H NMR(600MHz,Methanol-d 4)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).
制备例98：该制备例用于说明化合物98的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤3)中的吡啶-3-磺酰氯替换为等摩尔量的3-三氟甲基苯磺酰氯，将步骤6)中的(2S)-1,4-二恶烷-2-甲 醇替换为等摩尔量的2，-5-二氟苄醇，得到化合物98的盐酸盐，白色固体，步骤6)中的一步收率52％。
1H NMR(600MHz,Methanol-d 4)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).
制备例99：该制备例用于说明化合物99的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的2-(3,5-二氟苯基)-乙醇，得到化合物99的盐酸盐，白色固体，步骤6)中的一步收率48％。 1H NMR(600MHz,Methanol-d 4)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).
制备例100：该制备例用于说明化合物100的盐酸盐的合成过程
该制备例的制备方法与制备例1相似，不同之处在于：
将步骤6)中的(2S)-1,4-二恶烷-2-甲醇替换为等摩尔量的3-羟甲基呋喃，得到化合物100的盐酸盐，灰色固体，步骤6)中的一步收率51％。
1H NMR(600MHz,Methanol-d 4)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).
测试例1：H +/K +-ATPase生物学评价
该测试例是通过体外筛选试验来评价本发明的化合物对于H +/K +-ATPase酶活性的抑制作用，并用化合物IC 50值(通过不同浓度下的抑制率计算得到)来表示。
体外筛选试验：
(1)试剂准备：
化合物溶液：将本发明前述制备例中获得的产物(即为化合物或者化合物的盐酸盐)各自独立地用DMSO溶解配制成合适的浓度；
缓冲液I：50mmol/L HEPEs-Tris，pH＝6.5，5mmol/L氯化镁，10μmol/L缬氨霉素(百灵威化学技术有限公司，货号：227304)；
缓冲液II：50mmol/L HEPEs-Tris，pH＝6.5，5mmol/L氯化镁，10μmol/L缬氨霉素，5mmol/L氯化钾；
5-三磷酸腺苷(ATP，Sigma-Aldrich，货号：A2383)溶液：用缓冲液I稀释ATP至5mM；
孔雀石绿溶液：将0.12wt％孔雀石绿(百灵威化学技术有限公司，货号：913120)溶于2.5mol/L硫酸，7.5wt％钼酸铵(百灵威化学技术有限公司，货号：128321)和11％Tween 20(V/V)，使用时硫酸、钼酸铵、Tween 20按100:25:2比例混合；
兔胃黏膜微粒体(富含H+/K+-ATPase，自提)，提取方法为蔗糖梯度离心：把兔胃用分别自来水，3M的NaCl溶液洗净，然后用滤纸除去表面水分。加入预冷的匀浆缓冲液(4ml/g组织)，于组织匀浆机中匀浆2-5min。匀浆后，如果有较大的组织颗粒，可离心(600g，10min)去除，然后将上清移至干净的离心管中20000g离心30min后，然后将上清移至干净的离心管中，进一步离心，100000g离心90min，收集沉淀；利用匀浆液悬浮 沉淀，吹散均匀，利用Bradford法测蛋白浓度，调整浓度为10mg/ml；等比例加入7.5重量％的Ficoll分层液，100000g离心60min后，将中层(H+/K+-ATPaseenriched gastric membranes)收集于洁净离心管中，利用匀浆液4-5倍稀释，继续100 000g离心90min，收集沉淀；利用匀浆液悬浮沉淀，玻璃匀浆器匀浆均匀，利用Bradford法测蛋白浓度，调整浓度22.5mg/ml。冻于-80℃备用。
(2)实验过程：
