WO2023280290A1 - Pyrrole sulfonyl derivative, and preparation method therefor and use thereof - Google Patents

Pyrrole sulfonyl derivative, and preparation method therefor and use thereof Download PDF

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WO2023280290A1
WO2023280290A1 PCT/CN2022/104528 CN2022104528W WO2023280290A1 WO 2023280290 A1 WO2023280290 A1 WO 2023280290A1 CN 2022104528 W CN2022104528 W CN 2022104528W WO 2023280290 A1 WO2023280290 A1 WO 2023280290A1
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mmol
alkyl
compound
synthesis
room temperature
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PCT/CN2022/104528
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French (fr)
Chinese (zh)
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罗明
向俊峰
何锦
刘军华
王衡新
邓俐丽
宋志林
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天地恒一制药股份有限公司
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/402—1-aryl substituted, e.g. piretanide
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    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • the present invention relates to a new class of pyrrolesulfonyl derivatives, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a gastric acid secretion inhibitor and a potassium ion competitive acid blocker (P- CABs).
  • Gastrointestinal-related tumors account for five of the six most common cancers in the world, including gastric cancer, liver cancer, esophageal cancer, intestinal cancer, and pancreatic cancer.
  • PPIs proton pump Inhibitors
  • omeprazole was successfully developed by AstraZenaca and first launched in Sweden. Pump inhibitors used to treat duodenal ulcers, Zoller-Ellison syndrome, gastric ulcers, and reflux esophagitis. Subsequently, several PPIs products were launched in succession around the world. After years of clinical application, PPIs have become the drug of choice for the treatment of gastric acid-related diseases.
  • Proton Pump also known as gastric acid pump
  • H + /K + -adenosine triphosphatase H + /K + -ATPase
  • H + /K + -ATPase H + /K + -adenosine triphosphatase
  • ATP is degraded to provide energy for H + and K + exchange, and H + is specifically pumped into the gastric cavity, forming a strong acid state in the stomach.
  • the first-generation PPIs have a significant inhibitory effect on gastric acid secretion stimulated by basal, nocturnal gastric acid and pentagastrin, and test meals.
  • P-CABs Potassium-Competitive Acid Blockers
  • P-CABs are immediately ionized, and the ionized form inhibits H + /K + -ATPase through ionic binding, preventing H + transport and acid secretion into the gastric cavity, without the need to concentrate on the microcapsules and parietal cells.
  • the activation of microtubules and acid can rapidly increase the pH value in the stomach, and the enzyme activity will recover after dissociation. Humans and animals can absorb rapidly after oral administration and reach the peak plasma concentration.
  • Clinical and animal experiments also show that P-CABs has a faster onset of action than PPIs or histamine receptor 2 (H2) blockers, a stronger effect of increasing pH, and a linearity of blood drug concentration with oral administration dose.
  • the object of the present invention is to provide a new pyrrolesulfonyl derivative, its pharmaceutically acceptable salt, its tautomer or its stereoisomer, to screen out Compounds useful as gastric acid secretion inhibitors and potassium ion-competitive acid blockers (P-CABs) having excellent properties in terms of efficacy, safety and selectivity.
  • P-CABs potassium ion-competitive acid blockers
  • Another object of the present invention is to provide a preparation method of the derivative, its pharmaceutically acceptable salt, its tautomer or its stereoisomer.
  • Ring A is selected from phenyl or pyridyl, and phenyl or pyridyl is optionally substituted by 1 , 2 or 3 R;
  • Ring B is selected from 3-12 membered heterocyclic group, 5-8 membered aryl group, 5-8 membered heteroaryl group, 3-12 membered cycloalkyl group, 7-12 membered spirocyclic group, 7- 12-membered ring group, 7-12-membered bridged ring group, wherein, ring B is optionally substituted or oxo by 1, 2 or 3 R 2 ;
  • R 1 is selected from C 1-6 alkyl, C 1-6 alkoxy, halogen, cyano, C 2-6 alkynyl, C 2-6 alkenyl, OC 1-6 alkyl-OC 1-6 Alkyl, NR a R b ;
  • R 3 is selected from halogen, 5-8 membered aryl, 5-8 membered heteroaryl; or two R 3 together with their connected carbon atoms form a condensed ring aryl; wherein aryl, heteroaryl and condensed Cycloaryl can optionally be further substituted by 1, 2 or 3 C 1-6 alkyl, C 1-6 alkoxy, halogen;
  • R 4 is selected from the alkyl group of C 1-6 ; Wherein the alkyl group may be optionally further substituted by 1, 2 or 3 deuterium, halogen;
  • R a , R b , R c , R d are each independently selected from H, C 1-6 alkyl, 3-12 membered cycloalkyl;
  • n is selected from 0, 1, 2, 3;
  • n is selected from 0,1,2.
  • ring B is selected from 3-8 membered monoheterocyclyl, 7-12 membered bridging ring, 7-12 membered spiroheterocyclyl, 3-8 membered heterocyclyl and 3-8 Heterocyclyl, 3-8 membered monoheterocyclyl and 3-8 membered monocycloalkyl, 3-8 membered monoheterocyclyl and phenyl.
  • Ring B is selected from:
  • Z 4 , Z 5 , and Z 6 are independently selected from N and C;
  • L and P are independently selected from 1, 2, 3, 4;
  • Ring B is optionally substituted with 1, 2 or 3 R 2 .
  • Ring B is selected from:
  • Z 1 is selected from O, S, NR e ;
  • Ring B is optionally substituted with 1, 2 or 3 R 2 .
  • Ring B is selected from:
  • R 2 is selected from H, C 1-6 alkoxy, halogen;
  • R 3 is selected from halogen;
  • R 4 is C 1-6 alkyl.
  • the pharmaceutically acceptable salts of pyrrolesulfonyl derivatives provided by the present invention can be hydrochloride or trifluoroacetate.
  • pyrrolesulfonyl derivatives of the present invention can be selected from any one of the following structures:
  • the present invention provides a pharmaceutical composition, which comprises pyrrolesulfonyl derivatives, pharmaceutically acceptable salts, tautomers or stereoisomers thereof, and pharmaceutically acceptable carriers. and/or excipients.
  • the present invention provides the above-mentioned pyrrolesulfonyl derivatives, their pharmaceutically acceptable salts, their tautomers or their stereoisomers, or the pharmaceutical composition used in the preparation of gastric acid Use in secretion inhibitors, H + /K + -ATPase inhibitors or potassium ion competitive acid blockers.
  • the present invention provides a pyrrolesulfonyl derivative as described above, its pharmaceutically acceptable salt, its tautomer or its stereoisomer or the above-mentioned pharmaceutical composition for the treatment or prevention of the following diseases
  • Uses in medicine peptic ulcer, Zoller-Ellison syndrome, gastric erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagitis, functional dyspepsia, pylori spiral bacterial infection, gastric cancer, gastric MALT lymphoma, ulcers caused by non-steroidal anti-inflammatory drugs, hyperacidity caused by postoperative stress or ulcers caused by postoperative stress; or in the preparation of drugs for inhibiting peptic ulcer , acute stress ulcer, hemorrhagic gastritis or upper gastrointestinal bleeding caused by invasive stress.
  • the pyrrolesulfonyl derivatives provided by the present invention have less toxic
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl group includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl. Cycloalkyl groups can be optionally substituted or unsubstituted.
  • Spiro ring group refers to a polycyclic group containing two or more ring structures, and the single rings share one carbon atom (called spiro atom) with each other.
  • the ring may contain one or more double bonds, Can contain one or more heteroatoms, heteroatoms include oxygen, sulfur and nitrogen, etc., but none of the rings has an aromatic system with fully conjugated ⁇ electrons. Preferably it is 6 to 12 yuan.
  • the spiro ring group is divided into single spiro, double spiro or poly spiro ring group, preferably single spiro and double spiro ring group, preferably 4-membered/5-membered, 4-membered/6-membered Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan.
  • spirocyclyl include, but are not limited to:
  • “Bridged ring group” refers to a polycyclic group with 5 to 18 members, containing two or more ring structures, sharing two carbon atoms that are not directly connected to each other, and one or more rings may contain one or more bis Bond, one or more rings may contain one or more heteroatoms, heteroatoms include oxygen, sulfur and nitrogen, etc., but none of the rings has an aromatic system with fully conjugated ⁇ electrons, preferably 6 to 12 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridging rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • Non-limiting examples of "bridged ring groups” include, but are not limited to:
  • Heterocyclic group refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic heterocyclic group containing 3-12 ring atoms, wherein at least one ring atom is a heteroatom, such as oxygen, nitrogen, Sulfur atom etc. Preference is given to having a 3 to 8 membered monocyclic ring or a 7 to 10 membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine Base, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl.
  • a heterocyclyl group can be optionally substituted or unsubstituted.
  • Alternative ring group refers to a parallel ring structure formed by two, three or four ring structures sharing two adjacent atoms with each other.
  • Each single ring of the ring structure can be a single ring aryl group, a single ring heteroaryl group, monocyclic cycloalkyl or monocyclic heterocycloalkyl.
  • the ring-joining group referred to in the present invention is a saturated, unsaturated or partially saturated ring-joining structure, preferably a bicyclic or tricyclic ring-joining group; in the present invention, the ring-joining group is 3-20 members, preferably 3 -15 membered and cycloyl.
  • alkynyl include, but are not limited to: benzocyclobutenyl, 2,3-dihydro-1-H-indenyl, 1,2,3,4-tetrahydronaphthyl, 6,7, 8,9-tetrahydro-5H-benzo[7]annyl, 6,9-dihydro-5H-benzo[7]annyl, 5,6,7,8,9,10-hexahydro Benzo[8]annyl, 2,3-cyclopentenylpyridyl, 5,6-dihydro-4H-cyclopentyl[B]thienyl, 5,6-dihydro-4H-cyclopentyl [B]furyl, 2,3-dihydrobenzofuryl, 1,3-dihydroisobenzofuryl, indolinyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzo[b]thienyl, Hydrobenzopyranyl, 1,2,3,4-tetra
  • Aryl means a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
  • aryl includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferred aryl groups are C 6 -C 10 aryl groups, more preferred aryl groups are phenyl and naphthyl, most preferably phenyl.
  • Aryl groups can be substituted or unsubstituted.
  • the "aryl” can be fused with a heteroaryl, heterocyclyl or cycloalkyl, wherein the aryl ring is attached to the parent structure, non-limiting examples include but are not limited to:
  • Heteroaryl refers to an aromatic 5 to 8 membered monocyclic ring or 9 to 10 membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo-isodi Oxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:
  • fused ring aryl refers to an unsaturated, aromatic ring structure containing 8-10 ring carbon atoms formed by two or more ring structures sharing two adjacent atoms.
  • Group, preferably “9-10 membered fused ring aryl”, non-limiting examples include but are not limited to:
  • Alkoxy refers to a group of (alkyl-O-). Wherein, alkyl refers to relevant definitions herein. C 1 -C 6 alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Haloalkyl refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has a meaning as described herein.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms in a group are independently substituted by a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • the present invention provides a new structure of pyrrolesulfonyl derivatives, the test results show that the pyrrolesulfonyl derivatives exhibit excellent gastric acid secretion inhibition and potassium ion competitive acid blockers (P-CABs) activity, It can be used to prepare for the treatment or prevention of peptic ulcer, Zoller's syndrome, gastric erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagitis, functional dyspepsia, helicobacter pylorus bacterial infection, gastric cancer, gastric MALT lymphoma, ulcers caused by non-steroidal anti-inflammatory drugs, hyperacidity caused by postoperative stress or ulcers caused by postoperative stress; Drugs for upper gastrointestinal bleeding from stress ulcers, hemorrhagic gastritis, or invasive stress.
  • P-CABs potassium ion competitive acid blockers
  • the pyrrolesulfonyl derivatives provided by the present invention have less toxic and side effects and excellent safety performance; exhibit better pharmacokinetic properties, significant half-life extension, and more sustained acid-suppressing effect, which is expected to improve the prior art Nocturnal acid breakthrough phenomenon in proton pump inhibitor drugs.
  • Figure 1 shows the manual patch clamp hERG current test instruction voltage program.
  • the mass spectrum was measured by LC/MS instrument, and the ionization mode was ESI.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.
  • the solution in the reaction refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C-30°C.
  • Step 1 Synthesis of 1-(5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine (Int 1-2)
  • Step 2 Synthesis of tert-butyl ((5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 1-3)
  • Step 3 Synthesis of tert-butyl((1-((3-bromophenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)aminomethyl Ester (Int 1)
  • Step 2 Synthesis of tert-butyl((5-bromo-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 3-3)
  • Step 3 Synthesis of tert-butyl ((5-(2,4-difluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 3-5)
  • Step 4 Synthesis of tert-butyl((1-((3-bromophenyl)sulfonyl)-5-(2,4-difluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl ) carbamate (Int 3)
  • Step 1 Synthesis of tert-butyl ((1-((5-bromo-2-methoxyphenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl) (Methyl) carbamate (Int 5)
  • Step 1 Synthesis of tert-butyl ((1-((3-(3-oxa-8-azabicyclo[3.2.1]octane-8-yl)phenyl)sulfonyl)-5-(2- Fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (1-2)
  • Step 2 Synthesis of 1-(1-((3-(3-oxa-8-azabicyclo[3.2.1]octane-8-yl)phenyl)sulfonyl)-5-(2-fluoro- Phenyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III-1)
  • Step 1 Synthesis of tert-butyl 5-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrole-1 -yl)sulfonyl)phenyl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-carboxylate (2-2)
  • Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl) -1H-pyrrol-3-yl)-N-methylmethylamine (III-2)
  • Step 1 Synthesis of tert-butyl 8-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrole-1 -yl)sulfonyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (3-2)
  • Step 2 Synthesis of 1-(1-((3-(3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl) -1H-pyrrol-3-yl)-N-methylamine dihydrochloride (III-3)
  • Step 1 Synthesis of tert-butyl 4-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrole-1 -yl)sulfonyl)phenyl)piperazine-1-carboxylate (4-2)
  • Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(piperazin-1-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methyl Methylamine dihydrochloride (III-4)
  • Step 1 Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl) )sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (5-2)
  • Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonate Acyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III-5)
  • Step 1 Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrole -3-yl)methyl)(methyl)carbamate (6-2)
  • Step 2 Synthesis of (5-(2-fluorophenyl)-1-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl )-N-methylmethylamine hydrochloride (III-6)
  • Step 1 Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-morpholinophenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl) Urethane (7-1)
  • Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-morpholinophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III -7)
  • Step 1 Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrole-3- Base) methyl) (methyl) carbamate (8-2)
  • Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl) -N-Methylmethylamine hydrochloride (III-8)
  • Step 1 Synthesis of tert-butyl((1-((3-(3,6-dihydro-2H-pyran-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H -pyrrol-3-yl)methyl)(methyl)carbamate (9-2)
  • Step 2 Synthesis of 1-(1-((3-(3,6-dihydro-2H-pyran-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole -3-yl)-N-methylmethylamine (III-9)
  • Step 1 Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridine- 3-yl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (10-1)
  • Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridine-3 -yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III-10)
  • Step 1 Synthesis of 1-(1-((3-(3,3-difluoroazetidin-1-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole -3-yl)-N-methylmethylamine (11-2)
  • Step 2 Synthesis of 1-(1-((3-(3,3-difluoroazetidin-1-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole -3-yl)-N-methylmethylamine hydrochloride (III-11)
  • Step 1 Synthesis of tert-butyl 5-(benzylthio)isoindoline-2-carboxylate (12-3)
  • Step 2 Synthesis of tert-butyl 5-(chlorosulfonyl)isoindoline-2-carboxylate (12-4)
  • Step 3 Synthesis of 5-(((4-((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl) tert-butyl isoindoline-2-carboxylate (12-5)
  • Step 4 Synthesis of 1-(5-(2-fluorophenyl)-1-(isoindolin-5-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III -12)
  • Step 1 Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(5-fluoropyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl) Methyl)(methyl)carbamate (13-2)
  • Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-fluoropyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N -Methylmethylamine hydrochloride (III-13)
  • Step 1 Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl) (Methyl) carbamate (14-2)
  • Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methyl Methylamine trifluoroacetate (III-14)
  • Step 1 Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3(furan-2-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)( Methyl) carbamate (15-2)
  • Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(furan-2-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methyl Methylamine trifluoroacetate (III-15)
  • compound 15-2 (150 mg, 0.294 mmol) was dissolved in 1,4-dioxane (3 mL), added 4M hydrochloric acid/1,4-dioxane (3 mL, 12.0 mmol), and React for 1 hour, concentrate under reduced pressure, add water (10 mL), adjust pH to 8 with saturated sodium bicarbonate solution, extract with ethyl acetate (20 mL ⁇ 2), combine organic phases and wash with saturated brine (20 mL), anhydrous sulfuric acid Sodium-dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse column separation (5-100% acetonitrile/water (0.1% TFA)) to obtain 30 mg of yellow oil, with a yield of 19.5%, a purity of >95%, [M +H] + :411.3.
  • Step 1 Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)sulfonyl)- 1H-pyrrol-3-yl)methyl))(methyl)carbamate (16-2)
  • Step 1 Synthesis of ((5-(2-fluorophenyl)-1-((3-(thiophen-2-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl ) tert-butyl carbamate (17-2)
  • Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(thiophen-2-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methyl Methylamine hydrochloride (III-17)
  • Step 1 Synthesis of tert-butyl((1-((3-(3,5-dimethylisoxazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H- Pyrrol-3-yl)methyl)(methyl)carbamate (18-2)
  • Step 2 1-(1-((3-(3,5-Dimethylisoxazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3 -yl)-N-methylmethylamine hydrochloride (III-18)
  • Step 1 Synthesis of tert-butyl((1-((3-(3-oxa-9-azaspiro[5.5]undec-9-yl)phenyl)sulfonyl)-5-(2-fluoro -Phenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (19-2)
  • Step 2 Synthesis of 1-(1-((3-(3-oxa-9-azaspiro[5.5]undec-9-yl)phenyl)sulfonyl)-5-(2-fluorophenyl )-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-19)
  • Dissolve compound 19-2 (170 mg, 0.284 mmol) in 1,4-dioxane (3 mL) at room temperature, add 4M hydrochloric acid/1,4-dioxane (3 mL), and react at room temperature for 1 hour . Concentrate under reduced pressure, dissolve with dichloromethane, and concentrate under reduced pressure to obtain 50 mg of a gray solid with a yield of 32.9%, a purity of >95%, and [M+H] + : 498.9.
  • Step 1 Synthesis of tert-butyl((1-((5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)sulfonyl)-5-(2-fluoro Phenyl)-1H-pyrrol-3-yl))methyl)(methyl)carbamate (20-2)
  • Step 2 Synthesis of 1-(1-((5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)sulfonyl)-5-(2-fluorophenyl )-1H-pyrrol-3-yl)-N-methylmethylamine 2,2,2-trifluoroacetate (III-20)
  • Step 1 Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrole-3- Base) methyl) (methyl) carbamate (21-2)
  • Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl) -N-Methylmethylamine hydrochloride (III-21)
  • Step 1 Synthesis of tert-butyl ((5-(2,4-difluorophenyl)-1-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)- 1H-pyrrol-3-yl)methyl)(methyl)carbamate (22-1)
  • Step 2 Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H- Pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-22)
  • Step 1 Synthesis of tert-butyl ((5-(2,4-difluorophenyl)-1-((3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl )phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (23-1)
  • Step 2 Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzene Base)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine trifluoroacetate (III-23)
  • Dissolve compound 23-1 (100 mg, 0.262 mmol) in 1,4-dioxane (3 mL) at room temperature, add 4M hydrochloric acid/1,4-dioxane (3 mL), and react at room temperature for 1 hour Afterwards, the solvent was concentrated, and the crude product was separated and purified by a reverse-phase column to obtain 30 mg of a colorless oil, with a yield of 29.31%, a purity of >95%, and [M+H] + : 474.5.
  • Step 1 Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(furan-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl) (Methyl) carbamate (24-2)
  • Step 1 Synthesis of ((5-(2,4-difluorophenyl)-1-((3-(furan-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl) (Methyl) tert-butyl carbamate (25-1)
  • Step 2 Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(furan-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N -Methylmethylamine hydrochloride (III-25)
  • Step 1 Synthesis of ((5-(2,4-difluorophenyl)-1-((3-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrole-3- Base) methyl) (methyl) tert-butyl carbamate (26-1)
  • Step 2 Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrole-3 -yl)-N-methylmethylamine trifluoroacetate (III-26)
  • Step 1 Synthesis of tert-butyl((1-((3-(2,3-dihydrobenzofuran-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole -3-yl)methyl)(methyl)carbamate (27-2)
  • Step 2 Synthesis of 1-(1-((3-(2,3-dihydrobenzofuran-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3 -
  • Step 1 Synthesis of tert-butyl((1-((3-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl) -1H-pyrrol-3-yl)methyl)(methyl)carbamate (28-2)
  • Step 2 Synthesis of 1-(1-((3-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H -pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-28)
  • Step 1 Synthesis of tert-butyl((1-((3-(benzofuran-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methanol base) (methyl) carbamate (29-2)
  • Step 2 Synthesis of 1-(1-((3-(benzofuran-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N- Methylmethylamine hydrochloride (III-29)
  • compound 30-1 500 mg, 2.87 mmol was dissolved in DMF (10 mL), NaH (230 mg, 5.75 mmol) was added slowly, and after stirring for 10 minutes, 30-2 (766 mg, 4.31 mmol) was added.