向45μL缓冲液II中加入5μL的兔胃粘膜微粒体(H +/K +-ATPase)，再加入5μL的化合物溶液，然后加入5μL的5mM的ATP溶液启动反应，在37℃预反应30min。加入15μL孔雀石绿溶液终止反应，室温平衡20min，在620nm处读吸收光值。
同时，进行相同体积，不加氯化钾的反应作为背景，在计算酶活性时减去，结果如表1所示。
表1：化合物对H +/K +-ATPase酶活性的抑制作用
化合物编号 IC 50(nM) 化合物编号 IC 50(nM) 化合物编号 IC 50(nM) 化合物编号 IC 50(nM)
A1 66.7 A5 169.2 A9 33.8 A12 118.7
A2 154.8 A6 156.9 A10 27.7 A13 127.9
A3 51.6 A8 18.42 A11 14.1 - -
1 585.3 26 201.7 51 35.2 76 470.1
2 24.5 27 38.7 52 372.3 77 119.6
3 20.9 28 30.8 53 56.1 78 98.5
4 30.9 29 289.9 54 17.8 79 55.3
5 82.4 30 474.5 55 8.6 80 65.9
6 149.2 31 1211 56 13.3 81 56.6
7 253.5 32 821.8 57 46.3 82 3659
8 72.1 33 883.4 58 25.7 83 13340
9 25.4 34 285.2 59 41.3 84 109
10 55.3 35 8649 60 186.4 85 9781
11 65.2 36 2272 61 51.3 86 34.4
12 138 37 157.3 62 35.9 87 43.4
13 114.2 38 198.8 63 1057 88 449.8
14 442.7 39 34.6 64 163.7 89 1333
15 83.9 40 123.2 65 80.5 90 2692
16 253 41 566.6 66 484.6 91 692.6
17 264.9 42 400.9 67 41 92 1906
18 261.8 43 481.6 68 41.4 93 12372
19 233.1 44 500.4 69 114.3 94 48.4
20 293.8 45 203.5 70 88.1 95 9.5
21 2787 46 639.4 71 496.3 96 51.1
22 458.4 47 246.8 72 342.1 97 11.9
23 907.8 48 36 73 209 98 484.6
24 135.8 49 146.1 74 564.4 99 72.6
25 58.5 50 113.5 75 36.6 100 101.2
通过表1可以看出，本发明的化合物对H +/K +-ATPase酶的活性的具有优异的抑制作用。
测试例2：化合物对组胺诱导的大鼠胃酸分泌作用的抑制效应
取体重180-220g的SPF级SD大鼠(杭州医学院(生产))70只，将动物按体重随机分组，包括阴性对照组(等容积生理盐水)和模型对照组(等容积生理盐水)，本发明前述制备例获得的产物(即为化合物或者化合物的盐酸盐)(2mg/kg或4mg/kg)，每组10只，雌雄各半。禁食24h，不禁水。24h后，采取灌胃给药，给药容积为1ml/100g，各组均给药一次，阴性对照组和模型组灌胃给予等体积的生理盐水。之后将大鼠用水合氯醛300mg/kg(1ml/100g)麻醉后，固定在大鼠板上，自胸骨剑突下沿腹中线切开腹壁，切口约2～3cm，在左侧肋缘部位，用指轻轻往上一推，使胃暴露于切口。在幽门下穿一线将幽门结扎(邻近的其它血管不结扎)，然后缝合腹壁切口。动物于灌胃受试化合物或生理盐水1h后皮下给予组胺二盐酸盐(30mg/10ml/kg)。给予组胺3h后用过量CO 2窒息处死大鼠，取胃，收集胃内容物，3000rpm/min离心10min，用0.1mol/L的NaOH滴定酸液至PH7.0，计算3h期间的总酸及抑酸率。
抑酸率计算公式如下，结果如表2所示：
抑酸率(％)＝(模型组总酸量-给药组总酸量)/模型组总酸量×100％。
表2：化合物对组胺诱导的大鼠胃酸分泌作用的抑制效果
化合物编号 剂量(mg/kg) 抑酸率(％)
6 2 48
8 2 71
28 2 71
37 2 56
48 2 75
48 4 86
67 2 64
A1 2 68
A3 2 65
A4 2 60
A7 2 53
A8 2 58
A9 2 83
A9 4 93
A10 2 81
A10 4 87
A11 2 81
A12 2 63
A13 2 60
A14 2 63
A15 2 64
通过表2可以看出，本发明的化合物对组胺诱导的大鼠胃酸分泌作用具有良好的抑制效果。
测试例3：化合物48、化合物A9和对比化合物沃诺拉赞的大鼠组织分布试验
取健康雄性SD大鼠3只(体重范围为220-250克，浙江维通利华)分为1组(n＝3)。口服给予化合物48、化合物A9或对比化合物沃诺拉赞，给药剂量4mg/kg。
给药制剂配制用溶媒：纯水。给药前4h禁食。1h、2h、4h采集血浆，肝，胃(剩余SD大鼠取空白组织给分析组)。组织匀浆，用对应的空白组织配制标曲和QC定量。血液样品应在采集后1小时内离心取血浆，离 心前血液样品置于碎冰上。离心取得的血浆样品储存在冷冻冰箱直至检测分析。离心条件：4-10℃，8000rpm，6分钟。样品浓度以LC-MS-MS检测(MS03:Shimadzu LC30AD and API 4000))，暴露量数据用WINNOLIN软件计算得到，结果列于表3、表4和表5中。
表3：化合物48大鼠口服4mg/kg剂量下的组织分布情况
组织 暴露量(0-4h)/h*ng/mL 比值
血浆 85.8 1
肝脏 7585.5 88.4
胃 14693.7 171.3
表4：化合物A9大鼠口服4mg/kg剂量下的组织分布情况
组织 暴露量(0-4h)/h*ng/mL 比值
血浆 43.1 0.02
肝脏 2326.8 1
胃 13224.3 5.7
通过表3和表4可以看出，本发明的化合物具有非常明显的胃组织富集效果，同时在血浆中的暴露量较低，在肝脏中的暴露量也明显低于胃部。
表5：化合物A9和对比化合物沃诺拉赞口服4mg/kg剂量下肝脏药物浓度对比
化合物/时间点 15min 1h 2h 4h 24h
A9 1541.3 846 262 31.5 1.3
沃诺拉赞 9919 1192 632 162 23.7
通过表5可以看出，本发明的化合物在肝脏中的各个时间点的化合物浓度明显低于对比化合物沃诺拉赞。
综合表3、表4和表5的数据，本发明的化合物有望提高治疗效果的同时降低已上市药物沃诺拉赞存在的肝毒性等安全性风险。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于此。在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，包括各个技术特征以任何其它的合适方式进行组合，这些简单变型和组合同样应当视为本发明所公开的内容，均属于本发明的保护范围。

Claims (10)

  1. 一种含磺酰胺结构的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐，该化合物具有式(I)所示的结构，
    Figure PCTCN2021126527-appb-100001
    在式(I)中，
    X为CH 2或CH(CH 3)；
    R 1为H、取代或未取代的C 1-C 4的烷基、C 1-C 3的烷氧基、含有S的杂原子的饱和三元环基、含有O或S的杂原子的饱和四元环基、含有O或S的杂原子的饱和五元环基、含有1-2个氧原子的六元饱和杂环烷基、取代或未取代的含有1-2个氮原子的六元饱和杂环烷基、取代或未取代的含有至少一个氮原子的五元不饱和杂环烷基、取代或未取代的含有至少一个氮原子的六元不饱和杂环烷基、-C 1-C 4的亚烷基-O-C 1-C 3的烷基、取代或未取代的C 3-C 6的饱和环烷基、环氧乙烷基、含有至少两个卤素取代的苯基、二氟甲氧基取代的苯基、三氟甲氧基取代的苯基、羧基取代的苯基、萘基、含有至少两个甲基取代的苯基、吡啶-4-基、甲氧基取代的苯基、噻吩-3-基、苯并二氧戊环基、苯并二氧己环基、-CH 2-含有至少两个卤素取代的苯基、呋喃-3-基；R 1中任选存在的取代基选自卤素、氰基、硝基、羟基、C 1-C 6的烷基、C 1-C 6的烷氧基、C 1-C 3的醛基中的至少一种；