  • the reaction solution was raised to room temperature and continued to react for 1 hour. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (10 mL), then extracted with ethyl acetate (20 mL ⁇ 2), and the combined organic phases were washed with saturated brine (20 mL ⁇ 2).
  • Step 2 Synthesis of 5-(1H-indol-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (30-5)
  • Step 3 Synthesis of 1-(5-(1H-indol-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III- 30)
  • Step 2 Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(5-(2-methoxyethoxy)pyridin-3-yl)phenyl)sulfonyl) -1H-pyrrol-3-yl)methyl)(methyl)carbamate (31-5)
  • Step 3 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-(2-methoxyethoxy)pyridin-3-yl)phenyl)sulfonyl)-1H -pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-31)
  • Step 1 Synthesis of tert-butyl ((1-((3-(1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl) Methyl)(methyl)carbamate (32-2)
  • Step 2 Synthesis of tert-butyl((1-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H- Pyrrol-3-yl)methyl)(methyl)carbamate (32-4)
  • Step 3 Synthesis of 1-(1-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole- 3-
  • Step 1 Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)sulfonyl Acyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (33-2)
  • Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)sulfonyl) -1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-33)
  • Step 2 Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(5-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl) Sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (35-3)
  • Step 3 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)sulfonyl )-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-35)
  • Step 1 Synthesis of tert-butyl((1-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl) -1H-pyrrol-3-yl)methyl)(methyl)carbamate (36-1)
  • Step 2 Synthesis of 1-(1-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H -pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-36)
  • Step 1 Synthesis of tert-butyl((1-((3-fluoro-5-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H- Pyrrol-3-yl)methyl)(methyl)carbamate (37-1)
  • Step 2 Synthesis of 1-(1-((3-fluoro-5-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole- 3-
  • Step 1 Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl) Acyl)-1H-pyrrol-3-yl)methyl))(methyl)carbamate (38-1)
  • Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl) -1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-38)
  • Step 1 Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((2-methoxy-5-(5-methoxypyridin-3-yl))phenyl)sulfonyl) -1H-pyrrol-3-yl)methyl)(methyl)carbamate (39-1)
  • Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((2-methoxy-5-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H- Pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-39)
  • Step 1 Synthesis of tert-butyl((1-((3-fluoro-5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonyl)-5 -(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (40-1)
  • Step 2 Synthesis of 1-(1-((3-fluoro-5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonyl)-5-( 2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-40)
  • Step 1 Synthesis of tert-butyl((1-((3-(3,4-dimethoxythiophen-2-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole -3-yl)methyl)(methyl)carbamate (41-2)
  • Step 2 Synthesis of 1-(1-((3-(3,4-dimethoxythiophen-2-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3 -yl)-N-methylmethylamine hydrochloride (III-41)
  • Step 1 Synthesis of 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (42-2)
  • Step 2 Synthesis of tert-butyl((1-((3-(5,6-dimethoxypyridin-3-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole -3-yl)methyl)(methyl)carbamate (42-3)
  • Step 3 1-(1-((3-(5,6-dimethoxypyridin-3-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3- base)-N-methylmethylamine (III-42)
  • Step 2 Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-(5-(methylsulfonyl)pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrole -3-yl)methyl)(methyl)carbamate (43-3)
  • Step 3 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-(methylsulfonyl)pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrole-3 -yl)-N-methylmethylamine (III-43)
  • Step 1 Synthesis of tert-butyl(S)-((1-((3-(2-(dimethylcarbamoyl)pyrrolidin-1-yl)phenyl)sulfonyl)-5-(2-fluoro Phenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (44-2)
  • Step 2 Synthesis of (S)-1-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl) -N,N-Dimethylpyrrolidine-2-carboxamide (III-44)
  • Step 1 Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)phenyl)) Sulfonyl)-1H-pyrrol-3-yl)methyl))(methyl)carbamate (45-2)
  • Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)phenyl)sulfonyl )-1H-pyrrol-3-yl)-N-methylamine hydrochloride (III-45)
  • Step 1 Synthesis of tert-butyl ((1-((3-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)phenyl)sulfonyl) -5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (46-2)
  • Step 2 Synthesis of 1-(1-((3-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)phenyl)sulfonyl)-5 -(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-46)
  • Step 1 Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3'-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-1H -pyrrol-3-yl)methyl)(methyl)carbamate (47-2)
  • Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3'-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-1H-pyrrole -3-yl)-N-methylmethylamine hydrochloride (III-47)
  • Step 1 Synthesis of tert-butyl((1-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(2-fluoro Phenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (48-2)
  • Step 2 Synthesis of 1-(1-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(2-fluorophenyl )-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-48)
  • Step 1 Synthesis of tert-butyl ((1-((3',5'-dimethoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(2-fluoro-o Phenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (49-2)
  • Step 2 Synthesis of 1-(1-((3',5'-dimethoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(2-fluorophenyl) -1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-49)
  • Step 1 Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-(2-oxazetidin-1-yl)phenyl)sulfonyl)-1H-pyrrole- 3-yl)methyl)(methyl)carbamate (50-2)
  • Step 2 Synthesis of 1-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)azetidine Alkan-2-one hydrochloride (III-50)
  • Step 1 Synthesis of tert-butyl ((1-((3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)sulfonyl)-5-(2 -Fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (51-2)
  • Step 2 Synthesis of 1-(1-((3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)sulfonyl)-5-(2-fluoro Phenyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III-51)
  • Step 2 Synthesis of 1-((3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H -Pyrrole-3-carbaldehyde (52-3)
  • Step 3 Synthesis of 1-(1-((3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl )-1H-pyrrol-3-yl)-N-methylmethylamine (III-52)
  • Step 1 Synthesis of 1-((3-(1,4-dioxaspiro[4.5]decane-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole- 3-Formaldehyde (53-1)
  • Step 2 Synthesis of 1-(1-((3-(1,4-dioxaspiro[4.5]decane-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H -pyrrol-3-yl)-N-methylmethylamine (III-53)
  • K + -free buffer 50mM Tris-HCl pH 6.5, 5mM magnesium chloride, 10 ⁇ M valinomycin
  • K + containing buffer 50mM Tris-HCl pH 6.5, 5mM magnesium chloride, 10 ⁇ M valinomycin, 20mM KCl MLG chromogenic solution: 0.1% w/v malachite green, 1.5% w/v ammonium molybdate, 0.2% v/v Tween-20 rabbit gastric mucosal microsomes (rich in H + /K + -ATPase), the extraction method is sucrose gradient centrifugation: the rabbit stomach is washed with tap water and 3M NaCl solution, and then the surface water is removed with filter paper. Add pre-cooled homogenization buffer (4ml/g tissue), and homogenize in a tissue homogenizer for 2-5min.
  • 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 at 100,000g for 90min to collect the precipitate; use the homogenate to suspend the precipitate, blow it evenly, measure the protein concentration by the Bradford method, adjust the concentration to 10mg/ml; (H + /K + -ATPaseenriched gastric membranes) were collected in a clean centrifuge tube, diluted 4-5 times with the homogenate, and centrifuged at 100,000 g for 90 minutes to collect the precipitate; the homogenate was used to suspend the sediment, homogenate evenly, and the protein was measured by the Bradford method Concentration, adjust the concentration to 22.5mg/ml. Freeze at -80°C for later use.
  • the IC 50 value of the compound is calculated by the inhibition rate at different concentrations.
  • the compound of the present invention has obvious inhibitory activity on H + /K + -ATPase, and the IC 50 is 20 to 100 nM, preferably 20 to 50 nM.
  • the control group 1 is selected from Vonoprazan (Vonoprazan), and its preparation method refers to the patent CN101300229A; the control group 2 is selected from the group with the following structural formula.
  • the compound of the present invention has obvious inhibitory activity on H + /K + -ATPase.
  • DMEM Dulbecco's modified Eagle medium
  • the cell line HepG2 derived from human liver cancer was cultured and subcultured at 5% and 37°C, and the cells in the logarithmic growth phase were collected, counted, and the cells were resuspended with complete medium, Adjust the cell concentration to an appropriate concentration (determined according to the results of the cell density optimization test), inoculate a 96-well plate, and add 75 ⁇ L/well cell suspension according to the following platemap. Dilute the compound to be tested with the culture medium to the corresponding effect concentration set, and add 25 ⁇ L/well to the cells according to the platemap.
  • DMEM Dulbecco's modified Eagle medium
  • the concentration of the compounds to be tested starts from 100 ⁇ M, and is serially diluted 4 times, with a total of 9 concentrations and 2 duplicate wells.
  • Cells were incubated at 37°C, 100% relative humidity, 5% CO 2 incubator for 24h. Add 50 ⁇ L/well CellTiter Glo RT and incubate for 30min in the dark. After shaking gently, detect in Envision and calculate the inhibition rate.
  • cell growth inhibition rate% (1-As/Ac) ⁇ 100.
  • IC 50 >20 ⁇ M is +++
  • 20 ⁇ M>IC 50 >10 ⁇ M is ++
  • 10 ⁇ M>IC 50 is +.
  • liver microsomes from the desired species (eg, mouse, rat, dog, monkey, or human). Using DMSO as diluent, prepare 10mM sample stock solution and positive control stock solution. All stocks were then diluted to a working concentration of 0.25 mM with 70% acetonitrile.
  • the cofactor used in this study is the NADPH regeneration system, which consists of 6.5mM NADP, 16.5mM G-6-P, and 3U/mL G-6-PD.
  • the quenching reagent was a solution of tolbutamide and propranolol in acetonitrile.
  • the buffer used in this study was 100 mM potassium phosphate buffer.
  • a mixture containing 0.2 mg/mL liver microsomal protein and 1 ⁇ M test article/positive control was incubated in 100 mM potassium phosphate buffer.
  • the compound of the present invention has T 1/2 (min)>80min, preferably T 1/2 (min)>100min in liver microsomes, and has good metabolic stability of liver microsomes.
  • CHO-hERG cells Chinese hamster ovary (CHO) cell line, CHO-hERG cells were used in this experiment.
  • the complete medium is F12 medium, supplemented with 10% fetal bovine serum, 1% Selective antibiotic (G418), 89 ⁇ g/mL hygromycin B (HB).
  • the recovery medium is F12 medium supplemented with 10% fetal bovine serum.
  • CHO-hERG cells were grown in a high humidity incubator at 37°C ( ⁇ 2°C), 5% CO 2 (4% to 8%). Cells were revived with recovery medium, passaged in complete medium, and cells used for patch clamp experiments were replaced with recovery medium at the last passage.
  • Reagent External fluid mM
  • Internal fluid mM
  • CaCl2 2 5.37 MgCl2 1 1.75
  • KCl 4 120 NaCl 145 - Glucose 10 - HEPES 10 10 EGTA - 5 Na2ATP - 4 pH 7.3-7.4 7.2-7.3
  • the hERG current was recorded under the whole-cell patch clamp technique, and the recording temperature was room temperature.
  • the output signal of the patch clamp amplifier is converted by digital to analog and filtered by 2.9KHz low pass. Data records were collected with Patchmaster Pro software.
  • the cell species is placed on the inverted microscope stage in the cell recording tank, and a cell in the recording tank is randomly selected for the experiment.
  • the perfusion system was fixed on the inverted microscope stage and cells were continuously perfused with ECS.
  • Electrodes for manual patch clamp experiments were prepared from capillary glass tubes filled with intracellular fluid. On the day of the patch clamp test, electrodes were prepared using borosilicate glass tubes (BF150-117-10, SUTTER INSTRUMENT USA). After the electrode is filled with ICS, the resistance is between 2-5M ⁇ .
  • the clamping voltage was -80mV, the first step depolarized to +60mV and maintained for 850ms to open the hERG channel. Then, the voltage is set to -50mV and maintained for 1275ms, resulting in rebound current or tail current, the peak value of tail current will be measured and used for analysis. Finally, the voltage returns to the clamping voltage (-80mV). During the test, this command voltage program is repeated every 15s.
  • cisapride was tested at a concentration of 0.1 [mu]M in duplicates of the cells. According to scientific literature reports, cisapride at 0.1 ⁇ M inhibits hERG current by more than 50%. (Milnes, J.T., et al.).
  • a good whole-cell recording should meet the following conditions: path resistance (Rs) less than 10M ⁇ ; membrane resistance (Rm) greater than 500M ⁇ and membrane capacitance (Cm) less than 100pF.
  • the peak current amplitude before the test product/positive control product is acted is between 400pA and 5000pA. Otherwise, discard the cell.
  • Leakage current Under the clamping voltage of -80mV, the absolute value of the leakage current should be less than 200pA. The current amplitude will be corrected for the leakage current at -80mV. Scanning curves whose absolute value of leakage current is greater than 200pA cannot be used for analysis.
  • the percentage inhibition of each concentration of the test product and the positive control was calculated from the recorded current response using the following formula: (1- tail peak current recorded after perfusion of the test product/positive control/vehicle control perfusion Recorded tail peak current (initial current)) x 100%.
  • IC 50 >20 ⁇ M is +++
  • 20 ⁇ M>IC 50 >10 ⁇ M is ++
  • 10 ⁇ M>IC 50 >1 ⁇ M is +.

Abstract

The present invention relates to a class of pyrrole sulfonyl derivatives, a preparation method therefor, a pharmaceutical composition containing same, and the use thereof in the preparation of a drug. Specifically, the present invention relates to a pyrrole sulfonyl derivative as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing same and the use thereof as a therapeutic agent, specifically as a gastric acid secretion inhibitor and a potassium-competitive acid blocker (P-CAB).

Description

一种吡咯磺酰类衍生物、及其制备方法与应用A pyrrolesulfonyl derivative, its preparation method and application 技术领域technical field
本发明涉及一类新的吡咯磺酰类衍生物、其制备方法及含有该衍生物的药物组合物以及其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)中的用途。The present invention relates to a new class of pyrrolesulfonyl derivatives, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a gastric acid secretion inhibitor and a potassium ion competitive acid blocker (P- CABs).
背景技术Background technique
中国有肠胃病患者1.2亿，包括幽门螺杆菌感染、胃食管返流、消化性溃疡、十二指肠溃疡、胃溃疡以及食管炎，消化道溃疡发病率为10％，慢性胃炎发病率为30％。长期的胃肠道疾病可逐渐发展成胃肠道癌，在全球六大高发癌症中，消化道相关肿瘤就占了五个，包括胃癌，肝癌，食管癌，肠癌，胰腺癌。随着社会发展人们生活方式的转变，因吸烟、饮酒、情绪紧张、熬夜、药物刺激以及中国人嗜酸辣等饮食习惯引起的胃部相关疾病发病率正逐渐增高，消化性溃疡正在严重影响人们的工作和生活。现在医学界对其确切的发病机制还不清楚，但是抑制胃酸分泌已成为治疗此类疾病公认的首选方法。There are 120 million patients with gastrointestinal diseases in China, including Helicobacter pylori infection, gastroesophageal reflux, peptic ulcer, duodenal ulcer, gastric ulcer and esophagitis, the incidence of peptic ulcer is 10%, and the incidence of chronic gastritis is 30% %. Long-term gastrointestinal diseases can gradually develop into gastrointestinal cancers. Gastrointestinal-related tumors account for five of the six most common cancers in the world, including gastric cancer, liver cancer, esophageal cancer, intestinal cancer, and pancreatic cancer. With the development of society and the change of people's lifestyle, the incidence of stomach-related diseases caused by smoking, drinking, emotional stress, staying up late, drug stimulation, and Chinese people's eating habits such as hot and sour is gradually increasing, and peptic ulcer is seriously affecting people. work and life. The exact pathogenesis of it is still unclear in the medical community, but the inhibition of gastric acid secretion has become the first choice for the treatment of such diseases.
1987年第一个质子泵抑制剂(Proton Pump Inhibitors，PPIs)奥美拉唑由AstraZenaca公司研制开发成功并在瑞典首次上市，是世界上第一个应用于临床，抑制胃酸作用最强的的质子泵抑制剂，用来治疗十二指肠溃疡、卓-艾综合征、胃溃疡和反流性食管炎。后续全球陆续数个PPIs产品上市。经过多年的临床应用，PPIs已经成为治疗胃酸相关性疾病的首选药物。质子泵(Proton Pump)又称胃酸泵，其实质为H +/K +-腺苷三磷酸酶(H +/K +-ATPase)，是胃分泌H +的最终共同途径，它存在于胃壁细胞分泌小管的细胞膜上，借助ATP降解供能进行H +、K +交换，特异性地将H +泵入胃腔，形成胃内强酸状态。第一代PPIs对基础、夜间胃酸和五肽胃泌素、试餐等刺激的胃酸分泌有明显的抑制作用。但因在药动学及药效学方面的局限性，包括生物利用度、给药时间对药效的影响、夜间酸突破起效慢(Nocturnal acid breakthrough，NAB)、酸性条件下不稳定(经常需配制成肠制剂，需要数小时才能表现出效果)、对CYP450酶的依赖性(胃酸分泌抑制效果个体差异显著)等因素，影响了治疗效果与临床应用。与第一代PPIs相比，新一代PPIs在治疗胃食管返流病(Gastroesophageal Reflux Disease，GERD)及其他酸相关性疾病时具有明显优势。 In 1987, the first proton pump inhibitor (Proton Pump Inhibitors, PPIs) omeprazole was successfully developed by AstraZenaca and first launched in Sweden. Pump inhibitors used to treat duodenal ulcers, Zoller-Ellison syndrome, gastric ulcers, and reflux esophagitis. Subsequently, several PPIs products were launched in succession around the world. After years of clinical application, PPIs have become the drug of choice for the treatment of gastric acid-related diseases. Proton Pump (Proton Pump), also known as gastric acid pump, its essence is H + /K + -adenosine triphosphatase (H + /K + -ATPase), which is the final common way for gastric secretion of H + , which exists in gastric parietal cells On the cell membrane of the secretory tubule, ATP is degraded to provide energy for H + and K + exchange, and H + is specifically pumped into the gastric cavity, forming a strong acid state in the stomach. The first-generation PPIs have a significant inhibitory effect on gastric acid secretion stimulated by basal, nocturnal gastric acid and pentagastrin, and test meals. However, due to limitations in pharmacokinetics and pharmacodynamics, including bioavailability, the influence of administration time on drug efficacy, slow onset of nocturnal acid breakthrough (NAB), instability under acidic conditions (often It needs to be formulated into intestinal preparations, and it takes several hours to show the effect), dependence on CYP450 enzymes (the effect of inhibiting gastric acid secretion is significantly different among individuals), and other factors affect the therapeutic effect and clinical application. Compared with the first-generation PPIs, the new-generation PPIs have obvious advantages in the treatment of gastroesophageal reflux disease (GERD) and other acid-related diseases.
钾竞争性酸阻滞剂(Potassium-Competitive Acid Blockers，P-CABs)作为一类新型抑酸剂，通过竞争性、可逆地结合H +而抑制H +/K +-ATPase的活性，其作用机制明显不同于传统的PPIs，因此可称为酸泵阻滞剂。P-CABs具有亲脂性、弱碱性、解离常数高、半衰期长、在酸性时稳定、不主要由CYP2C19代谢，耐受性和依存性较好的特点。在酸性环境下，P-CABs立刻离子化，离子化形式通过离子型结合抑制H +/K +-ATPase，阻止H +运送以及酸分泌到胃腔中，不需要集中于胃壁细胞的微囊和微管及酸的激活，能迅速升高胃内pH值，离 解后酶活性恢复。人和动物口服后能吸收迅速，达到血浆浓度的峰值。临床和动物实验也表明，P-CABs比PPIs或组胺受体2(Histamine receptor 2，H2)阻滞剂起效更快，升高pH的作用更强，血药浓度与口服给药剂量线性相关，提示该类药物可以比较容易地达到最佳抑酸状态，具有明显的优势。Takeda(武田)的富马酸沃诺拉赞(Vonoprazan Fumarate)2014年12月在日本获批；于2019年12月中国获批进口，并有部分P-CABs制剂已进入临床研究。 Potassium-Competitive Acid Blockers (P-CABs), as a new class of acid inhibitors, inhibit the activity of H + /K + -ATPase by competitively and reversibly binding H + , and their mechanism of action Significantly different from traditional PPIs, so they can be called acid pump blockers. P-CABs have the characteristics of lipophilicity, weak alkalinity, high dissociation constant, long half-life, stable in acidity, not mainly metabolized by CYP2C19, and good tolerance and dependence. In an acidic environment, P-CABs are immediately ionized, and the ionized form inhibits H + /K + -ATPase through ionic binding, preventing H + transport and acid secretion into the gastric cavity, without the need to concentrate on the microcapsules and parietal cells. The activation of microtubules and acid can rapidly increase the pH value in the stomach, and the enzyme activity will recover after dissociation. Humans and animals can absorb rapidly after oral administration and reach the peak plasma concentration. Clinical and animal experiments also show that P-CABs has a faster onset of action than PPIs or histamine receptor 2 (H2) blockers, a stronger effect of increasing pH, and a linearity of blood drug concentration with oral administration dose. Correlation, suggesting that this type of drug can easily achieve the best state of acid suppression, and has obvious advantages. Takeda's Vonoprazan Fumarate was approved in Japan in December 2014; it was approved for import in China in December 2019, and some P-CABs preparations have entered clinical research.
目前公开了一系列的P-CABs的专利申请，其中包括W02005041961，W02006134460，W02009041447或W02010021149等。A series of patent applications for P-CABs have been published, including WO2005041961, WO2006134460, WO2009041447 or WO2010021149.
尽管目前已公开了一系列的P-CABs药物或化合物，但仍需要开发结构类型更丰富，具有更好药效和更安全的新化合物，经过不断努力，本发明设计具有通式(Ⅰ)所示的结构的化合物，并发现具有此类结构的化合物表现出优异的作用效果，具有毒副作用小，较好的安全性和代谢稳定性。Although a series of P-CABs drugs or compounds have been disclosed at present, there is still a need to develop new compounds with more abundant structure types, better drug efficacy and safety. Compounds with the structures shown, and found that the compounds with such structures exhibit excellent effects, have less toxic and side effects, and have better safety and metabolic stability.
发明内容Contents of the invention
为了解决现有技术的上述问题，本发明的目的在于提供一种新的吡咯磺酰类衍生物、其药学上可接受的盐、其互变异构体或其立体异构体，以筛选出在有效性、安全性和选择性等性能方面均具有优异性能的用作胃酸分泌抑制剂和钾离子竞争性酸阻滞剂(P-CABs)的化合物。In order to solve the above-mentioned problems of the prior art, the object of the present invention is to provide a new pyrrolesulfonyl derivative, its pharmaceutically acceptable salt, its tautomer or its stereoisomer, to screen out Compounds useful as gastric acid secretion inhibitors and potassium ion-competitive acid blockers (P-CABs) having excellent properties in terms of efficacy, safety and selectivity.
本发明的另一个目的是提供所述衍生物、其药学上可接受的盐、其互变异构体或其立体异构体的制备方法。Another object of the present invention is to provide a preparation method of the derivative, its pharmaceutically acceptable salt, its tautomer or its stereoisomer.
为达到此发明目的，本发明采用以下技术方案：To achieve this purpose of the invention, the present invention adopts the following technical solutions:
一种吡咯磺酰类衍生物、其互变异构体或其立体异构体，及其药学上可接受的盐，其特征在于，吡咯磺酰类衍生物的结构如式(I)所示：A pyrrolesulfonyl derivative, its tautomer or its stereoisomer, and a pharmaceutically acceptable salt thereof, characterized in that the structure of the pyrrolesulfonyl derivative is shown in formula (I) :
Figure PCTCN2022104528-appb-000001
Figure PCTCN2022104528-appb-000001
其中：in:
环A选自苯基或吡啶基，苯基或吡啶基任选被1、2或3个R 1所取代； Ring A is selected from phenyl or pyridyl, and phenyl or pyridyl is optionally substituted by 1 , 2 or 3 R;
环B选自3-12元的杂环基、5-8元的芳基、5-8元的杂芳基、3-12元的环烷基、7-12元的螺环基、7-12元的并环基、7-12元的桥环基，其中，环B任选地被1、2或3个R 2所取代 或氧代； Ring B is selected from 3-12 membered heterocyclic group, 5-8 membered aryl group, 5-8 membered heteroaryl group, 3-12 membered cycloalkyl group, 7-12 membered spirocyclic group, 7- 12-membered ring group, 7-12-membered bridged ring group, wherein, ring B is optionally substituted or oxo by 1, 2 or 3 R 2 ;
或者环A和环B一起形成稠环芳基；Or ring A and ring B together form a condensed ring aryl;
R 1选自C 1-6的烷基、C 1-6烷氧基、卤素、氰基、C 2-6炔基、C 2-6烯基、O-C 1-6烷基-O-C 1-6烷基、NR aR b； R 1 is selected from C 1-6 alkyl, C 1-6 alkoxy, halogen, cyano, C 2-6 alkynyl, C 2-6 alkenyl, OC 1-6 alkyl-OC 1-6 Alkyl, NR a R b ;
R 2选自H、C 1-6的烷基、C 1-6烷氧基、卤素、氰基、C 2-6炔基、C 2-6烯基、3-12元的环烷基、-NH 2、-C(＝O)R c、-O-C 1-6烷基-O-C1-6烷基、-C 1-6烷基-O-C 1-6烷基、-O-C 1-6烷基-C(＝O)NHR d、-S(＝O) m-C 1-6烷基，其中，烷基、烷氧基、环烷基任选进一步被1、2或3个氯素所取代； R 2 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, halogen, cyano, C 2-6 alkynyl, C 2-6 alkenyl, 3-12 membered cycloalkyl, -NH 2 , -C(=O)R c , -OC 1-6 alkyl-O-C1-6 alkyl, -C 1-6 alkyl-OC 1-6 alkyl, -OC 1-6 alkane Group -C(=O)NHR d , -S(=O) m -C 1-6 alkyl, wherein the alkyl, alkoxy and cycloalkyl groups are optionally further replaced by 1, 2 or 3 chlorine replace;
R 3选自卤素、5-8元的芳基、5-8元的杂芳基；或者两个R 3连同它们连接的碳原子一起形成稠环芳基；其中芳基、杂芳基和稠环芳基可任选地进一步被1、2或3个C 1-6烷基、C 1-6烷氧基、卤素所取代； R 3 is selected from halogen, 5-8 membered aryl, 5-8 membered heteroaryl; or two R 3 together with their connected carbon atoms form a condensed ring aryl; wherein aryl, heteroaryl and condensed Cycloaryl can optionally be further substituted by 1, 2 or 3 C 1-6 alkyl, C 1-6 alkoxy, halogen;
R 4选自C 1-6的烷基；其中烷基可任选地进一步被1、2或3个氘、卤素所取代； R 4 is selected from the alkyl group of C 1-6 ; Wherein the alkyl group may be optionally further substituted by 1, 2 or 3 deuterium, halogen;
R a、R b、R c、R d各自独立的选自H、C 1-6的烷基、3-12元的环烷基； R a , R b , R c , R d are each independently selected from H, C 1-6 alkyl, 3-12 membered cycloalkyl;
n选自0、1、2、3；n is selected from 0, 1, 2, 3;
m选自0、1、2。m is selected from 0,1,2.
在一些实施例方案中：环B选自3-8元单杂环基、7-12元的桥环基、7-12元的螺杂环基、3-8元杂环基并3-8元杂环基、3-8元单杂环基并3-8元单环烷基、3-8元单杂环基并苯基。In some embodiments, ring B is selected from 3-8 membered monoheterocyclyl, 7-12 membered bridging ring, 7-12 membered spiroheterocyclyl, 3-8 membered heterocyclyl and 3-8 Heterocyclyl, 3-8 membered monoheterocyclyl and 3-8 membered monocycloalkyl, 3-8 membered monoheterocyclyl and phenyl.
在一些实施例方案中：In some embodiment schemes:
环B选自：Ring B is selected from:
Figure PCTCN2022104528-appb-000002
Figure PCTCN2022104528-appb-000002
Z 1、Z 2、Z 3各自独立的选自C、O、S、S(＝O)、S(＝O) 2、NR e；R e选自H、C 1-6的烷基、多卤代C 1-6烷基、-C 1-6烷基-O-C 1-6烷基、3-12元的环烷基、-C(＝O)C 1-6烷基； Z 1 , Z 2 , and Z 3 are each independently selected from C, O, S, S(=O), S(=O) 2 , NR e ; R e is selected from H, C 1-6 alkyl, poly Halogenated C 1-6 alkyl, -C 1-6 alkyl-OC 1-6 alkyl, 3-12 membered cycloalkyl, -C(=O)C 1-6 alkyl;
Z 4、Z 5、Z 6各自独立的选自N、C； Z 4 , Z 5 , and Z 6 are independently selected from N and C;
L、P各自独立的选自1、2、3、4；L and P are independently selected from 1, 2, 3, 4;
环B任选地被1、2或3个R 2所取代。 Ring B is optionally substituted with 1, 2 or 3 R 2 .
在一些实施例方案中：In some embodiment schemes:
环B选自：Ring B is selected from:
Figure PCTCN2022104528-appb-000003
Figure PCTCN2022104528-appb-000003
其中，Z 1选自O、S、NR e；R e选自H、C 1-3的烷基、多卤代C 1-3烷基、3-6元的环烷基、-C(＝O)C 1-6烷基； Wherein, Z 1 is selected from O, S, NR e ; R e is selected from H, C 1-3 alkyl, polyhalogenated C 1-3 alkyl, 3-6 membered cycloalkyl, -C(= O) C 1-6 alkyl;
环B任选地被1、2或3个R 2所取代。 Ring B is optionally substituted with 1, 2 or 3 R 2 .
在一些优选实施例方案中：In some preferred embodiments:
环B选自：Ring B is selected from:
Figure PCTCN2022104528-appb-000004
Figure PCTCN2022104528-appb-000004
在一些优选实施例方案中：R 2选自H、C 1-6烷氧基、卤素；R 3选自卤素；R 4为C 1-6烷基。 In some preferred embodiments: R 2 is selected from H, C 1-6 alkoxy, halogen; R 3 is selected from halogen; R 4 is C 1-6 alkyl.
本发明提供的吡咯磺酰类衍生物其药学上可接受的盐，所述的盐可为盐酸盐或三氟乙酸盐。The pharmaceutically acceptable salts of pyrrolesulfonyl derivatives provided by the present invention can be hydrochloride or trifluoroacetate.
进一步的，本发明所述吡咯磺酰类衍生物可选自如下结构的任意一种：Further, the pyrrolesulfonyl derivatives of the present invention can be selected from any one of the following structures:
Figure PCTCN2022104528-appb-000005
Figure PCTCN2022104528-appb-000005
Figure PCTCN2022104528-appb-000006
Figure PCTCN2022104528-appb-000006
Figure PCTCN2022104528-appb-000007
Figure PCTCN2022104528-appb-000007
另一方面，本发明提供一种药物组合物，其药物组合物包括吡咯磺酰类衍生物、其药学上可接受的盐、其互变异构体或其立体异构体及可药用载体和/或赋形剂。In another aspect, the present invention provides a pharmaceutical composition, which comprises pyrrolesulfonyl derivatives, pharmaceutically acceptable salts, tautomers or stereoisomers thereof, and pharmaceutically acceptable carriers. and/or excipients.
另一方面，本发明提供一种如上所述的吡咯磺酰类衍生物、其药学上可接受的盐、其互变异构体或其立体异构体或所述的药物组合物在制备胃酸分泌抑制剂、H +/K +-ATPase抑制剂或钾离子竞争性酸阻滞剂中的用途。 In another aspect, the present invention provides the above-mentioned pyrrolesulfonyl derivatives, their pharmaceutically acceptable salts, their tautomers or their stereoisomers, or the pharmaceutical composition used in the preparation of gastric acid Use in secretion inhibitors, H + /K + -ATPase inhibitors or potassium ion competitive acid blockers.
本发明提供一种如上所述吡咯磺酰类衍生物、其药学上可接受的盐、其互变异构体或其立体异构体或如上所述的药物组合物在制备治疗或预防如下疾病用药物中的用途：消化性溃疡、卓-艾综合征、胃糜烂性食管炎、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、幽门螺旋杄菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡、手术后应激导致的胃酸过多或手术后应激导致的溃疡的药物中的用途；或者在制备抑制消化性溃疡、急应激性溃疡、出血性胃炎或侵入性应激造成的上消化道出血的药物中的用途。同 时，本发明提供的吡咯磺酰类衍生物与现有技术相比具有毒副作用小，较好的安全性和代谢稳定性。The present invention provides a pyrrolesulfonyl derivative as described above, its pharmaceutically acceptable salt, its tautomer or its stereoisomer or the above-mentioned pharmaceutical composition for the treatment or prevention of the following diseases Uses in medicine: peptic ulcer, Zoller-Ellison syndrome, gastric erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagitis, functional dyspepsia, pylori spiral bacterial infection, gastric cancer, gastric MALT lymphoma, ulcers caused by non-steroidal anti-inflammatory drugs, hyperacidity caused by postoperative stress or ulcers caused by postoperative stress; or in the preparation of drugs for inhibiting peptic ulcer , acute stress ulcer, hemorrhagic gastritis or upper gastrointestinal bleeding caused by invasive stress. At the same time, compared with the prior art, the pyrrolesulfonyl derivatives provided by the present invention have less toxic and side effects, better safety and metabolic stability.
术语解释Terminology Explanation
除非有相反陈述，否则本发明在说明书和权利要求书中所使用的部分术语定义如下：Unless otherwise stated, some terms used in the present invention in the specification and claims are defined as follows:
“环烷基”是指饱和或部分不饱和单环或多环环状烃取代基，环烷基包括3至20个碳原子，优选包括3至12个碳原子。单环环烷基的非限制性实施例包括，但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是任选取代的或未取代的。"Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl group includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl. Cycloalkyl groups can be optionally substituted or unsubstituted.
“螺环基”指含有两个或两个以上环状结构，且单环之间彼此共用一个碳原子(称螺原子)的多环基团，环内可以含有1个或多个双键，可以含有一个或多个杂原子，杂原子包括氧、硫和氮等，但没有一个环具有完全共轭的π电子的芳香系统。优选为6至12元。根据环与环之间共用螺原子的数目将螺环基分为单螺、双螺或多螺环基，优选为单螺和双螺环基，优选为4元/5元、4元/6元、5元/5元或5元/6元。“螺环基”的非限制性实施例包括但不限于："Spiro ring group" refers to a polycyclic group containing two or more ring structures, and the single rings share one carbon atom (called spiro atom) with each other. The ring may contain one or more double bonds, Can contain one or more heteroatoms, heteroatoms include oxygen, sulfur and nitrogen, etc., but none of the rings has an aromatic system with fully conjugated π electrons. Preferably it is 6 to 12 yuan. According to the number of shared spiro atoms between the ring and the ring, the spiro ring group is divided into single spiro, double spiro or poly spiro ring group, preferably single spiro and double spiro ring group, preferably 4-membered/5-membered, 4-membered/6-membered Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan. Non-limiting examples of "spirocyclyl" include, but are not limited to:
Figure PCTCN2022104528-appb-000008
Figure PCTCN2022104528-appb-000008
“桥环基”指5至18元，含有两个或两个以上环状结构，彼此共用两个不直接相连接碳原子的多环基团，一个或多个环可以含有一个或多个双键，一个或多个环可以含有一个或多个杂原子，杂原子包括氧、硫和氮等，但没有一个环具有完全共轭的π电子的芳香系统，优选为6至12元。根据组成环的数目可以分为双环、三环、四环或多环桥环基，优选为双环、三环或四环，更优选为双环或三环。“桥环基”的非限制性实施例包括但不限于："Bridged ring group" refers to a polycyclic group with 5 to 18 members, containing two or more ring structures, sharing two carbon atoms that are not directly connected to each other, and one or more rings may contain one or more bis Bond, one or more rings may contain one or more heteroatoms, heteroatoms include oxygen, sulfur and nitrogen, etc., but none of the rings has an aromatic system with fully conjugated π electrons, preferably 6 to 12 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridging rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged ring groups" include, but are not limited to:
Figure PCTCN2022104528-appb-000009
Figure PCTCN2022104528-appb-000009
“杂环基”是指包含3-12个环原子的饱和或部分不饱和的单环、双环或三环的非芳香性杂环基，其中至少一个环原子是杂原子，如氧、氮、硫原子等。优选具有3至8元单环或7至10元双-或三环，其可以包含1，2或3个选自氮、氧和/或硫中的原子。“杂环基”的实例包括但不限于吗啉基，氧杂环丁烷基，硫代吗啉基，四氢吡喃基，1，1-二氧代-硫代吗啉基，哌 啶基，2-氧代-哌啶基，吡咯烷基，2-氧代-吡咯烷基，哌嗪-2-酮，8-氧杂-3-氮杂-双环[3.2.1]辛基和哌嗪基。所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基。杂环基可以是任选取代的或未取代的。"Heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic heterocyclic group containing 3-12 ring atoms, wherein at least one ring atom is a heteroatom, such as oxygen, nitrogen, Sulfur atom etc. Preference is given to having a 3 to 8 membered monocyclic ring or a 7 to 10 membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine Base, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl. The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl. A heterocyclyl group can be optionally substituted or unsubstituted.
“并环基”是指有两个、三个或四个环状结构彼此共用两个相邻原子形成的并环结构，环状结构每个单环可以为单环芳基、单环杂芳基、单环环烷基或单环杂环烷基。本发明所指并环基团为饱和、不饱和或者部分饱和的并环结构，优选二环或三环并环基团；本发明中，所述并环基团为3-20元，优选3-15元并环基。并环基的具体实施例包括但不限于：苯并环丁烯基、2，3-二氢-1-H-茚基、1，2，3，4-四氢萘基、6，7，8，9-四氢-5H-苯并[7]轮烯基、6，9-二氢-5H-苯并[7]轮烯基、5，6，7，8，9，10-六氢苯并[8]轮烯基、2，3-环戊烯并吡啶基、5，6-二氢-4H-环戊基[B]噻吩基、5，6-二氢-4H-环戊基[B]呋喃基、2，3-二氢苯并呋喃基、1，3-二氢异苯并呋喃基、二氢吲哚基、2，3-二氢苯并[b]噻吩基、二氢苯并哌喃基、1，2，3，4-四氢喹啉基、2，3-二氢-1，4-苯并二噁烷基、3，4-二氢-2H-1，4-苯并噁嗪基、萘啶基、萘基基、苯并呋喃基、苯并噻吩基、苯并吡咯基、苯并噻唑基、苯并噁唑基、吲唑基、苯并哒嗪基、苯并咪唑基、吲哚基、喹啉基、异喹啉基、嘌呤基、喋啶基、"Alternative ring group" refers to a parallel ring structure formed by two, three or four ring structures sharing two adjacent atoms with each other. Each single ring of the ring structure can be a single ring aryl group, a single ring heteroaryl group, monocyclic cycloalkyl or monocyclic heterocycloalkyl. The ring-joining group referred to in the present invention is a saturated, unsaturated or partially saturated ring-joining structure, preferably a bicyclic or tricyclic ring-joining group; in the present invention, the ring-joining group is 3-20 members, preferably 3 -15 membered and cycloyl. Specific examples of alkynyl include, but are not limited to: benzocyclobutenyl, 2,3-dihydro-1-H-indenyl, 1,2,3,4-tetrahydronaphthyl, 6,7, 8,9-tetrahydro-5H-benzo[7]annyl, 6,9-dihydro-5H-benzo[7]annyl, 5,6,7,8,9,10-hexahydro Benzo[8]annyl, 2,3-cyclopentenylpyridyl, 5,6-dihydro-4H-cyclopentyl[B]thienyl, 5,6-dihydro-4H-cyclopentyl [B]furyl, 2,3-dihydrobenzofuryl, 1,3-dihydroisobenzofuryl, indolinyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzo[b]thienyl, Hydrobenzopyranyl, 1,2,3,4-tetrahydroquinolyl, 2,3-dihydro-1,4-benzodioxanyl, 3,4-dihydro-2H-1, 4-Benzoxazinyl, naphthyridyl, naphthyl, benzofuryl, benzothienyl, benzopyrrolyl, benzothiazolyl, benzoxazolyl, indazolyl, benzopyridazine Base, benzimidazolyl, indolyl, quinolinyl, isoquinolyl, purinyl, pteridyl,
Figure PCTCN2022104528-appb-000010
Figure PCTCN2022104528-appb-000010
Figure PCTCN2022104528-appb-000011
等。
Figure PCTCN2022104528-appb-000011
Wait.