    R 2为3-吡啶基、取代或未取代的苯基；R 2中任选存在的取代基选自卤素、C 1-C 6的烷基、C 1-C 6的烷氧基、-O-C 1-C 4的亚烷基-O-C 1-C 3的烷基、由1-6个卤素取代的C 1-C 3的烷基、由1-6个卤素取代的C 1-C 3的烷氧基、氰基、-O-C 1-C 4的亚烷基-C 3-C 6的环烷基中的至少一种；
    R 3为C 1-C 3的烷基；
    R 4为H、C 1-C 3的烷氧基、卤素；
    R 5和R 6中的一者为H，另一者选自F、C 1-C 3的烷基。
  2. 根据权利要求1所述的化合物，其中，在式(I)中，
    X为CH 2或CH(CH 3)；
    R 1为H、取代或未取代的C 1-C 4的烷基、C 1-C 3的烷氧基、含有1-2个氧原子的六元饱和杂环烷基、取代或未取代的含有至少1个氮原子的六元饱和杂环烷基、-C 1-C 4的亚烷基-O-C 1-C 3的烷基、取代或未取代的C 3-C 6的饱和环烷基、环氧乙烷基、含有O原子的饱和四元环基、含有O原子的饱和五元环基、取代的含有至少一个氮原子的五元不饱和杂环烷基、取代的含有至少一个氮原子的六元不饱和杂环烷基、含有至少两个卤素取代的苯基、二氟甲氧基取代的苯基、三氟甲氧基取代的苯基、羧基取代的苯基、萘基、含有至少两个甲基取代的苯基、吡啶-4-基、甲氧基取代的苯基、噻吩-3-基、苯并二氧戊环基、苯并二氧己环基、-CH 2-含有至少两个卤素取代的苯基、呋喃-3-基；R 1中任选存在的取代基选自氟、氯、溴、羟基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 2的醛基、氰基、硝基中的至少一种；
    R 2为3-吡啶基、取代或未取代的苯基；R 2中任选存在的取代基选自氟、氯、溴、碘、C 1-C 6的烷基、C 1-C 6的烷氧基、-O-C 1-C 4的亚烷基-O-C 1-C 2的烷基、由1-3个卤素取代的C 1-C 3的烷基、由1-3个卤素取代的C 1-C 3的烷氧基、氰基、-O-C 1-C 4的亚烷基-C 3-C 6的环烷基中的至少一种；
    R 3为甲基、乙基、正丙基或异丙基；
    R 4为H、甲氧基、乙氧基、正丙氧基、异丙氧基、氟、氯或溴；
    R 5和R 6中的一者为H，另一者选自F、甲基、乙基、正丙基、异丙基。
  3. 根据权利要求2所述的化合物，其中，在式(I)中，
    X为CH 2或CH(CH 3)；
    R 1为H、取代或未取代的C 1-C 4的烷基、C 1-C 3的烷氧基、含有1-2个氧原子的六元饱和杂环烷基、取代或未取代的含有1-2个氮原子的六元饱和杂环烷基、-C 1-C 4的亚烷基-O-C 1-C 3的烷基、取代或未取代的C 3-C 6的饱和环烷基、环氧乙烷基、含有O原子的饱和四元环基、含有O原子的饱和五元环基、取代的含有至少一个N原子的不饱和五元环、取代的含有至少一个N原子的不饱和六元环；含有至少两个卤素取代的苯基、二氟甲氧基取代的苯基、三氟甲氧基取代的苯基、羧基取代的苯基、萘基、含有至少两个甲基取代的苯基、吡啶-4-基、甲氧基取代的苯基、噻吩-3-基、苯并二氧戊环基、苯并二氧己环基、-CH 2-含有至少两个卤素取代的苯基、呋喃-3-基；R 1中任选存在的取代基选自氟、氯、溴、羟基、C 1-C 4烷基、C 1-C 4烷氧基、乙醛基中的至少一种；
    R 2为3-吡啶基、取代或未取代的苯基；R 2中任选存在的取代基选自氟、氯、溴、C 1-C 6的烷基、C 1-C 6的烷氧基、-O-C 1-C 4的亚烷基-O-C 1-C 2的烷基、由1-3个卤素取代的C 1-C 3的烷基、由1-3个卤素取代的C 1-C 3的烷氧基、氰基、-O-C 1-C 4的亚烷基-C 3-C 6的环烷基中的至少一种；
    R 3为甲基或乙基；
    R 4为H、甲氧基或氟；
    R 5和R 6中的一者为H，另一者选自F、甲基、乙基、正丙基、异丙基。
  4. 根据权利要求3所述的化合物，其中，在式(I)中，
    X为CH 2或CH(CH 3)；