“芳基”是指含有一个或者两个环的碳环芳香系统，其中所述环可以以稠合的方式连接在一起。术语“芳基”包括比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C 6-C 10芳基，更优选芳基为苯基和萘基，最优选为苯基。芳基可以是取代或未取代的。所述“芳基”可与杂芳基、杂环基或环烷基稠合，其中与母体结构连接在一起的为芳基环，非限制性实施例包括但不限于： "Aryl" means a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferred aryl groups are C 6 -C 10 aryl groups, more preferred aryl groups are phenyl and naphthyl, most preferably phenyl. Aryl groups can be substituted or unsubstituted. The "aryl" can be fused with a heteroaryl, heterocyclyl or cycloalkyl, wherein the aryl ring is attached to the parent structure, non-limiting examples include but are not limited to:
Figure PCTCN2022104528-appb-000012
Figure PCTCN2022104528-appb-000012
“杂芳基”是指芳香族5至8元单环或9至10元双环，其可以包含1至4个选自氮、氧和/或硫中的原子。“杂芳基”的实施例包括但不限于呋喃基，吡啶基，2-氧代-1，2-二氢吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异噁唑基、噁唑基、噁二唑基、咪唑基、吡咯基、吡唑基、三唑基、四唑基、噻唑基、异噻唑基、1，2，3-噻二唑基、苯并间二氧杂环戊烯基、苯并咪唑基、吲哚基、异吲哚基、1，3-二氧代-异吲哚基、喹啉基、吲唑基、苯并异噻唑基、苯并噁唑基和苯并异噁唑基。杂芳基可以是任选取代或未取代的。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包括但不限于："Heteroaryl" refers to an aromatic 5 to 8 membered monocyclic ring or 9 to 10 membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo-isodi Oxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzo Oxazolyl and Benzisoxazolyl. Heteroaryl groups can be optionally substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:
Figure PCTCN2022104528-appb-000013
Figure PCTCN2022104528-appb-000013
“稠环芳基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的、含有8-10个环碳原子的、不饱和的、具有芳香性的环状基团，优选“9-10元稠环芳基”，非限制性实施例包括但不限于："Fused ring aryl" refers to an unsaturated, aromatic ring structure containing 8-10 ring carbon atoms formed by two or more ring structures sharing two adjacent atoms. Group, preferably "9-10 membered fused ring aryl", non-limiting examples include but are not limited to:
Figure PCTCN2022104528-appb-000014
Figure PCTCN2022104528-appb-000014
“烷氧基”是指(烷基-O-)的基团。其中，烷基见本文有关定义。C 1-C 6的烷氧基为优先选择。其实例包括，但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。 "Alkoxy" refers to a group of (alkyl-O-). Wherein, alkyl refers to relevant definitions herein. C 1 -C 6 alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
“卤代烷基”指具有一个或者多个卤素取代基的烷基，其中烷基基团具有如本发明所述的含义。卤代烷基的实例包括，但并不限于氟甲基、二氟甲基、三氟甲基、全氟乙基、1，1-二氯乙基、1，2-二氯丙基等。"Haloalkyl" refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has a meaning as described herein. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.
“任选”意味着其所描述的事件可以但不必发生。例如，“A任选地被1到多个R 2取代”该说明包含着A基团可以被1到多个R 2取代或者不被R 2取代的情形。 "Optional" means that the event it describes can but need not occur. For example, the statement "A is optionally substituted with 1 to more R2" includes the situation that the A group may be substituted with 1 to more R2 or not substituted with R2.
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1-3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms in a group are independently substituted by a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
本发明提供了一种新结构的吡咯磺酰类衍生物，试验结果表明，该吡咯磺酰类衍生物表现出优异的胃酸分泌抑制和钾离子竞争性酸阻滞剂(P-CABs)活性，可用于制备治疗或预防消化性溃疡、卓一艾综合征、胃糜烂性食管炎、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、幽门螺旋杄菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡、手术后应激导致的胃酸过多或手术后应激导致的溃疡的药物；或者在制备抑制肖化性溃疡、急应激性溃疡、出血性胃炎或侵入性应激造成的上消化道出血的药物。以及本发明提供的吡咯磺酰类衍生物具有毒副作用小，优异的安全性能；表现出具有较好的药代动力学性质，显著的半衰期延长，更持续的抑酸效果，有望改善现有技术中质子泵抑制剂药物的夜间酸突破现象。The present invention provides a new structure of pyrrolesulfonyl derivatives, the test results show that the pyrrolesulfonyl derivatives exhibit excellent gastric acid secretion inhibition and potassium ion competitive acid blockers (P-CABs) activity, It can be used to prepare for the treatment or prevention of peptic ulcer, Zoller's syndrome, gastric erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagitis, functional dyspepsia, helicobacter pylorus bacterial infection, gastric cancer, gastric MALT lymphoma, ulcers caused by non-steroidal anti-inflammatory drugs, hyperacidity caused by postoperative stress or ulcers caused by postoperative stress; Drugs for upper gastrointestinal bleeding from stress ulcers, hemorrhagic gastritis, or invasive stress. And the pyrrolesulfonyl derivatives provided by the present invention have less toxic and side effects and excellent safety performance; exhibit better pharmacokinetic properties, significant half-life extension, and more sustained acid-suppressing effect, which is expected to improve the prior art Nocturnal acid breakthrough phenomenon in proton pump inhibitor drugs.
附图说明Description of drawings
图1为手动膜片钳hERG电流测试指令电压程序。Figure 1 shows the manual patch clamp hERG current test instruction voltage program.
具体实施方式detailed description
下面通过具体实施例对本发明的方法进行说明，以使本发明技术方案更易于理解、掌握，但本发明并不局限于此。下述实施例中 1H NMR图谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。 1H NMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，q＝四重峰，m＝多重峰，br＝变宽的，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。 The method of the present invention will be described below through specific examples to make the technical solution of the present invention easier to understand and grasp, but the present invention is not limited thereto. In the following examples, the 1 H NMR spectrum is measured by Bruker instrument (400 MHz), and the chemical shift is expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. Notation of 1 H NMR: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadened, dd = doublet of doublet, dt = triplet peak doublet. If the coupling constant is provided, its unit is Hz.
质谱是用LC/MS仪测定得到，离子化方式为ESI。The mass spectrum was measured by LC/MS instrument, and the ionization mode was ESI.
在下列实例中，除非另有指明，所有温度为摄氏温度，除非另有指明，各种起始原料和试剂来自市售或者是根据已知的方法合成，市售原料和试剂均不经进一步纯化直接使用。In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and unless otherwise indicated, various starting materials and reagents were either commercially available or synthesized according to known methods, and commercially available materials and reagents were not further purified Use directly.
CD 3OD：氘代甲醇 CD 3 OD: deuterated methanol
CDCl 3：氘代氯仿 CDCl 3 : deuterated chloroform
DMSO-d 6：氘代二甲基亚砜 DMSO-d 6 : deuterated dimethyl sulfoxide
氢气氛围是指反应瓶连接一个约1L容积的氢气气球。The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.
实施例中无特殊说明，反应中的溶液是指水溶液。Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温，为20℃-30℃。Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C-30°C.
中间体的制备Preparation of intermediates
中间体Int 1的合成Synthesis of intermediate Int 1
Figure PCTCN2022104528-appb-000015
Figure PCTCN2022104528-appb-000015
步骤1：合成1-(5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺(Int 1-2)Step 1: Synthesis of 1-(5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine (Int 1-2)
在室温下，将化合物Int 1-1(3.8g，20.1mmol)溶于30％甲胺醇溶液(20mL)，搅拌1小时后，分批加入NaBH 4(2.3g，60.3mmol)，继续搅拌1小时。加水(20mL)，用乙酸乙酯(100mL)萃取，有机相用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥，过滤后减压浓缩，得到黄色固体4.1g，产率：97.6％。 At room temperature, compound Int 1-1 (3.8g, 20.1mmol) was dissolved in 30% methylamino alcohol solution (20mL), after stirring for 1 hour, NaBH 4 (2.3g, 60.3mmol) was added in portions, and stirring was continued for 1 hour. Hour. Add water (20 mL), extract with ethyl acetate (100 mL), wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain 4.1 g of yellow solid, yield: 97.6%.
步骤2：合成((5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯(Int 1-3)Step 2: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 1-3)
在室温下，将化合物Int 1-2(4.1g，20.6mmol)溶于二氯甲烷(50mL)，分别加入三乙胺(11mL，78.9mmol)，Boc 2O(9.0g，41.2mmol)。在室温下反应2小时，减压浓缩，粗品用柱层析分离纯化(正己烷/乙酸乙酯)，得到白色固体5.2g，产率82.5％。 Compound Int 1-2 (4.1 g, 20.6 mmol) was dissolved in dichloromethane (50 mL) at room temperature, and triethylamine (11 mL, 78.9 mmol) and Boc 2 O (9.0 g, 41.2 mmol) were added respectively. Reacted at room temperature for 2 hours, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (n-hexane/ethyl acetate) to obtain 5.2 g of white solid with a yield of 82.5%.
步骤3：合成叔丁基((1-((3-溴苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(Int 1)Step 3: Synthesis of tert-butyl((1-((3-bromophenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)aminomethyl Ester (Int 1)
室温下，将化合物Int 1-3(3g，9.86mmol)溶于DMF(50mL)中，冷至0℃，加入氢化钠(600mg，14.8mmol)，室温搅拌10分钟后，加入3-溴苯磺酰氯(3g，11.8mmol)。继续反应1小时，加水(50mL)猝灭反应，用乙酸乙酯(100mL)萃取，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩，粗品用柱层析分离纯化(正己烷/乙酸乙酯)，得到白色固体4.8g，产率93.0％。At room temperature, dissolve compound Int 1-3 (3g, 9.86mmol) in DMF (50mL), cool to 0°C, add sodium hydride (600mg, 14.8mmol), stir at room temperature for 10 minutes, then add 3-bromobenzenesulfonate Acid chloride (3 g, 11.8 mmol). Continue the reaction for 1 hour, add water (50 mL) to quench the reaction, extract with ethyl acetate (100 mL), wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure, and the crude product is subjected to column chromatography Separation and purification (n-hexane/ethyl acetate) gave 4.8 g of a white solid with a yield of 93.0%.
中间体Int 2的合成Synthesis of intermediate Int 2
Figure PCTCN2022104528-appb-000016
Figure PCTCN2022104528-appb-000016
合成叔丁基((1-((5-溴吡啶-3-基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(Int 2)Synthesis of tert-butyl((1-((5-bromopyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)aminomethyl Ester (Int 2)
在冰浴下，将化合物Int 1-3(3.0g，9.87mmol)溶解在DMF(40ml)中，然后加入NaH(789mg，19.71mmol)，搅拌半个小时，然后加入化合物Int 2-1(3.03g，11.83mmo l)，继续搅拌2h。反应完全后，加入乙酸乙酯(150mL)稀释，用饱和食盐水(100mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩，通过柱层析(PE/EA＝3:1)纯化得到4.5g黄色油状化合物，产率87.2％。Under ice bath, compound Int 1-3 (3.0g, 9.87mmol) was dissolved in DMF (40ml), then NaH (789mg, 19.71mmol) was added, stirred for half an hour, then compound Int 2-1 (3.03 g, 11.83mmol), continue stirring for 2h. After the reaction was complete, ethyl acetate (150 mL) was added for dilution, washed with saturated brine (100 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and passed through column chromatography (PE/EA=3: 1) Purified to obtain 4.5g of yellow oily compound with a yield of 87.2%.
中间体Int 3的合成Synthesis of intermediate Int 3
Figure PCTCN2022104528-appb-000017
Figure PCTCN2022104528-appb-000017
步骤1：合成1-(5-溴-1H-吡咯-3-基)-N-甲基甲胺(Int 3-2)Step 1: Synthesis of 1-(5-bromo-1H-pyrrol-3-yl)-N-methylmethylamine (Int 3-2)
在室温下，将化合物Int 3-1(5.0g，28.74mmol)溶解在甲胺的甲醇溶液(50mL)中，室温搅拌2h，然后冰水浴冷却，加入硼氢化钠(2.2g，57.47mmol)，继续搅拌2h。待反应完成后，加入饱和氯化铵的水溶液淬灭反应，用二氯甲烷(100mL×2)萃取，合并有机相用饱和食盐水(150mL×1)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩，得到5.43g的黄色油状化合物，没有纯化直接进行下一步反应，[M+H] +:189.1。 Compound Int 3-1 (5.0 g, 28.74 mmol) was dissolved in methanol solution of methylamine (50 mL) at room temperature, stirred at room temperature for 2 h, then cooled in an ice-water bath, sodium borohydride (2.2 g, 57.47 mmol) was added, Stirring was continued for 2h. After the reaction was completed, the aqueous solution of saturated ammonium chloride was added to quench the reaction, extracted with dichloromethane (100mL×2), the combined organic phase was washed with saturated brine (150mL×1), and the organic phase was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, 5.43 g of a yellow oily compound was obtained, which was directly carried out to the next reaction without purification, [M+H] + : 189.1.
步骤2：合成叔丁基((5-溴-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(Int 3-3)Step 2: Synthesis of tert-butyl((5-bromo-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 3-3)
在室温下，将化合物Int 3-2(15.43g，28.72mmol)和三乙胺(7.98mL，57.44mmol)溶解在二氯甲烷(50mL)中，然后缓慢加入Boc 2O(7.52g，34.47mmol)，室温搅拌3h。待反应结束后，将反应液减压浓缩，通过柱层析(PE/EA＝5:1)纯化得到8.2g无色油状化合 物，产率98.60％，[M+H] +:289.1。 Compound Int 3-2 (15.43 g, 28.72 mmol) and triethylamine (7.98 mL, 57.44 mmol) were dissolved in dichloromethane (50 mL) at room temperature, then Boc 2 O (7.52 g, 34.47 mmol) was added slowly ), stirred at room temperature for 3h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (PE/EA=5:1) to obtain 8.2 g of a colorless oily compound with a yield of 98.60%, [M+H] + : 289.1.
步骤3：合成叔丁基((5-(2，4-二氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(Int 3-5)Step 3: Synthesis of tert-butyl ((5-(2,4-difluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 3-5)
将化合物Int 3-3(8.0g，27.67mmol)，Int 3-4(8.0g，33.20mmol)，Pd(dppf)Cl 2(2.1g，2.77mmol)，和碳酸钾(9.6g，69.16mmol)溶解在1，4-二氧六环和水(80/16mL)中，在氮气保护下，115℃下搅拌4h。待反应完成后，用二氯甲烷(100mL×2)萃取，合并有机相用饱和食盐水(150mL×1)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩，通过柱层析(PE/EA＝3:1)纯化得到6.2g棕色油状化合物，产率69.66％，[M+H] +:323.2。 Compound Int 3-3 (8.0g, 27.67mmol), Int 3-4 (8.0g, 33.20mmol), Pd(dppf)Cl2 (2.1g, 2.77mmol ), and potassium carbonate (9.6g, 69.16mmol) Dissolve in 1,4-dioxane and water (80/16mL), and stir at 115°C for 4h under nitrogen protection. After the reaction is complete, extract with dichloromethane (100mL×2), combine the organic phases and wash with saturated brine (150mL×1), dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and pass through column chromatography ( PE/EA=3:1) was purified to obtain 6.2 g of brown oily compound, the yield was 69.66%, [M+H] + : 323.2.
步骤4：合成叔丁基((1-((3-溴苯基)磺酰基)-5-(2，4-二氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(Int 3)Step 4: Synthesis of tert-butyl((1-((3-bromophenyl)sulfonyl)-5-(2,4-difluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl ) carbamate (Int 3)
在冰浴下，将化合物Int 3-5(2.0g，6.20mmol)溶解在DMF(15mL)中，加入氢化钠(373mg，9.31mmol)，搅拌30分钟，然后向反应体系中加入化合物Int 3-6(1.9g，7.45mmol)，继续搅拌2h。待反应完成后，加入饱和氯化铵的水溶液淬灭反应，用乙酸乙酯(30mL×2)萃取，合并有机相用饱和食盐水(50mL×1)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩，通过柱层析(PE/EA＝3:1)纯化得到3.0g棕色油状化合物，产率89.55％。Under ice bath, compound Int 3-5 (2.0g, 6.20mmol) was dissolved in DMF (15mL), sodium hydride (373mg, 9.31mmol) was added, stirred for 30 minutes, then compound Int 3-5 was added to the reaction system 6 (1.9g, 7.45mmol), stirring was continued for 2h. After the reaction was completed, the aqueous solution of saturated ammonium chloride was added to quench the reaction, extracted with ethyl acetate (30mL×2), the combined organic phase was washed with saturated brine (50mL×1), and the organic phase was dried over anhydrous sodium sulfate. It was filtered, concentrated under reduced pressure, and purified by column chromatography (PE/EA=3:1) to obtain 3.0 g of brown oily compound with a yield of 89.55%.
中间体Int 4的合成Synthesis of intermediate Int 4
Figure PCTCN2022104528-appb-000018
Figure PCTCN2022104528-appb-000018
合成叔丁基((1-((3-溴-5-氟苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(Int 4)Synthesis of tert-butyl((1-((3-bromo-5-fluorophenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)amino Formate (Int 4)
将化合物Int 1-3(1.0g，3.29mmol)溶解在DMF(15mL)溶液中，冷却到室温，将氢化钠(198mg，4.93mmol)加入到反应溶液中，冰水浴下搅拌30分钟。然后将化合物I nt 4-1(1.1g，3.94mmol)缓慢加入到反应体系中，继续搅拌2h。待反应结束后，用饱和的氯化铵水溶液淬灭反应体系，用乙酸乙酯(20mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩。通过柱层析(PE/EA＝10:1)纯化得到700mg黄色油状化合物，产率39.54％，[M+H] +:541.1。 Compound Int 1-3 (1.0g, 3.29mmol) was dissolved in DMF (15mL) solution, cooled to room temperature, sodium hydride (198mg, 4.93mmol) was added to the reaction solution, and stirred under ice-water bath for 30 minutes. Then compound Int 4-1 (1.1 g, 3.94 mmol) was slowly added to the reaction system, and stirring was continued for 2 h. After the reaction was completed, the reaction system was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (20 mL×2), and the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (PE/EA=10:1) gave 700 mg of a yellow oily compound with a yield of 39.54%, [M+H] + : 541.1.
中间体Int 5的合成Synthesis of intermediate Int 5
Figure PCTCN2022104528-appb-000019
Figure PCTCN2022104528-appb-000019
步骤1：合成叔丁基((1-((5-溴-2-甲氧基苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(Int 5)Step 1: Synthesis of tert-butyl ((1-((5-bromo-2-methoxyphenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl) (Methyl) carbamate (Int 5)
在室温下，将化合物Int 1-3(1000mg，3.29mmol)溶解在DMF(10mL)中，0℃下加入NaH(118.44mg，4.94mmol)，加毕，室温搅拌30min后加入Int 5-1(1127mg，3.95mmol)搅拌3h。反应结束后，加水(40mL)，用乙酸乙酯(60mL×2)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸镁干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝2:1)得到红色油状化合物882mg，产率48.5％，[M+H] +:554.20。 At room temperature, the compound Int 1-3 (1000 mg, 3.29 mmol) was dissolved in DMF (10 mL), and NaH (118.44 mg, 4.94 mmol) was added at 0°C. 1127mg, 3.95mmol) was stirred for 3h. After the reaction, add water (40mL), extract with ethyl acetate (60mL×2), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, and the filtrate is concentrated under reduced pressure, separated and purified by column chromatography ( PE/EA=2:1) to obtain 882 mg of red oily compound, the yield was 48.5%, [M+H] + : 554.20.
实施例1Example 1
1-(1-((3-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)苯基)磺酰基)-5-(2-氟-苯基)-1H-吡咯-3-基)-N-甲基甲胺(III-1)的合成1-(1-((3-(3-oxa-8-azabicyclo[3.2.1]octane-8-yl)phenyl)sulfonyl)-5-(2-fluoro-phenyl)- Synthesis of 1H-pyrrol-3-yl)-N-methylmethylamine (III-1)
Figure PCTCN2022104528-appb-000020
Figure PCTCN2022104528-appb-000020
步骤1：合成叔丁基((1-((3-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(1-2)Step 1: Synthesis of tert-butyl ((1-((3-(3-oxa-8-azabicyclo[3.2.1]octane-8-yl)phenyl)sulfonyl)-5-(2- Fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (1-2)
将化合物Int-1(150mg，0.29mmol)，1-1(52mg，0.35mmol)，Pd(OAc) 2(7mg，0.03mmol)，xantphos(中文名称：4，5-双(二苯基膦)-9，9-二甲基氧杂蒽，33mg，0.06mmol)和碳酸铯(234mg，0.72mmol)加入到甲苯(5mL)溶液中，在氮气保护下，110℃搅拌过 夜。反应完全后，加入乙酸乙酯(20mL)稀释，用饱和食盐水(20mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩，通过反相制备纯化得到50mg白色固体化合物，产率31.44％，[M+H] +:556.2。 Compound Int-1 (150mg, 0.29mmol), 1-1 (52mg, 0.35mmol), Pd(OAc) 2 (7mg, 0.03mmol), xantphos (Chinese name: 4,5-bis(diphenylphosphine) -9,9-Dimethylxanthene, 33mg, 0.06mmol) and cesium carbonate (234mg, 0.72mmol) were added to a toluene (5mL) solution, and stirred overnight at 110°C under nitrogen protection. After the reaction was complete, ethyl acetate (20 mL) was added to dilute, washed with saturated brine (20 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase preparation to obtain 50 mg of a white solid compound. Yield 31.44%, [M+H] + : 556.2.