    R 1为H、甲基、异丙基、叔丁基、羟基取代的叔丁基、二氟甲基、甲氧基、二氧六环基、取代或未取代的哌啶基、-C 1-C 4的亚烷基-O-C 1-C 3的烷基、取代或未取代的C 3-C 6的饱和环烷基、环氧乙烷基、含有O原子的饱和四元环基、含有O原子的饱和五元环基、取代的含有至少一个N原子的不饱和五元环基、取代的含有至少一个N原子的不饱和六元环基、含有至少两个卤素取代的苯基、二氟甲氧基取代的苯基、三氟甲氧基取代的苯基、羧基取代的苯基、萘基、含有至少两个甲基取代的苯基、吡啶-4-基、甲氧基取代的苯基、噻吩-3-基、苯并二氧戊环基、苯并二氧己环基、-CH 2-含有至少两个卤素取代的苯基、呋喃-3-基；R 1中任选存在的取代基选自氟、氯、溴、羟基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、乙醛基中的至少一种；
    R 2为3-吡啶基、取代或未取代的苯基；R 2中任选存在的取代基选自氟、氯、溴、C 1-C 6的烷基、C 1-C 6的烷氧基、-O-C 1-C 4的亚烷基-O-C 1-C 2的烷基、由1-3个卤素取代的C 1-C 3的烷基、由1-3个卤素取代的C 1-C 3的烷氧基、氰基、-O-C 1-C 4的亚烷基-C 3-C 6的环烷基中的至少一种；
    R 3为甲基或乙基；
    R 4为H、甲氧基或氟；
    R 5和R 6中的一者为H，另一者选自F、甲基、乙基、正丙基、异丙基。
  5. 根据权利要求1-4中任意一项所述的方法，其中，式(I)所示的化合物选自以下中的任意一种：
    Figure PCTCN2021126527-appb-100002
    Figure PCTCN2021126527-appb-100003
    Figure PCTCN2021126527-appb-100004
    Figure PCTCN2021126527-appb-100005
    Figure PCTCN2021126527-appb-100006
    Figure PCTCN2021126527-appb-100007
  6. 一种制备含磺酰胺结构的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐的方法，其特征在于，该化合物具有式(I)所示的结构，
    Figure PCTCN2021126527-appb-100008
    该方法包括：将式(II)所示的化合物与式(III)所示的化合物进行接触反应；
    Figure PCTCN2021126527-appb-100009
    其中，在式(I)、式(II)和式(III)中，各基团的定义与权利要求1-5中任意一项所述的定义相同。
  7. 一种药物组合物，该药物组合物含有治疗有效量的权利要求1-5中任意一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐，以及该药物组合物中还含有药物可接受的载体、赋形剂或稀释剂。
  8. 权利要求1-5中任意一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐，或者权利要求7所述的药物组合物，在制备H +/K +-ATPase抑制剂药物和/或制备钾离子竞争性酸阻滞剂药物中的应用。
  9. 权利要求1-5中任意一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐，或者权利要求7所述的药物组合物，在制备用于治疗或预防消化性溃疡、卓-艾综合症、胃炎、糜烂性食管炎、反流性食管炎、症状性胃食管反流疾病、巴雷特食管炎、功能性消化不良、幽门螺旋杆菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡或手术后应激导致的胃酸过多或溃疡的药物中的应用。
  10. 根据权利要求9所述的应用，其中，所述消化性溃疡包括胃溃疡、十二指肠溃疡和吻合口溃疡中的至少一种；所述症状性胃食管反流疾病包括非糜烂性的反流性疾病和无食管炎的胃食管反流疾病中的至少一种。
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