步骤2：合成1-(1-((3-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)苯基)磺酰基)-5-(2-氟-苯基)-1H-吡咯-3-基)-N-甲基甲胺(III-1)Step 2: Synthesis of 1-(1-((3-(3-oxa-8-azabicyclo[3.2.1]octane-8-yl)phenyl)sulfonyl)-5-(2-fluoro- Phenyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III-1)
在室温下，将化合物1-2(50mg，0.09mmol)溶于二氯甲烷(2mL)溶液中，加入4M盐酸/1，4-二氧六环(2mL)，搅拌两小时，待反应完全后，浓缩，通过反相制备纯化得到30mg黄色固体化合物，产率73.17％，纯度>95％，[M+H] +:456.2。 Dissolve compound 1-2 (50 mg, 0.09 mmol) in dichloromethane (2 mL) solution at room temperature, add 4M hydrochloric acid/1,4-dioxane (2 mL), stir for two hours, and wait for the reaction to complete , concentrated, and purified by reverse-phase preparation to obtain 30 mg of a yellow solid compound with a yield of 73.17%, a purity of >95%, and [M+H] + : 456.2.
1HNMR：(400MHz，CDCl 3)δ7.40-7.34(m，2H)，7.23-7.18(m，2H)，7.11(t，J＝7.6Hz，1H)，7.05(t，J＝7.6Hz，1H)，6.87(d，J＝8.4Hz，1H)，6.82(d，J＝8.0Hz，1H)，6.69(s，1H)，6.25(s，1H)，3.93-3.91(m，2H)，3.76(d，J＝11.2Hz，2H)，3.64(s，2H)，3.50(d，J＝11.2Hz，2H)，2.47(s，3H)，2.10-2.07(m，2H)，1.99-1.96(m，2H). 1 HNMR: (400MHz, CDCl 3 ) δ7.40-7.34(m, 2H), 7.23-7.18(m, 2H), 7.11(t, J=7.6Hz, 1H), 7.05(t, J=7.6Hz, 1H), 6.87(d, J=8.4Hz, 1H), 6.82(d, J=8.0Hz, 1H), 6.69(s, 1H), 6.25(s, 1H), 3.93-3.91(m, 2H), 3.76(d, J=11.2Hz, 2H), 3.64(s, 2H), 3.50(d, J=11.2Hz, 2H), 2.47(s, 3H), 2.10-2.07(m, 2H), 1.99-1.96 (m, 2H).
实施例2Example 2
1-(5-(2-氟苯基)-1-((3-(六氢吡咯并[3，4-c]吡咯-2(1H)-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(III-2)的合成1-(5-(2-fluorophenyl)-1-((3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrole Synthesis of -3-yl)-N-methylmethylamine (III-2)
Figure PCTCN2022104528-appb-000021
Figure PCTCN2022104528-appb-000021
步骤1：合成叔丁基5-(3-((4-(((叔丁氧基羰基)(甲基)氨基)甲基)-2-(2-氟苯基)-1H-吡咯-1-基)磺酰基)苯基)六氢吡咯[3，4-c]吡咯-2(1H)-羧酸酯(2-2)Step 1: Synthesis of tert-butyl 5-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrole-1 -yl)sulfonyl)phenyl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-carboxylate (2-2)
将化合物Int 1(200mg，0.38mmol)，2-1(123mg，0.58mmol)，Pd(OAc) 2(9mg，0.04mmol)，xantphos(22mg，0.04mmol)和碳酸铯(313mg，0.96mmol)加入在甲苯(5mL)溶液中，在氮气保护下，110℃搅拌过夜。反应完全后，加入乙酸乙酯(20mL)稀释，用饱和食盐水(20mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩，通过柱层析(PE/EA＝2:1)纯化得到180mg黄色油状化合物，产率72.00％，[M+H] +:655.2。 Compounds Int 1 (200 mg, 0.38 mmol), 2-1 (123 mg, 0.58 mmol), Pd(OAc) 2 (9 mg, 0.04 mmol), xantphos (22 mg, 0.04 mmol) and cesium carbonate (313 mg, 0.96 mmol) were added In a solution of toluene (5 mL), under the protection of nitrogen, stir overnight at 110°C. After the reaction was complete, ethyl acetate (20 mL) was added for dilution, washed with saturated brine (20 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and passed through column chromatography (PE/EA=2: 1) Purified to obtain 180 mg of yellow oily compound, yield 72.00%, [M+H] + : 655.2.
步骤2：合成1-(5-(2-氟苯基)-1-((3-(六氢吡咯并[3，4-c]吡咯-2(1H)-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(III-2)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl) -1H-pyrrol-3-yl)-N-methylmethylamine (III-2)
在室温下，将化合物2-2(180mg，0.26mmol)溶于二氯甲烷(3mL)溶液中，加入4M盐酸/1，4-二氧六环(3mL)，搅拌2h，待反应完全后，浓缩，通过反相制备纯化得到50mg黄色固体化合物，产率40.32％，纯度>95％，[M+H] +:455.2。 Dissolve compound 2-2 (180mg, 0.26mmol) in dichloromethane (3mL) solution at room temperature, add 4M hydrochloric acid/1,4-dioxane (3mL), stir for 2h, after the reaction is complete, Concentrate and purify by reverse-phase preparation to obtain 50 mg of yellow solid compound with a yield of 40.32%, a purity of >95%, and [M+H] + : 455.2.
1HNMR：(400MHz，CDCl 3)δ7.40-7.34(m，2H)，7.23-7.17(m，2H)，7.11(t，J＝7.6Hz，1H)，7.07(t，J＝7.6Hz，1H)，6.79(d，J＝8.4Hz，1H)，6.70(d，J＝8.0Hz，1H)，6.56(s，1H)，6.23(s，1H)，3.64(s，2H)，3.36-3.32(m，2H)，3.21-3.16(m，2H)，3.09(d，J＝9.6Hz，2H)，2.94-2.92(m，2H)，3.83(d，J＝11.2Hz，2H)，2.47(s，3H). 1 HNMR: (400MHz, CDCl 3 ) δ7.40-7.34(m, 2H), 7.23-7.17(m, 2H), 7.11(t, J=7.6Hz, 1H), 7.07(t, J=7.6Hz, 1H), 6.79(d, J=8.4Hz, 1H), 6.70(d, J=8.0Hz, 1H), 6.56(s, 1H), 6.23(s, 1H), 3.64(s, 2H), 3.36- 3.32(m, 2H), 3.21-3.16(m, 2H), 3.09(d, J=9.6Hz, 2H), 2.94-2.92(m, 2H), 3.83(d, J=11.2Hz, 2H), 2.47 (s, 3H).
实施例3Example 3
1-(1-((3-(3，8-二氮杂双环[3.2.1]辛烷-8-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲胺二盐酸盐(III-3)的合成1-(1-((3-(3,8-diazabicyclo[3.2.1]octane-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole Synthesis of -3-yl)-N-methylamine dihydrochloride (III-3)
Figure PCTCN2022104528-appb-000022
Figure PCTCN2022104528-appb-000022
步骤1：合成叔丁基8-(3-((4-(((叔丁氧基羰基)(甲基)氨基)甲基)-2-(2-氟苯基)-1H-吡咯-1-基)磺酰基)苯基)-3，8-二氮杂双环[3.2.1]辛烷-3-羧酸盐(3-2)Step 1: Synthesis of tert-butyl 8-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrole-1 -yl)sulfonyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (3-2)
于100mL反应瓶中加入化合物Int 1(150mg，0.287mmol)，化合物3-1(73mg，0.345mmol)，Pd(OAc) 2(7mg，0.029mmol)，xantphos(33mg，0.057mmol)，Cs 2CO 3(234mg，0.718mmol)，甲苯(5mL)，搅拌，氮气置换3次，升温至110℃搅拌12h。TLC点板监测，反应完全，有新点产生(PE/EA＝3:1，Rf＝0.3)。加入水30mL，乙酸乙酯(30mL×2)萃取，有机相合并，饱和食盐水(30mL)洗涤一次，有机相用无水硫酸钠干燥，控温45℃减压浓缩，柱层析分离(PE/EA＝2:1淋洗)得200mg无色油状物。 Add compound Int 1 (150mg, 0.287mmol), compound 3-1 (73mg, 0.345mmol), Pd(OAc) 2 (7mg, 0.029mmol), xantphos (33mg, 0.057mmol), Cs 2 CO 3 (234mg, 0.718mmol), toluene (5mL), stirred, nitrogen replacement 3 times, heated to 110°C and stirred for 12h. TLC plate monitoring showed that the reaction was complete and new spots were generated (PE/EA=3:1, Rf=0.3). Add 30mL of water, extract with ethyl acetate (30mL×2), combine the organic phases, wash with saturated brine (30mL) once, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure at 45°C under temperature control, and separate by column chromatography (PE /EA=2:1 rinse) to obtain 200 mg colorless oil.
步骤2：合成1-(1-((3-(3，8-二氮杂双环[3.2.1]辛烷-8-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲胺二盐酸盐(III-3)Step 2: Synthesis of 1-(1-((3-(3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl) -1H-pyrrol-3-yl)-N-methylamine dihydrochloride (III-3)
在室温下，于反应瓶中加入化合物3-2(200mg)，MeOH(5mL)，搅拌溶清，加入4M盐酸/1，4-二氧六环(5mL)，室温反应1h，TLC点板监测，反应完全，有新点产生(DCM/MeOH＝10:1，Rf＝0.2)。旋干，得淡紫色油状物，加入二氯甲烷，有固体析出，过滤，抽干，得50mg淡紫色固体，纯度>95％，[M+H] +:455.6。 At room temperature, add compound 3-2 (200mg), MeOH (5mL) to the reaction flask, stir to dissolve, add 4M hydrochloric acid/1,4-dioxane (5mL), react at room temperature for 1h, and monitor by TLC , the reaction was complete, and new spots were generated (DCM/MeOH=10:1, Rf=0.2). Spin to dry to obtain a lavender oil, add dichloromethane, a solid precipitates out, filter, and drain to obtain 50 mg of a lavender solid with a purity of >95%, [M+H] + : 455.6.
1HNMR：(400MHz，CD 3OD)δ7.81(d，J＝2.0Hz，1H)，7.54-7.47(m，1H)，7.39(t，J＝8.0Hz， 1H)，7.20(t，J＝7.2Hz，2H)，7.17-7.04(m，2H)，6.95(d，J＝9.6Hz，1H)，6.79(t，J＝2.0Hz，1H)，6.43(d，J＝1.6Hz，1H)，4.36(s，2H)，4.13(s，2H)，3.23-3.13(m，4H)，2.73(s，3H)，2.34-2.21(m，2H)，2.12(d，J＝7.2Hz，2H). 1 HNMR: (400MHz, CD 3 OD) δ7.81(d, J=2.0Hz, 1H), 7.54-7.47(m, 1H), 7.39(t, J=8.0Hz, 1H), 7.20(t, J =7.2Hz, 2H), 7.17-7.04(m, 2H), 6.95(d, J=9.6Hz, 1H), 6.79(t, J=2.0Hz, 1H), 6.43(d, J=1.6Hz, 1H ), 4.36(s, 2H), 4.13(s, 2H), 3.23-3.13(m, 4H), 2.73(s, 3H), 2.34-2.21(m, 2H), 2.12(d, J=7.2Hz, 2H).
实施例4Example 4
1-(5-(2-氟苯基)-1-((3-(哌嗪-1-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺二盐酸盐(III-4)的合成1-(5-(2-fluorophenyl)-1-((3-(piperazin-1-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine di Synthesis of Hydrochloride (III-4)
Figure PCTCN2022104528-appb-000023
Figure PCTCN2022104528-appb-000023
步骤1：合成叔丁基4-(3-((4-(((叔丁氧基羰基)(甲基)氨基)甲基)-2-(2-氟苯基)-1H-吡咯-1-基)磺酰基)苯基)哌嗪-1-羧酸盐(4-2)Step 1: Synthesis of tert-butyl 4-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrole-1 -yl)sulfonyl)phenyl)piperazine-1-carboxylate (4-2)
于100mL反应瓶中加入化合物Int 1(150m，0.287mmol)，化合物4-1(70mg，0.345mmol)，Pd(OAc) 2(7mg，0.029mmol)，xantphos(33mg，0.057mmol)，Cs 2CO 3(234mg，0.718mmol)，甲苯(5mL)，搅拌，氮气置换3次，升温至110℃搅拌12h。TLC点板监测，反应完全，有新点产生(PE/EA＝3:1，Rf＝0.3)。加入水30mL，乙酸乙酯(30mL×2)萃取，有机相合并，饱和食盐水(30mL)水洗一次，有机相用无水硫酸钠干燥，控温45℃减压浓缩，柱层析分离，(PE/EA＝2:1)得170mg无色油状物。 Add compound Int 1 (150m, 0.287mmol), compound 4-1 (70mg, 0.345mmol), Pd(OAc) 2 (7mg, 0.029mmol), xantphos (33mg, 0.057mmol), Cs 2 CO 3 (234mg, 0.718mmol), toluene (5mL), stirred, nitrogen replacement 3 times, heated to 110°C and stirred for 12h. TLC plate monitoring showed that the reaction was complete and new spots were generated (PE/EA=3:1, Rf=0.3). Add 30 mL of water, extract with ethyl acetate (30 mL×2), combine the organic phases, wash with saturated brine (30 mL) once, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure at 45° C., and separate by column chromatography, ( PE/EA=2:1) to obtain 170 mg of colorless oil.
步骤2：合成1-(5-(2-氟苯基)-1-((3-(哌嗪-1-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺二盐酸盐(III-4)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(piperazin-1-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methyl Methylamine dihydrochloride (III-4)
在室温下，于反应瓶中加入化合物4-2(170mg)，MeOH(5mL)，搅拌溶清，加入4M盐酸/1，4-二氧六环(5mL)，室温反应1h，TLC点板监测，反应完全，有新点产生(DCM/MeOH＝10:1，Rf＝0.2)。旋干，得淡紫色油状物，加入二氯甲烷，有固体析出过滤，抽干，得50mg淡紫色固体，纯度>95％，[M+H] +:429.5。 At room temperature, add compound 4-2 (170mg), MeOH (5mL) to the reaction flask, stir to dissolve, add 4M hydrochloric acid/1,4-dioxane (5mL), react at room temperature for 1h, and monitor by TLC , the reaction was complete, and new spots were generated (DCM/MeOH=10:1, Rf=0.2). Spin to dry to obtain a lavender oil, add dichloromethane, a solid precipitates, filter, and drain to obtain 50 mg of a lavender solid with a purity of >95%, [M+H] + : 429.5.
1H NMR：(400MHz，CD 3OD)δ7.81(s，1H)，7.54-7.48(m，1H)，7.41(t，J＝8.0Hz，1H)，7.32(d，J＝8.0Hz，1H)，7.20(t，J＝7.6Hz，1H)，7.15-7.08(m，2H)，7.05(d，J＝7.6Hz，1H)，6.93(s，1H)，6.42(s，1H)，4.12(s，2H)，3.39(s，8H)，2.73(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ7.81(s, 1H), 7.54-7.48(m, 1H), 7.41(t, J=8.0Hz, 1H), 7.32(d, J=8.0Hz, 1H), 7.20(t, J=7.6Hz, 1H), 7.15-7.08(m, 2H), 7.05(d, J=7.6Hz, 1H), 6.93(s, 1H), 6.42(s, 1H), 4.12(s, 2H), 3.39(s, 8H), 2.73(s, 3H).
实施例5Example 5
1-(5-(2-氟苯基)-1-((3-(四氢-1H-呋喃[3，4-c]吡咯-5(3H)-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲 基甲胺(III-5)的合成1-(5-(2-fluorophenyl)-1-((3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonyl)-1H Synthesis of -pyrrol-3-yl)-N-methylmethylamine (III-5)
Figure PCTCN2022104528-appb-000024
Figure PCTCN2022104528-appb-000024
步骤1：合成叔丁基((5-(2-氟苯基)-1-((3-(四氢-1H-呋喃[3，4-c]吡咯-5(3H)-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(5-2)Step 1: Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl) )sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (5-2)
在室温下，将化合物Int 1(200mg，0.382mmol)加入10mL单口瓶中，用甲苯(3mL)溶解，分别加入5-1(75mg，0.497mmol)，Pd(OAc) 2(9mg，0.038mmol)，Xantpho s(76mg，0.076mmol)，碳酸铯(436mg，1.34mmol)。N 2置换后加热至110℃搅拌过夜。减压浓缩，粗品用柱层析分离纯化(正己烷/乙酸乙酯)，得到白色固体100mg，产率47.2％。 At room temperature, compound Int 1 (200mg, 0.382mmol) was added to a 10mL single-necked bottle, dissolved with toluene (3mL), and 5-1 (75mg, 0.497mmol), Pd(OAc) 2 (9mg, 0.038mmol) were added , Xantpho s (76 mg, 0.076 mmol), cesium carbonate (436 mg, 1.34 mmol). After N2 replacement, it was heated to 110°C and stirred overnight. After concentration under reduced pressure, the crude product was separated and purified by column chromatography (n-hexane/ethyl acetate) to obtain 100 mg of white solid with a yield of 47.2%.
步骤2：合成1-(5-(2-氟苯基)-1-((3-(四氢-1H-呋喃[3，4-c]吡咯-5(3H)-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(III-5)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonate Acyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III-5)
在室温下，将化合物5-2(100mg，0.180mmol)溶于4M盐酸/1，4-二氧六环(2mL)中，室温下反应1小时。减压浓缩，通过反相制备纯化得到白色固体30mg，产率：37.4％，纯度>95％，[M+H] +:456.5。 Compound 5-2 (100 mg, 0.180 mmol) was dissolved in 4M hydrochloric acid/1,4-dioxane (2 mL) at room temperature, and reacted at room temperature for 1 hour. Concentrated under reduced pressure, purified by reverse phase preparation to obtain 30 mg of white solid, yield: 37.4%, purity >95%, [M+H] + : 456.5.
1H NMR：(400MHz，DMSO-d 6)δ7.36-7.31(m，2H)，7.19-7.15(m，2H)，7.10-7.06(m，1H)，7.04-7.00(m，1H)，6.79-6.77(m，1H)，6.69-6.67(m，1H)，6.54-6.53(m，1H)，6.23-6.22(m，1H)，4.00-3.96(m，2H)，3.68(d，J＝3.2Hz，1H)，3.66(d，J＝3.6Hz，1H)，3.63(s，2H)，3.38＝3.33(m，2H)，3.12(d，J＝2.8Hz，1H)，3.10(d，J＝2.8Hz，1H)，3.05＝3.03(m，2H)，2.45(s，3H). 1 H NMR: (400MHz, DMSO-d 6 ) δ7.36-7.31(m, 2H), 7.19-7.15(m, 2H), 7.10-7.06(m, 1H), 7.04-7.00(m, 1H), 6.79-6.77(m, 1H), 6.69-6.67(m, 1H), 6.54-6.53(m, 1H), 6.23-6.22(m, 1H), 4.00-3.96(m, 2H), 3.68(d, J =3.2Hz, 1H), 3.66(d, J=3.6Hz, 1H), 3.63(s, 2H), 3.38=3.33(m, 2H), 3.12(d, J=2.8Hz, 1H), 3.10(d , J=2.8Hz, 1H), 3.05=3.03(m, 2H), 2.45(s, 3H).
实施例6Example 6
1-(5-(2-氟苯基)-1-((3-(1-甲基-1H-吡唑-4-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-6)的合成1-(5-(2-fluorophenyl)-1-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)- Synthesis of N-Methylmethylamine Hydrochloride (III-6)
Figure PCTCN2022104528-appb-000025
Figure PCTCN2022104528-appb-000025
步骤1：合成叔丁基((5-(2-氟苯基)-1-((3-(1-甲基-1H-吡唑-4-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(6-2)Step 1: Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrole -3-yl)methyl)(methyl)carbamate (6-2)
将化合物Int 1(150mg，0.29mmol)，6-1(90mg，0.43mmol)，Pd(dppf)Cl 2(21mg，0.03mmol)和碳酸钾(99mg，0.72mmol)溶解在1，4-二氧六环/水(10/2mL)中，在氮气保护下，110℃搅拌过夜。反应完全后，加入乙酸乙酯(20mL)稀释，用饱和食盐水(20mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩，通过柱层析(PE/EA＝1:1)纯化得到130mg黄色油状化合物，产率86.67％，[M+H] +:525.1。 Compound Int 1 (150 mg, 0.29 mmol), 6-1 (90 mg, 0.43 mmol), Pd(dppf)Cl 2 (21 mg, 0.03 mmol) and potassium carbonate (99 mg, 0.72 mmol) were dissolved in 1,4-diox Hexane/water (10/2mL), stirred overnight at 110°C under nitrogen protection. After the reaction was complete, ethyl acetate (20 mL) was added to dilute, washed with saturated brine (20 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and passed column chromatography (PE/EA=1: 1) Purified to obtain 130 mg of yellow oily compound, yield 86.67%, [M+H] + : 525.1.
步骤2：合成(5-(2-氟苯基)-1-((3-(1-甲基-1H-吡唑-4-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-6)Step 2: Synthesis of (5-(2-fluorophenyl)-1-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl )-N-methylmethylamine hydrochloride (III-6)
在室温下，将化合物6-2(130mg，0.24mmol)溶解在二氯甲烷(3mL)溶液中，加入4M盐酸/1，4-二氧六环(3mL)，搅拌2h，待反应完全后，过滤得到51mg白色固体化合物，产率63.75％，纯度>95％，[M+H] +:460.1。 Dissolve compound 6-2 (130 mg, 0.24 mmol) in dichloromethane (3 mL) solution at room temperature, add 4M hydrochloric acid/1,4-dioxane (3 mL), stir for 2 h, after the reaction is complete, 51 mg of white solid compound was obtained by filtration, yield 63.75%, purity >95%, [M+H] + : 460.1.
1H NMR：(400MHz，DMSO-d 6)δ9.39(s，2H)，8.25(s，1H)，7.92-7.85(m，3H)，7.55-7.50(m，3H)，7.25-7.17(m，3H)，7.06(t，J＝6.0Hz，1H)，6.56(s，1H)，3.97(t，J＝5.6Hz，2H)，3.89(s，3H)，2.47(t，J＝5.2Hz，3H). 1 H NMR: (400MHz, DMSO-d 6 ) δ9.39(s, 2H), 8.25(s, 1H), 7.92-7.85(m, 3H), 7.55-7.50(m, 3H), 7.25-7.17( m, 3H), 7.06(t, J=6.0Hz, 1H), 6.56(s, 1H), 3.97(t, J=5.6Hz, 2H), 3.89(s, 3H), 2.47(t, J=5.2 Hz, 3H).
实施例7Example 7
1-(5-(2-氟苯基)-1-((3-吗啉代苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(III-7)的合成1-(5-(2-fluorophenyl)-1-((3-morpholinophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III-7) synthesis
Figure PCTCN2022104528-appb-000026
Figure PCTCN2022104528-appb-000026
步骤1：合成叔丁基((5-(2-氟苯基)-1-((3-吗啉代苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(7-1)Step 1: Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-morpholinophenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl) Urethane (7-1)
室温下，将化合物Int 1(200mg，0.382mmol)溶于甲苯(3mL)中，分别加入Pd(O Ac) 2(9mg，0.038mmol)，xantphos(45mg，0.076mmol)，碳酸铯(374mg，1.15mmol)和吗啉(50mg，0.573mmol)。封管加热至110℃搅拌过夜。减压浓缩，粗品用柱层析分离纯化(正己烷/乙酸乙酯)，得到黄色油状物80mg，产率39.6％。 At room temperature, compound Int 1 (200 mg, 0.382 mmol) was dissolved in toluene (3 mL), and Pd(OAc) 2 (9 mg, 0.038 mmol), xantphos (45 mg, 0.076 mmol), cesium carbonate (374 mg, 1.15 mmol) and morpholine (50 mg, 0.573 mmol). Seal the tube and heat to 110°C and stir overnight. After concentration under reduced pressure, the crude product was separated and purified by column chromatography (n-hexane/ethyl acetate) to obtain 80 mg of a yellow oil with a yield of 39.6%.
步骤2：合成1-(5-(2-氟苯基)-1-((3-吗啉代苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(III-7)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-morpholinophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III -7)
在室温下，将化合物7-1(80mg，0.151mmol)溶于4M盐酸/1，4-二氧六环(2mL)中，室温下反应1小时。减压浓缩，粗品用饱和碳酸氢钠溶液调节pH到9，用乙酸乙酯萃取(20mL)，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤后旋干，粗品用DCM/MeOH打浆，得到黄色固体30mg，产率：42.9％，纯度>95％，[M+H] +:430.1。 Compound 7-1 (80 mg, 0.151 mmol) was dissolved in 4M hydrochloric acid/1,4-dioxane (2 mL) at room temperature, and reacted at room temperature for 1 hour. Concentrate under reduced pressure, the crude product was adjusted to pH 9 with saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and spin-dried, the crude product was washed with DCM /MeOH beating to obtain 30 mg of yellow solid, yield: 42.9%, purity >95%, [M+H] + : 430.1.
1H NMR：(400MHz，CDCl 3)δ7.37-7.33(m，2H)，7.23-7.16(m，2H)，7.11-7.07(m，1H)，7.04-6.98(m，2H)，6.94-6.92(m，1H)，6.81(s，1H)，6.24(s，1H)，3.81(t，J＝4.8Hz，4H)，3.64(s，2H)，3.05(t，J＝4.8Hz，4H)，2.45(s，3H) 1 H NMR: (400MHz, CDCl 3 ) δ7.37-7.33(m, 2H), 7.23-7.16(m, 2H), 7.11-7.07(m, 1H), 7.04-6.98(m, 2H), 6.94- 6.92(m, 1H), 6.81(s, 1H), 6.24(s, 1H), 3.81(t, J=4.8Hz, 4H), 3.64(s, 2H), 3.05(t, J=4.8Hz, 4H ), 2.45(s, 3H)
实施例8Example 8
1-(5-(2-氟苯基)-1-((3-(4-甲基哌嗪-1-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-8)的合成1-(5-(2-fluorophenyl)-1-((3-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methyl Synthesis of methylamine hydrochloride (III-8)
Figure PCTCN2022104528-appb-000027
Figure PCTCN2022104528-appb-000027
步骤1：合成叔丁基((5-(2-氟苯基)-1-((3-(4-甲基哌嗪-1-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(8-2)Step 1: Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrole-3- Base) methyl) (methyl) carbamate (8-2)
于100mL反应瓶中加入化合物Int 1(150mg，0.287mmol)，化合物8-1(36mg，0.345mmol)，Pd(OAc) 2(7mg，0.029mmol)，xantphos(33mg，0.057mmol)，Cs 2CO 3(234mg，0.718mmol)，甲苯(5mL)，搅拌，氮气置换3次，升温至110℃搅拌12h。TLC点板监测，反应完全，有新点产生(PE/EA＝3:1，Rf＝0.3)。加入水30mL，乙酸乙酯(30mL×2)萃取，有机相合并，饱和食盐水(30mL)水洗一次，有机相用无水硫酸钠干燥，控温45℃减压浓缩，柱层析分离(PE/EA＝2:1)得170mg无色油状物。 Add compound Int 1 (150mg, 0.287mmol), compound 8-1 (36mg, 0.345mmol), Pd(OAc) 2 (7mg, 0.029mmol), xantphos (33mg, 0.057mmol), Cs 2 CO 3 (234mg, 0.718mmol), toluene (5mL), stirred, nitrogen replacement 3 times, heated to 110°C and stirred for 12h. TLC plate monitoring showed that the reaction was complete and new spots were generated (PE/EA=3:1, Rf=0.3). Add 30mL of water, extract with ethyl acetate (30mL×2), combine the organic phases, wash once with saturated brine (30mL), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure at 45°C under temperature control, and separate by column chromatography (PE /EA=2:1) to obtain 170 mg of colorless oil.
步骤2：合成1-(5-(2-氟苯基)-1-((3-(4-甲基哌嗪-1-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-8)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl) -N-Methylmethylamine hydrochloride (III-8)
在室温下，于反应瓶中加入化合物8-2(150mg)，DCM(4mL)，搅拌溶清，加入4M盐酸/1，4-二氧六环(4mL)，室温反应1h，TLC点板监测，反应完全，有新点产生(DCM/MeOH＝10:1，Rf＝0.2)。旋干，加入无水乙醚，有固体析出，过滤，抽干，得60mg类白色固体，纯度>95％，[M+H] +:442.2。 At room temperature, add compound 8-2 (150mg), DCM (4mL) to the reaction flask, stir to dissolve, add 4M hydrochloric acid/1,4-dioxane (4mL), react at room temperature for 1h, and monitor by TLC , the reaction was complete, and new spots were generated (DCM/MeOH=10:1, Rf=0.2). Spin dry, add anhydrous diethyl ether, a solid precipitates out, filter, and drain to obtain 60 mg of off-white solid, purity >95%, [M+H] + : 442.2.
1H NMR：(400MHz，CD 3OD)δ7.81(s，1H)，7.57-7.48(m，1H)，7.41(t，J＝8.0Hz，1H)，7.33(d，J＝8.0Hz，1H)，7.21(t，J＝7.6Hz，1H)，7.16-7.09(m，2H)，7.06(d，J＝6.8Hz，1H)，6.92(s 1H)，6.42(s，1H)，4.12(s，2H)，3.79(d，J＝14.0Hz，2H)，3.65(d，J＝11.6Hz，2H)，3.27(t，J＝10.8Hz，2H)，3.10(t，J＝10.8Hz，2H)，3.00(s，3H)，2.73(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ7.81(s, 1H), 7.57-7.48(m, 1H), 7.41(t, J=8.0Hz, 1H), 7.33(d, J=8.0Hz, 1H), 7.21(t, J=7.6Hz, 1H), 7.16-7.09(m, 2H), 7.06(d, J=6.8Hz, 1H), 6.92(s 1H), 6.42(s, 1H), 4.12 (s, 2H), 3.79(d, J=14.0Hz, 2H), 3.65(d, J=11.6Hz, 2H), 3.27(t, J=10.8Hz, 2H), 3.10(t, J=10.8Hz , 2H), 3.00(s, 3H), 2.73(s, 3H).
实施例9Example 9
1-(1-((3-(3，6-二氢-2H-吡喃-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺1-(1-((3-(3,6-dihydro-2H-pyran-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl )-N-methylmethylamine
(III-9)的合成Synthesis of (III-9)
Figure PCTCN2022104528-appb-000028
Figure PCTCN2022104528-appb-000028
步骤1：合成叔丁基((1-((3-(3，6-二氢-2H-吡喃-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(9-2)Step 1: Synthesis of tert-butyl((1-((3-(3,6-dihydro-2H-pyran-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H -pyrrol-3-yl)methyl)(methyl)carbamate (9-2)
于100mL反应瓶中加入化合物Int 1(260mg，0.5mmol)，化合物9-1(126mg，0.6mmol)，Pd(dppf)Cl 2(37mg，0.05mmol)，K 2CO 3(174mg，1.25mmol)，1，4-二氧六环/水(5/1mL)，搅拌，氮气置换3次，升温至100℃搅拌12h。TLC点板监测，反应完全，有新点产生(PE/EA＝3/1，Rf＝0.3)。加入水30mL，乙酸乙酯(30mL×2)萃取，有机相合并，饱和食盐水(30mL)水洗一次，有机相用无水硫酸钠干燥，控温45℃减压浓缩，柱层析分离(PE/EA＝2:1)得200mg黄色油状物。 Add compound Int 1 (260mg, 0.5mmol), compound 9-1 (126mg, 0.6mmol), Pd(dppf)Cl 2 (37mg, 0.05mmol), K 2 CO 3 (174mg, 1.25mmol) into a 100mL reaction vial , 1,4-dioxane/water (5/1mL), stirred, nitrogen replacement 3 times, heated to 100°C and stirred for 12h. TLC plate monitoring showed that the reaction was complete and new spots were generated (PE/EA=3/1, Rf=0.3). Add 30mL of water, extract with ethyl acetate (30mL×2), combine the organic phases, wash once with saturated brine (30mL), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure at 45°C under temperature control, and separate by column chromatography (PE /EA=2:1) to obtain 200 mg of yellow oil.
步骤2：合成1-(1-((3-(3，6-二氢-2H-吡喃-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺(III-9)Step 2: Synthesis of 1-(1-((3-(3,6-dihydro-2H-pyran-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole -3-yl)-N-methylmethylamine (III-9)
在室温下，于反应瓶中加入化合物9-2(200mg)，DCM(8mL)，搅拌溶清，加入4M盐 酸/1，4-二氧六环(2mL)，室温反应1h，TLC点板监测，反应完全，有新点产生(DCM/Me OH＝10:1，Rf＝0.2)。加入饱和碳酸氢钠水溶液，调节pH至8，乙酸乙酯萃取，有机相用饱和食盐水水洗，无水硫酸钠干燥，旋干。TLC板分离，得70mg棕色固体，纯度>95％，[M+H] +:426.5。 At room temperature, add compound 9-2 (200mg), DCM (8mL) to the reaction flask, stir to dissolve, add 4M hydrochloric acid/1,4-dioxane (2mL), react at room temperature for 1h, and monitor by TLC , the reaction was complete, and a new point was generated (DCM/MeOH=10:1, Rf=0.2). Saturated aqueous sodium bicarbonate was added to adjust the pH to 8, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried. Separation on a TLC plate yielded 70 mg of a brown solid with a purity of >95%, [M+H] + : 426.5.
1H NMR：(400MHz，CD 3OD)δ7.72(d，J＝7.2，1H)，7.57(s，1H)，7.50-7.41(m，3H)，7.36(s，1H)，7.16(t，J＝7.6Hz，1H)，7.13-7.05(m，2H)，6.32(s，1H)，6.19(s，1H)，4.32(s，2H)，3.93(t，J＝5.2Hz，2H)，3.71(s，2H)，2.44-2.39(m，5H). 1 H NMR: (400MHz, CD 3 OD) δ7.72(d, J=7.2, 1H), 7.57(s, 1H), 7.50-7.41(m, 3H), 7.36(s, 1H), 7.16(t , J=7.6Hz, 1H), 7.13-7.05(m, 2H), 6.32(s, 1H), 6.19(s, 1H), 4.32(s, 2H), 3.93(t, J=5.2Hz, 2H) , 3.71(s, 2H), 2.44-2.39(m, 5H).
实施例10Example 10
1-(5-(2-氟苯基)-1-((5-(四氢-1H-呋喃并[3，4-c]吡咯-5(3H)-基)吡啶-3-基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(III-10)的合成1-(5-(2-fluorophenyl)-1-((5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-3-yl)sulfonate Synthesis of Acyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III-10)
Figure PCTCN2022104528-appb-000029
Figure PCTCN2022104528-appb-000029
步骤1：合成叔丁基((5-(2-氟苯基)-1-((5-(四氢-1H-呋喃[3，4-c]吡咯-5(3H)-基)吡啶-3-基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(10-1)Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridine- 3-yl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (10-1)
将化合物Int 2(200mg，0.38mmol)，5-1(95mg，0.58mmol)，Pd(OAc) 2(9mg，0.04mmol)，xantphos(22mg，0.04mmol)和碳酸铯(313mg，0.96mmol)溶解在甲苯(8mL)溶液中，在氮气保护下，100℃搅拌过夜。反应完全后，加入乙酸乙酯(20mL)稀释，用饱和食盐水(20mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩，通过柱层析(PE/EA＝1:1)纯化得到150mg黄色油状化合物，产率43.73％。 Compound Int 2 (200 mg, 0.38 mmol), 5-1 (95 mg, 0.58 mmol), Pd(OAc) 2 (9 mg, 0.04 mmol), xantphos (22 mg, 0.04 mmol) and cesium carbonate (313 mg, 0.96 mmol) were dissolved In a solution of toluene (8 mL), under the protection of nitrogen, stir overnight at 100°C. After the reaction was complete, ethyl acetate (20 mL) was added to dilute, washed with saturated brine (20 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and passed column chromatography (PE/EA=1: 1) Purified to obtain 150 mg of yellow oily compound with a yield of 43.73%.
步骤2：合成1-(5-(2-氟苯基)-1-((5-(四氢-1H-呋喃并[3，4-c]吡咯-5(3H)-基)吡啶-3-基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(III-10)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridine-3 -yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III-10)
在室温下，将化合物10-1(150mg，0.27mmol)二氯甲烷(3mL)溶液中，加入4M盐酸/1，4-二氧六环(3mL)，搅拌两小时，待反应完全后，加入二氯甲烷20mL，水洗(10mL×3)。有机相过滤，滤液用无水硫酸钠干燥后浓缩，通过反相制备纯化得到20mg黄色固体化合物，产率9.76％，纯度>95％，[M+H] +:457.1。 At room temperature, add 4M hydrochloric acid/1,4-dioxane (3mL) to compound 10-1 (150mg, 0.27mmol) dichloromethane (3mL) solution, stir for two hours, after the reaction is complete, add Dichloromethane 20mL, washed with water (10mL×3). The organic phase was filtered, the filtrate was dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase preparation to obtain 20 mg of a yellow solid compound with a yield of 9.76%, a purity of >95%, and [M+H] + : 457.1.
1H NMR：(400MHz，CD 3OD)δ8.11(s，1H)，7.87(s，1H)，7.52-7.46(m，2H)，7.21-7.09(m，3H)，6.79(s，1H)，6.34(s，1H)，3.99-3.95(m，2H)，3.73-3.71(m，2H)，3.66(s，2H)，3.48-3.44(m，2H)，3.24-3.20(m，2H)，3.20-3.11(m，2H)，2.39(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ8.11(s, 1H), 7.87(s, 1H), 7.52-7.46(m, 2H), 7.21-7.09(m, 3H), 6.79(s, 1H ), 6.34(s, 1H), 3.99-3.95(m, 2H), 3.73-3.71(m, 2H), 3.66(s, 2H), 3.48-3.44(m, 2H), 3.24-3.20(m, 2H ), 3.20-3.11(m, 2H), 2.39(s, 3H).
实施例11Example 11
1-(1-((3-(3，3-二氟氮杂环丁烷-1-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-11)的合成1-(1-((3-(3,3-difluoroazetidin-1-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl Synthesis of )-N-methylmethylamine hydrochloride (III-11)
Figure PCTCN2022104528-appb-000030
Figure PCTCN2022104528-appb-000030
步骤1：合成1-(1-((3-(3，3-二氟氮杂环丁烷-1-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺(11-2)Step 1: Synthesis of 1-(1-((3-(3,3-difluoroazetidin-1-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole -3-yl)-N-methylmethylamine (11-2)
在室温下，向250mL的单口瓶中依次加入化合物Int 1(0.3g，0.57mmol)，化合物11-1(110mg，0.86mmol)，xantphos(29.00mg，0.05mmol)，Pd(OAc) 2(13.00mg，0.05mmol)，碳酸铯(446mg，1.43mmol)，甲苯(12mL)。氮气保护下，在110℃下反应过夜，反应完全后，过滤，滤饼用乙酸乙酯(10mL×2)洗涤，合并有机相，旋干，粗品柱层析分离纯化(PE/EA＝5:1)得到棕色油状物0.21g，产率84.0％，[M+H] +:436.1。 At room temperature, compound Int 1 (0.3g, 0.57mmol), compound 11-1 (110mg, 0.86mmol), xantphos (29.00mg, 0.05mmol), Pd(OAc) 2 (13.00 mg, 0.05mmol), cesium carbonate (446mg, 1.43mmol), toluene (12mL). Under nitrogen protection, react overnight at 110°C. After the reaction is complete, filter, wash the filter cake with ethyl acetate (10mL×2), combine the organic phases, spin dry, and separate and purify the crude product by column chromatography (PE/EA=5: 1) Obtain 0.21 g of brown oil, yield 84.0%, [M+H] + : 436.1.
步骤2：合成1-(1-((3-(3，3-二氟氮杂环丁烷-1-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-11)Step 2: Synthesis of 1-(1-((3-(3,3-difluoroazetidin-1-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole -3-yl)-N-methylmethylamine hydrochloride (III-11)
向25mL的单口瓶中加入化合物11-2(100mg，0.18mmol)，4M盐酸/1，4-二氧六环(1mL)和二氯甲烷(3mL))，室温下搅拌2h。待反应完成后，析出固体，过滤，收集固体，得到50mg黄色固体化合物，产率48％，[M+H] +:436.1。 Add compound 11-2 (100 mg, 0.18 mmol), 4M hydrochloric acid/1,4-dioxane (1 mL) and dichloromethane (3 mL)) into a 25 mL one-necked bottle, and stir at room temperature for 2 h. After the reaction was completed, a solid was precipitated, filtered, and collected to obtain 50 mg of a yellow solid compound with a yield of 48%, [M+H] + : 436.1.
1H NMR：(400MHz，CD 3OD)δ8.20(s，1H)，8.07(d，J＝2.0Hz，1H)，7.86(d，J＝1.6Hz，1H)，7.59-7.56(m，1H)，7.28-7.14(m，4H)，6.98(s，1H)，6.48(s，1H)，4.43(t，J＝1.6Hz4H)，4.37(s，2H)，2.73(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ8.20(s, 1H), 8.07(d, J=2.0Hz, 1H), 7.86(d, J=1.6Hz, 1H), 7.59-7.56(m, 1H), 7.28-7.14(m, 4H), 6.98(s, 1H), 6.48(s, 1H), 4.43(t, J=1.6Hz4H), 4.37(s, 2H), 2.73(s, 3H).
实施例12Example 12
1-(5-(2-氟苯基)-1-(异二氢吲哚-5-基磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(III-12)的合成1-(5-(2-fluorophenyl)-1-(isoindolin-5-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III-12) synthesis
Figure PCTCN2022104528-appb-000031
Figure PCTCN2022104528-appb-000031
步骤1：合成5-(苄硫基)异二氢吲哚-2-羧酸叔丁酯(12-3)Step 1: Synthesis of tert-butyl 5-(benzylthio)isoindoline-2-carboxylate (12-3)
在室温下，向250mL的单口瓶中依次加入化合物12-1(1.5g，5.03mmol)，12-2(1mL，6.04mmol)，xantphos(0.4g，1.7mmol)，Pd 2(dba) 3(0.3g，0.5mmol)，DIEA(2.5mL，13.26mmol)，甲苯(30mL)。氮气保护下，在135℃下反应过夜，反应完全后，过滤，滤饼用乙酸乙酯(50mL×2)洗涤，合并有机相，旋干，粗品柱层析分离纯化(PE/EA＝5:1)得到黄色稠状物化合物1.3g，产率75.04％。 At room temperature, compound 12-1 (1.5g, 5.03mmol), 12-2 (1mL, 6.04mmol), xantphos (0.4g, 1.7mmol), Pd 2 (dba) 3 ( 0.3 g, 0.5 mmol), DIEA (2.5 mL, 13.26 mmol), toluene (30 mL). Under the protection of nitrogen, react overnight at 135°C. After the reaction is complete, filter, wash the filter cake with ethyl acetate (50mL×2), combine the organic phases, spin dry, and separate and purify the crude product by column chromatography (PE/EA=5: 1) Obtain 1.3 g of compound in yellow thick substance, yield 75.04%.
步骤2：合成5-(氯磺酰基)异二氢吲哚-2-羧酸叔丁酯(12-4)Step 2: Synthesis of tert-butyl 5-(chlorosulfonyl)isoindoline-2-carboxylate (12-4)
在0℃下，向100mL的单口瓶中加入化合物12-3(1.3g，3.81mmol)，二氯海因(1.5g，7.6mmol)，乙酸(0.8mL)和水(0.8mL)，乙腈(13mL)。0℃下搅拌反应0.5h。待反应完全后，将反应液倒入冰水(100mL)中，乙酸乙酯(50mL×3)萃取，合并有机相用饱和食盐水(100mL×1)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩，得到黄色油状物化合物0.6g，产率：49.53％。At 0°C, compound 12-3 (1.3g, 3.81mmol), dichlorohydantoin (1.5g, 7.6mmol), acetic acid (0.8mL) and water (0.8mL), acetonitrile ( 13mL). The reaction was stirred at 0°C for 0.5h. After the reaction was complete, the reaction solution was poured into ice water (100 mL), extracted with ethyl acetate (50 mL×3), the combined organic phase was washed with saturated brine (100 mL×1), and the organic phase was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, 0.6 g of compound in yellow oil was obtained, yield: 49.53%.
步骤3：合成5-(((4-((叔丁氧基羰基)(甲基)氨基)甲基)-2-(2-氟苯基)-1H-吡咯-1-基)磺酰基)异二氢吲哚-2-羧酸叔丁酯(12-5)Step 3: Synthesis of 5-(((4-((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl) tert-butyl isoindoline-2-carboxylate (12-5)
在室温下，向25mL的单口瓶中加入NaH(26.13mg，0.65mmol，纯度：60％)，化合物Int 1-3(115mg，0.33mmol)和四氢呋喃(5mL)，室温搅拌半小时，然后加入化合物12-4(0.1g，0.32mmol)，继续搅拌2小时，待反应完成后，加入饱和氯化铵的水溶液(10mL)淬灭反应，用乙酸乙酯(10mL×2)萃取，合并有机相用饱和食盐水(10mL×1)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩，通过柱层析(DCM/MeOH＝20:1)得到黄色固体化 合物0.1g，产率51.13％。At room temperature, NaH (26.13mg, 0.65mmol, purity: 60%), compound Int 1-3 (115mg, 0.33mmol) and tetrahydrofuran (5mL) were added to a 25mL single-necked bottle, stirred at room temperature for half an hour, and then the compound 12-4 (0.1g, 0.32mmol), continue to stir for 2 hours, after the reaction is complete, add saturated aqueous ammonium chloride solution (10mL) to quench the reaction, extract with ethyl acetate (10mL×2), combine the organic phases for Washed with saturated brine (10 mL×1), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 0.1 g of yellow solid compound was obtained by column chromatography (DCM/MeOH=20:1), with a yield of 51.13%.
步骤4：合成1-(5-(2-氟苯基)-1-(异二氢吲哚-5-基磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(III-12)Step 4: Synthesis of 1-(5-(2-fluorophenyl)-1-(isoindolin-5-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III -12)
向25mL的单口瓶中加入化合物12-5(100mg，0.17mmol)和4M盐酸/1，4-二氧六环(0.3mL)，二氯甲烷(1mL)继续搅拌2小时，析出固体，过滤，收集固体，减压浓缩干燥，得到50mg淡紫色固体化合物，产率75％，纯度>95％，[M+H] +:457.1。 Compound 12-5 (100mg, 0.17mmol) and 4M hydrochloric acid/1,4-dioxane (0.3mL) were added to a 25mL single-necked bottle, dichloromethane (1mL) was stirred for 2 hours, a solid precipitated, filtered, The solid was collected, concentrated and dried under reduced pressure to obtain 50 mg of a lavender solid compound with a yield of 75%, a purity of >95%, and [M+H] + : 457.1.
1H NMR：(400MHz，CDCl 3)δ7.82(s，1H)，7.58-7.50(m，4H)，7.23-7.20(m，1H)，7.15-7.10(m，2H)，6.43(s，1H)，4.66(s，2H)，4.62(s，2H)，4.12(s，2H)，2.72(s，3H). 1 H NMR: (400MHz, CDCl 3 ) δ7.82(s, 1H), 7.58-7.50(m, 4H), 7.23-7.20(m, 1H), 7.15-7.10(m, 2H), 6.43(s, 1H), 4.66(s, 2H), 4.62(s, 2H), 4.12(s, 2H), 2.72(s, 3H).
实施例13Example 13
1-(5-(2-氟苯基)-1-((3-(5-氟吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-13)的合成1-(5-(2-fluorophenyl)-1-((3-(5-fluoropyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethyl Synthesis of Amine Hydrochloride (III-13)
Figure PCTCN2022104528-appb-000032
Figure PCTCN2022104528-appb-000032
步骤1：合成叔丁基((5-(2-氟苯基)-1-((3-(5-氟吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(13-2)Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(5-fluoropyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl) Methyl)(methyl)carbamate (13-2)
在室温下，将化合Int 1(200mg，0.38mmol)，13-1(81mg，0.57mmol)，Pd(dppf)Cl 2(28mg，0.04mmol)和碳酸钾(133mg，0.96mmol)溶解在二氧六环/水(5/1mL)中，在氮气保护下，100℃下搅拌过夜。冷却到室温，加水(20mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝1:1)得到无色油状化合物155mg，产率75.56％，[M+H] +:540.2。 Compounds Int 1 (200 mg, 0.38 mmol), 13-1 (81 mg, 0.57 mmol), Pd(dppf)Cl 2 (28 mg, 0.04 mmol) and potassium carbonate (133 mg, 0.96 mmol) were dissolved in dioxygen at room temperature Hexane/water (5/1 mL), stirred overnight at 100°C under nitrogen protection. Cool to room temperature, add water (20 mL), extract with ethyl acetate (15 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=1 : 1) Obtained 155 mg of colorless oily compound, yield 75.56%, [M+H] + : 540.2.
步骤2：合成1-(5-(2-氟苯基)-1-((3-(5-氟吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-13)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-fluoropyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N -Methylmethylamine hydrochloride (III-13)
在室温下，将化合物13-2(155mg，0.28mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。加无水乙醚(5mL)稀释，析出白色固体，过滤干燥得到目标化合物13mg，产率9.44％，纯度>95％，[M+H] +:440.2。 Compound 13-2 (155 mg, 0.28 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. Diluted with anhydrous diethyl ether (5 mL), a white solid was precipitated, filtered and dried to obtain 13 mg of the target compound, with a yield of 9.44%, a purity of >95%, and [M+H] + : 440.2.
1H NMR：(400MHz，CD 3OD)δ8.84(s，1H)，8.82(s，1H)，8.29(d，J＝9.2Hz，1H)，8.10(d，J＝8.0Hz，1H)，7.88(s，1H)，7.76(s，1H)，7.74-7.66(m，2H)，7.47-7.44(m，1H)， 7.16-7.14(m，2H)，7.06(t，J＝8.4Hz，1H)，6.44(s，1H)，4.12(s，2H)，2.72(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ8.84(s, 1H), 8.82(s, 1H), 8.29(d, J=9.2Hz, 1H), 8.10(d, J=8.0Hz, 1H) , 7.88(s, 1H), 7.76(s, 1H), 7.74-7.66(m, 2H), 7.47-7.44(m, 1H), 7.16-7.14(m, 2H), 7.06(t, J=8.4Hz , 1H), 6.44(s, 1H), 4.12(s, 2H), 2.72(s, 3H).
实施例14Example 14
1-(5-(2-氟苯基)-1-((3-(吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺三氟乙酸盐(III-14)的合成1-(5-(2-fluorophenyl)-1-((3-(pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine trifluoro Synthesis of Acetate (III-14)
Figure PCTCN2022104528-appb-000033
Figure PCTCN2022104528-appb-000033
步骤1：合成叔丁基((5-(2-氟苯基)-1-((3-(吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(14-2)Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl) (Methyl) carbamate (14-2)
在室温下，将化合物Int 1(200mg，0.38mmol)，14-1(71mg，0.57mmol)，Pd(dppf)Cl 2(28mg，0.04mmol)和碳酸钾(133mg，0.96mmol)溶解1，4-二氧六环/水(5/1mL)中，在氮气保护下，100℃下搅拌过夜。冷却到室温，加水(20mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝1:1)得到无色油状化合物150mg，产率75.26％，[M+H] +:522.2。 Compound Int 1 (200 mg, 0.38 mmol), 14-1 (71 mg, 0.57 mmol), Pd(dppf)Cl 2 (28 mg, 0.04 mmol) and potassium carbonate (133 mg, 0.96 mmol) were dissolved at room temperature 1,4 - In dioxane/water (5/1 mL), under nitrogen protection, stir overnight at 100°C. Cool to room temperature, add water (20 mL), extract with ethyl acetate (15 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=1 : 1) 150 mg of colorless oily compound was obtained, yield 75.26%, [M+H] + : 522.2.
步骤2：合成1-(5-(2-氟苯基)-1-((3-(吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺三氟乙酸盐(III-14)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methyl Methylamine trifluoroacetate (III-14)
在室温下，将化合物14-2(150mg，0.28mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)，室温搅拌2h。加水(5mL)稀释，调节pH＝8，二氯甲烷(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，反相制备(5-100％乙腈/水(0.1％TFA))纯化得到白色固体60mg，产率39.21％，纯度>95％，[M+H] +:422.2。 Compound 14-2 (150 mg, 0.28 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (2 mL), and stirred at room temperature for 2 h. Dilute with water (5 mL), adjust pH=8, extract with dichloromethane (15 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, reverse phase preparation (5-100% acetonitrile/ Water (0.1% TFA)) was purified to obtain 60 mg of white solid, yield 39.21%, purity >95%, [M+H] + : 422.2.
1H NMR：(400MHz，CD 3OD)δ8.93-8.89(m，1H)，8.80-7.78(m，1H)，8.47-8.37(m，1H)，8.09-8.07(m，1H)，7.94-7.89(m，1H)，7.85(s，1H)，7.78-7.65(m，3H)，7.46-7.40(m，1H)，7.16-7.13(m，2H)，7.04(t，J＝8.4Hz，1H)，6.43(s，1H)，4.12(s，2H)，2.72(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ8.93-8.89(m, 1H), 8.80-7.78(m, 1H), 8.47-8.37(m, 1H), 8.09-8.07(m, 1H), 7.94 -7.89(m, 1H), 7.85(s, 1H), 7.78-7.65(m, 3H), 7.46-7.40(m, 1H), 7.16-7.13(m, 2H), 7.04(t, J=8.4Hz , 1H), 6.43(s, 1H), 4.12(s, 2H), 2.72(s, 3H).
实施例15Example 15
1-(5-(2-氟苯基)-1-((3-(呋喃-2-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺三氟乙酸盐(III-15) 的合成1-(5-(2-fluorophenyl)-1-((3-(furan-2-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine trifluoro Synthesis of Acetate (III-15)
Figure PCTCN2022104528-appb-000034
Figure PCTCN2022104528-appb-000034
步骤1：合成叔丁基((5-(2-氟苯基)-1-((3(呋喃-2-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(15-2)Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3(furan-2-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)( Methyl) carbamate (15-2)
在室温下，将化合物Int 1(200mg，0.38mmol)，15-1(65mg，0.573mmol)，Pd(dppf) 2Cl 2·CH 2Cl 2(32mg，0.038mmol)和碳酸钾(132mg，0.955mmol)溶解在1，4-二氧六环和水(7.2mL，5/1)溶液中，氮气保护下，100℃反应2小时，反应完全后，过滤，滤液通过减压浓缩，残余物硅胶柱层析分离纯化(PE/EA＝5:1)得到白色固体150mg，产率77.3％。 Compound Int 1 (200 mg, 0.38 mmol), 15-1 (65 mg, 0.573 mmol), Pd(dppf) 2 Cl 2 · CH 2 Cl 2 (32 mg, 0.038 mmol) and potassium carbonate (132 mg, 0.955 mmol) was dissolved in 1,4-dioxane and water (7.2mL, 5/1) solution, under nitrogen protection, reacted at 100°C for 2 hours, after the reaction was complete, filtered, the filtrate was concentrated under reduced pressure, and the residue was silica gel Separation and purification by column chromatography (PE/EA=5:1) gave 150 mg of a white solid with a yield of 77.3%.
步骤2：合成1-(5-(2-氟苯基)-1-((3-(呋喃-2-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺三氟乙酸盐(III-15)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(furan-2-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methyl Methylamine trifluoroacetate (III-15)
在室温下，将化合物15-2(150mg，0.294mmol)溶于1，4-二氧六环(3mL)中，加入4M盐酸/1，4-二氧六环(3mL，12.0mmol)，室温反应1小时，减压浓缩，加水(10mL)，用饱和碳酸氢钠溶液调节pH到8，用乙酸乙酯萃取(20mL×2)，合并有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液通过减压浓缩，残余物反向柱分离纯化(5-100％乙腈/水(0.1％TFA))得到黄色油状物30mg，产率19.5％，纯度>95％，[M+H] +:411.3。 At room temperature, compound 15-2 (150 mg, 0.294 mmol) was dissolved in 1,4-dioxane (3 mL), added 4M hydrochloric acid/1,4-dioxane (3 mL, 12.0 mmol), and React for 1 hour, concentrate under reduced pressure, add water (10 mL), adjust pH to 8 with saturated sodium bicarbonate solution, extract with ethyl acetate (20 mL×2), combine organic phases and wash with saturated brine (20 mL), anhydrous sulfuric acid Sodium-dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse column separation (5-100% acetonitrile/water (0.1% TFA)) to obtain 30 mg of yellow oil, with a yield of 19.5%, a purity of >95%, [M +H] + :411.3.
1HNMR：(400MHz，CDCl 3)δ9.18(s，2H)，7.83-7.81(m，1H)，7.62(d，J＝1.6Hz，1H)，7.56(s，1H)，7.48(d，J＝1.2Hz，1H)，7.41-7.35(m，2H)，7.31-7.29(m，1H)，7.11-7.06(m，2H)，6.96(t，J＝8.8Hz，1H)，6.62(d，J＝3.2Hz，1H)，6.50-6.48(m，1H)，6.30(d，J＝2.0Hz，1H)，4.00(s，2H)，2.61(t，J＝4.8Hz，3H). 1 HNMR: (400MHz, CDCl 3 ) δ9.18(s, 2H), 7.83-7.81(m, 1H), 7.62(d, J=1.6Hz, 1H), 7.56(s, 1H), 7.48(d, J=1.2Hz, 1H), 7.41-7.35(m, 2H), 7.31-7.29(m, 1H), 7.11-7.06(m, 2H), 6.96(t, J=8.8Hz, 1H), 6.62(d , J=3.2Hz, 1H), 6.50-6.48(m, 1H), 6.30(d, J=2.0Hz, 1H), 4.00(s, 2H), 2.61(t, J=4.8Hz, 3H).
实施例16Example 16
1-(5-(2-氟苯基)-1-((5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺三氟乙酸盐(III-16)的合成1-(5-(2-fluorophenyl)-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)sulfonyl)-1H-pyrrole-3- Synthesis of -N-methylmethylamine trifluoroacetate (III-16)
Figure PCTCN2022104528-appb-000035
Figure PCTCN2022104528-appb-000035
步骤1：合成叔丁基((5-(2-氟苯基)-1-((5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)磺酰基)-1H-吡咯-3-基)甲基))(甲基)氨基甲酸酯(16-2)Step 1: Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)sulfonyl)- 1H-pyrrol-3-yl)methyl))(methyl)carbamate (16-2)
在室温下，将化合Int 2(500mg，0.95mmol)，6-1(209mg，1.43mmol)，Pd(dppf)Cl 2(70mg，0.09mmol)和碳酸钾(330mg，2.38mmol)溶解1，4-二氧六环/水(10/2mL)中，在氮气保护下，100℃下搅拌过夜。冷却到室温，加水(30mL)，用乙酸乙酯(30mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(DCM/MeOH＝20:1)得到无色油状化合物480mg，产率95.78％，[M+H] +:526.2。 Compound Int 2 (500 mg, 0.95 mmol), 6-1 (209 mg, 1.43 mmol), Pd(dppf)Cl 2 (70 mg, 0.09 mmol) and potassium carbonate (330 mg, 2.38 mmol) were dissolved at room temperature 1,4 - In dioxane/water (10/2mL), under nitrogen protection, stir overnight at 100°C. Cool to room temperature, add water (30 mL), extract with ethyl acetate (30 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (DCM/MeOH=20 : 1) Obtain 480 mg of colorless oily compound, yield 95.78%, [M+H] + : 526.2.
步骤2：1-(5-(2-氟苯基)-1-((5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺三氟乙酸盐(III-16)Step 2: 1-(5-(2-fluorophenyl)-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)sulfonyl)-1H-pyrrole -3-yl)-N-methylmethylamine trifluoroacetate (III-16)
在室温下，将化合物16-2(450mg，0.86mmol)溶解在DCM(4mL)溶液中，然后加入4M盐酸/1，4-二氧六环(4mL)室温搅拌2h。加水(10mL)稀释，调节pH＝8，二氯甲烷(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，反相制备(TFA/H 2O/MeCN)纯化得到白色固体380mg，产率82.61％，纯度>95％，[M+H] +:426.2。 Compound 16-2 (450 mg, 0.86 mmol) was dissolved in DCM (4 mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (4 mL) and stirred at room temperature for 2 h. Dilute with water (10 mL), adjust pH=8, extract with dichloromethane (15 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, reverse phase preparation (TFA/H 2 O/ MeCN) was purified to obtain 380 mg of white solid, yield 82.61%, purity>95%, [M+H] + : 426.2.
1H NMR：(400MHz，CD 3OD)δ9.03(s，1H)，8.41(s，1H)，8.14(s，1H)，7.88-7.83(m，3H)，7.52-7.49(m，1H)，7.23-7.15(m，2H)，7.08(t，J＝8.8Hz，1H)，6.45(s，1H)，4.12(s，2H)，3.98(s，3H)，2.72(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ9.03(s, 1H), 8.41(s, 1H), 8.14(s, 1H), 7.88-7.83(m, 3H), 7.52-7.49(m, 1H ), 7.23-7.15(m, 2H), 7.08(t, J=8.8Hz, 1H), 6.45(s, 1H), 4.12(s, 2H), 3.98(s, 3H), 2.72(s, 3H) .
实施例17Example 17
1-(5-(2-氟苯基)-1-((3-(噻吩-2-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-17)的合成1-(5-(2-fluorophenyl)-1-((3-(thiophen-2-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride Synthesis of Salt (III-17)
Figure PCTCN2022104528-appb-000036
Figure PCTCN2022104528-appb-000036
步骤1：合成((5-(2-氟苯基)-1-((3-(噻吩-2-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯(17-2)Step 1: Synthesis of ((5-(2-fluorophenyl)-1-((3-(thiophen-2-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl ) tert-butyl carbamate (17-2)
在室温下，将化合物Int 1(100mg，191.05μmol)，化合物17-1(36.67mg，386.58μmol)，Pd(dppf) 2Cl 2(0.1g，86.58μmol)和碳酸钾(66.01mg，477.63μmol)溶解在1,4-二氧六环/水(5/1mL)中，氮气保护下，80℃反应过夜，反应完全后，加水(8mL)，用乙酸乙酯(10mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到黄色稠状固体80mg，产率79.51％，[M+H] +:527.1。 Compound Int 1 (100 mg, 191.05 μmol), Compound 17-1 (36.67 mg, 386.58 μmol), Pd(dppf) 2 Cl 2 (0.1 g, 86.58 μmol) and potassium carbonate (66.01 mg, 477.63 μmol) were mixed at room temperature ) was dissolved in 1,4-dioxane/water (5/1mL), and reacted overnight at 80°C under nitrogen protection. After the reaction was complete, water (8mL) was added, extracted with ethyl acetate (10mL×2), and combined The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, separated and purified by column chromatography (PE/EA=3:1) to obtain 80 mg of a yellow thick solid, with a yield of 79.51%, [M+H] + :527.1.
步骤2：合成1-(5-(2-氟苯基)-1-((3-(噻吩-2-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-17)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(thiophen-2-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methyl Methylamine hydrochloride (III-17)
在室温下，向10mL的单口瓶中加入化合物17-2(80mg，151.91μmol)，4M盐酸/1，4-二氧六环(1mL，4N)，二氯甲烷(2mL)。室温下搅拌反应2小时。反应完全后，减压浓缩除去溶剂。加入二氯甲烷(1mL)溶清后，搅拌下加入乙醚(2mL)，室温下搅拌0.5小时，类紫色固体析出，过滤，收集固体，减压干燥得到类紫色固体40mg，产率57.12％，纯度>95％，[M+H] +:427.5。 Compound 17-2 (80 mg, 151.91 μmol), 4M hydrochloric acid/1,4-dioxane (1 mL, 4N), and dichloromethane (2 mL) were added to a 10 mL one-necked bottle at room temperature. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. After dichloromethane (1 mL) was added to dissolve it, diethyl ether (2 mL) was added with stirring, and stirred at room temperature for 0.5 hours, a violet-like solid precipitated, filtered, the solid was collected, and dried under reduced pressure to obtain 40 mg of a violet-like solid with a yield of 57.12%. >95%, [M+H] + : 427.5.
1H NMR：(400MHz，CD 3OD)δ7.99-7.97(m，1H)，7.82(d，J＝2.0Hz，1H)，7.68-7.67(m，1H)，7.59-7.56(m，2H)，7.54-7.52(m，1H)，7.47-7.42(m，2H)，7.37-7.35(m，1H)，7.14-7.03(m，3H)，6.40(s，1H)，4.11(s，2H)，2.70(s，3H) 1 H NMR: (400MHz, CD 3 OD) δ7.99-7.97(m, 1H), 7.82(d, J=2.0Hz, 1H), 7.68-7.67(m, 1H), 7.59-7.56(m, 2H ), 7.54-7.52(m, 1H), 7.47-7.42(m, 2H), 7.37-7.35(m, 1H), 7.14-7.03(m, 3H), 6.40(s, 1H), 4.11(s, 2H ), 2.70(s, 3H)
实施例18Example 18
1-(1-((3-(3，5-二甲基异恶唑-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-18)的合成1-(1-((3-(3,5-Dimethylisoxazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl) Synthesis of -N-Methylmethylamine Hydrochloride (III-18)
Figure PCTCN2022104528-appb-000037
Figure PCTCN2022104528-appb-000037
步骤1：合成叔丁基((1-((3-(3，5-二甲基异恶唑-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(18-2)Step 1: Synthesis of tert-butyl((1-((3-(3,5-dimethylisoxazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H- Pyrrol-3-yl)methyl)(methyl)carbamate (18-2)
在室温下，将化合Int 1(200mg，0.38mmol)，18-1(128mg，0.57mmol)，Pd(dppf)Cl 2(28mg，0.04mmol)和碳酸钾(132mg，0.95mmol)溶解1,4-二氧六环/水(5/1mL)中，在氮气保护下，100℃下搅拌过夜。冷却到室温，加水(10mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到无色油状化合物150mg，产率72.82％，[M+H] +:540.2。 Compound Int 1 (200 mg, 0.38 mmol), 18-1 (128 mg, 0.57 mmol), Pd(dppf)Cl 2 (28 mg, 0.04 mmol) and potassium carbonate (132 mg, 0.95 mmol) were dissolved at room temperature 1,4 - In dioxane/water (5/1 mL), under nitrogen protection, stir overnight at 100°C. Cool to room temperature, add water (10 mL), extract with ethyl acetate (15 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=3 : 1) Obtain 150 mg of colorless oily compound, yield 72.82%, [M+H] + : 540.2.
步骤2：1-(1-((3-(3，5-二甲基异恶唑-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-18)Step 2: 1-(1-((3-(3,5-Dimethylisoxazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3 -yl)-N-methylmethylamine hydrochloride (III-18)
在室温下，将化合物18-2(150mg，0.28mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。过滤，得到棕色固体80mg，产率60.61％，纯度>95％，[M+H] +:440.2。 Compound 18-2 (150 mg, 0.28 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. After filtration, 80 mg of brown solid was obtained, the yield was 60.61%, the purity was >95%, [M+H] + : 440.2.
1H NMR：(400MHz，CD 3OD)δ7.84(s，1H)，7.71-7.68(m，1H)，7.61(t，J＝7.6Hz，1H)，7.52-7.49(m，1H)，7.45-7.42(m，1H)，7.32(s，1H)，7.16-7.14(m，2H)，7.01(t，J＝8.8Hz，1H)，6.44(m，1H)，4.12(s，2H)，2.74(s，3H)，2.37(s，3H)，2.20(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ7.84(s, 1H), 7.71-7.68(m, 1H), 7.61(t, J=7.6Hz, 1H), 7.52-7.49(m, 1H), 7.45-7.42(m, 1H), 7.32(s, 1H), 7.16-7.14(m, 2H), 7.01(t, J=8.8Hz, 1H), 6.44(m, 1H), 4.12(s, 2H) , 2.74(s, 3H), 2.37(s, 3H), 2.20(s, 3H).
实施例19Example 19
1-(1-((3-(3-氧杂-9-氮杂螺[5.5]十一碳-9-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-19)的合成1-(1-((3-(3-Oxa-9-azaspiro[5.5]undec-9-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H- Synthesis of pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-19)
Figure PCTCN2022104528-appb-000038
Figure PCTCN2022104528-appb-000038
步骤1：合成叔丁基((1-((3-(3-氧杂-9-氮杂螺[5.5]十一碳-9-基)苯基)磺酰基)-5-(2-氟-苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸甲酯(19-2)Step 1: Synthesis of tert-butyl((1-((3-(3-oxa-9-azaspiro[5.5]undec-9-yl)phenyl)sulfonyl)-5-(2-fluoro -Phenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (19-2)
在室温下，将化合物Int 1(200mg，0.382mmol)，19-1(110mg，0.573mmol)，Pd(OAc) 2(9mg，0.038mmol)，xantphos(45mg，0.076mmol)和碳酸铯(374mg，1.15mmol)加入至甲苯(4mL)中，氮气保护下，100℃反应2小时，反应完全后，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝5:1)得到白色固体170mg，产率74.4％，[M+H] +:598.9。 Compound Int 1 (200 mg, 0.382 mmol), 19-1 (110 mg, 0.573 mmol), Pd(OAc) 2 (9 mg, 0.038 mmol), xantphos (45 mg, 0.076 mmol) and cesium carbonate (374 mg, 1.15mmol) was added to toluene (4mL), under the protection of nitrogen, reacted at 100°C for 2 hours, after the reaction was complete, filtered, the filtrate was concentrated under reduced pressure, separated and purified by column chromatography (PE/EA=5:1) to obtain a white solid 170 mg, yield 74.4%, [M+H] + : 598.9.
步骤2：合成1-(1-((3-(3-氧杂-9-氮杂螺[5.5]十一碳-9-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-19)Step 2: Synthesis of 1-(1-((3-(3-oxa-9-azaspiro[5.5]undec-9-yl)phenyl)sulfonyl)-5-(2-fluorophenyl )-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-19)
在室温下，将化合物19-2(170mg，0.284mmol)溶于1，4-二氧六环(3mL)中，加入4M盐酸/1，4-二氧六环(3mL)，室温反应1小时。减压浓缩，用二氯甲烷溶解，减压浓缩得到灰色固体50mg，产率32.9％，纯度>95％，[M+H] +:498.9。 Dissolve compound 19-2 (170 mg, 0.284 mmol) in 1,4-dioxane (3 mL) at room temperature, add 4M hydrochloric acid/1,4-dioxane (3 mL), and react at room temperature for 1 hour . Concentrate under reduced pressure, dissolve with dichloromethane, and concentrate under reduced pressure to obtain 50 mg of a gray solid with a yield of 32.9%, a purity of >95%, and [M+H] + : 498.9.
1H NMR：(400MHz，CDCl 3)δ10.11(s，2H)，8.24(s，1H)，7.82(s，1H)，7.70(s，1H)，7.50(s，1H)，7.35(br s，2H)，7.04-6.98(m，3H)，6.72(s，1H)，3.97(s，2H)，3.70(br s，12H)，2.74(s，3H)，2.17(br s，4H). 1 H NMR: (400MHz, CDCl 3 ) δ10.11(s, 2H), 8.24(s, 1H), 7.82(s, 1H), 7.70(s, 1H), 7.50(s, 1H), 7.35(br s, 2H), 7.04-6.98 (m, 3H), 6.72 (s, 1H), 3.97 (s, 2H), 3.70 (br s, 12H), 2.74 (s, 3H), 2.17 (br s, 4H) .
实施例20Example 20
1-(1-((5-(1-(二氟甲基)-1H-吡唑-4-基)吡啶-3-基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺2，2，2-三氟乙酸盐(III-20)的合成1-(1-((5-(1-(Difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H- Synthesis of pyrrol-3-yl)-N-methylmethylamine 2,2,2-trifluoroacetate (III-20)
Figure PCTCN2022104528-appb-000039
Figure PCTCN2022104528-appb-000039
步骤1：合成叔丁基((1-((5-(1-(二氟甲基)-1H-吡唑-4-基)吡啶-3-基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基))甲基)(甲基)氨基甲酸酯(20-2)Step 1: Synthesis of tert-butyl((1-((5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)sulfonyl)-5-(2-fluoro Phenyl)-1H-pyrrol-3-yl))methyl)(methyl)carbamate (20-2)
在室温下，将化合Int 2(200mg，0.38mmol)，20-1(140mg，0.57mmol)，Pd(dppf)Cl 2(28mg，0.04mmol)和碳酸钾(132mg，0.95mmol)溶解在1,4-二氧六环/水(5/1mL)中，在氮气保护下，110℃下搅拌4h。冷却到室温，加水(20mL)，用乙酸乙酯(15mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到无色油状化合物180mg，产率80.04％，[M+H] +:562.2。 Compound Int 2 (200 mg, 0.38 mmol), 20-1 (140 mg, 0.57 mmol), Pd(dppf)Cl 2 (28 mg, 0.04 mmol) and potassium carbonate (132 mg, 0.95 mmol) were dissolved in 1, In 4-dioxane/water (5/1 mL), under nitrogen protection, stir at 110° C. for 4 h. Cool to room temperature, add water (20 mL), extract with ethyl acetate (15 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=3 : 1) Obtained 180 mg of colorless oily compound, yield 80.04%, [M+H] + : 562.2.
步骤2：合成1-(1-((5-(1-(二氟甲基)-1H-吡唑-4-基)吡啶-3-基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺2，2，2-三氟乙酸盐(III-20)Step 2: Synthesis of 1-(1-((5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)sulfonyl)-5-(2-fluorophenyl )-1H-pyrrol-3-yl)-N-methylmethylamine 2,2,2-trifluoroacetate (III-20)
在室温下，将化合物20-2(180mg，0.39mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。减压浓缩，通过反相制备纯化得到白色固体80mg(流动相包含三氟乙酸)，产率43.48％，纯度>95％，[M+H] +:462.1。 Compound 20-2 (180 mg, 0.39 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. Concentrated under reduced pressure, purified by reverse phase preparation to obtain 80 mg of white solid (mobile phase contains trifluoroacetic acid), yield 43.48%, purity >95%, [M+H] + : 462.1.
1H NMR：(400MHz，CDCl 3)δ9.46(s，2H)，8.95(s，1H)，8.52(s，1H)，8.19(s，1H)，7.92(s，1H)，7.76(s，1H)，7.70(s，1H)，7.46-7.41(m，1H)，7.28-7.26(m，1H)，7.17-7.11(m，2H)，7.00(t，J＝9.2Hz，1H)，6.38(s，1H)，4.03(s，2H)，2.67(s，3H). 1 H NMR: (400MHz, CDCl 3 ) δ9.46(s, 2H), 8.95(s, 1H), 8.52(s, 1H), 8.19(s, 1H), 7.92(s, 1H), 7.76(s , 1H), 7.70(s, 1H), 7.46-7.41(m, 1H), 7.28-7.26(m, 1H), 7.17-7.11(m, 2H), 7.00(t, J=9.2Hz, 1H), 6.38(s, 1H), 4.03(s, 2H), 2.67(s, 3H).
实施例21Example 21
1-(5-(2-氟苯基)-1-((3-(5-甲氧基吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-21)的合成1-(5-(2-fluorophenyl)-1-((3-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methyl Synthesis of methylamine hydrochloride (III-21)
Figure PCTCN2022104528-appb-000040
Figure PCTCN2022104528-appb-000040
步骤1：合成叔丁基((5-(2-氟苯基)-1-((3-(5-甲氧基吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(21-2)Step 1: Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrole-3- Base) methyl) (methyl) carbamate (21-2)
在室温下，将化合Int 1(200mg，0.38mmol)，21-1(70mg，0.46mmol)，Pd(dppf)Cl 2(28mg，0.04mmol)和碳酸钾(132mg，0.95mmol)溶解在1,4-二氧六环/水(5/1mL)中，在氮气保护下，110℃下搅拌4h。冷却到室温，加水(20mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到无色油状化合物150mg，产率71.43％，[M+H] +:552.2。 Compound Int 1 (200 mg, 0.38 mmol), 21-1 (70 mg, 0.46 mmol), Pd(dppf)Cl 2 (28 mg, 0.04 mmol) and potassium carbonate (132 mg, 0.95 mmol) were dissolved in 1, In 4-dioxane/water (5/1 mL), under nitrogen protection, stir at 110° C. for 4 h. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=3 : 1) 150 mg of colorless oily compound was obtained, yield 71.43%, [M+H] + : 552.2.
步骤2：合成1-(5-(2-氟苯基)-1-((3-(5-甲氧基吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-21)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl) -N-Methylmethylamine hydrochloride (III-21)
在室温下，将化合物21-2(150mg，0.27mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。减压浓缩得到白色固体100mg，产率75.76％，纯度>95％，[M+H] +:452.1。 Compound 21-2 (150 mg, 0.27 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. Concentration under reduced pressure gave 100 mg of white solid, yield 75.76%, purity >95%, [M+H] + : 452.1.
1H NMR：(400MHz，CD 3OD)δ8.70(s，2H)，8.31(s，1H)，8.15(d，J＝7.6Hz，1H)， 7.90(s，1H)，7.83(s，1H)，7.77-7.69(m，2H)，7.48-7.45(s，1H)7.17-7.15(m，2H)，7.07(t，J＝9.2Hz，1H)，6.45(s，1H)，4.16(s，3H)，4.13(s，2H)，2.73(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ8.70(s, 2H), 8.31(s, 1H), 8.15(d, J=7.6Hz, 1H), 7.90(s, 1H), 7.83(s, 1H), 7.77-7.69(m, 2H), 7.48-7.45(s, 1H), 7.17-7.15(m, 2H), 7.07(t, J=9.2Hz, 1H), 6.45(s, 1H), 4.16( s, 3H), 4.13(s, 2H), 2.73(s, 3H).
实施例22Example 22
1-(5-(2，4-二氟苯基)-1-((3-(1-甲基-1H-吡唑-4-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺氢氯化物盐(III-22)的合成1-(5-(2,4-difluorophenyl)-1-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrole-3- Synthesis of -N-methylmethylamine hydrochloride salt (III-22)
Figure PCTCN2022104528-appb-000041
Figure PCTCN2022104528-appb-000041
步骤1：合成叔丁基((5-(2，4-二氟苯基)-1-((3-(1-甲基-1H-吡唑-4-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(22-1)Step 1: Synthesis of tert-butyl ((5-(2,4-difluorophenyl)-1-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)- 1H-pyrrol-3-yl)methyl)(methyl)carbamate (22-1)
在室温下，将化合物Int 3(200mg，0.37mmol)，6-1(100mg，0.48mmol)，Pd(dppf)Cl 2(27mg，0.04mmol)和碳酸钾(128mg，0.92mmol)溶解在1,4-二氧六环/水(5/1mL)中，在氮气保护下，110℃下搅拌4h。冷却到室温，加水(20mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到无色油状化合物150mg，产率74.83％，[M+H] +:543.2。 Compound Int 3 (200 mg, 0.37 mmol), 6-1 (100 mg, 0.48 mmol), Pd(dppf)Cl 2 (27 mg, 0.04 mmol) and potassium carbonate (128 mg, 0.92 mmol) were dissolved in 1, In 4-dioxane/water (5/1 mL), under nitrogen protection, stir at 110° C. for 4 h. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=3 : 1) Obtained 150 mg of colorless oily compound, yield 74.83%, [M+H] + : 543.2.
步骤2：合成1-(5-(2，4-二氟苯基)-1-((3-(1-甲基-1H-吡唑-4-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-22)Step 2: Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H- Pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-22)
在室温下，将化合物22-1(150mg，0.27mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。析出白色固体，过滤得到目标化合物56mg，产率45.78％，纯度>95％，[M+H] +:443.2。 Compound 22-1 (150 mg, 0.27 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. A white solid was precipitated, and 56 mg of the target compound was obtained by filtration, with a yield of 45.78%, a purity of >95%, and [M+H] + : 443.2.
1H NMR：(400MHz，DMSO-d 6)δ9.24(br，2H)，8.26(s，1H)，7.92(d，J＝8.0Hz，1H)，7.88(s，2H)，7.56-7.52(m，2H)，7.30-7.25(m，2H)，7.13-7.08(m，2H)，6.55(s，1H)，3.98(s，2H)，3.88(s，3H)，2.48(s，3H). 1 H NMR: (400MHz, DMSO-d 6 )δ9.24(br, 2H), 8.26(s, 1H), 7.92(d, J=8.0Hz, 1H), 7.88(s, 2H), 7.56-7.52 (m, 2H), 7.30-7.25(m, 2H), 7.13-7.08(m, 2H), 6.55(s, 1H), 3.98(s, 2H), 3.88(s, 3H), 2.48(s, 3H ).
实施例23Example 23
1-(5-(2，4-二氟苯基)-1-((3-(四氢-1H-呋喃[3，4-c]吡咯-5(3H)-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺三氟乙酸盐(III-23)的合成1-(5-(2,4-difluorophenyl)-1-((3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonyl Synthesis of )-1H-pyrrol-3-yl)-N-methylmethylamine trifluoroacetate (III-23)
Figure PCTCN2022104528-appb-000042
Figure PCTCN2022104528-appb-000042
步骤1：合成叔丁基((5-(2，4-二氟苯基)-1-((3-(四氢-1H-呋喃[3，4-c]吡咯-5(3H)-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(23-1)Step 1: Synthesis of tert-butyl ((5-(2,4-difluorophenyl)-1-((3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl )phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (23-1)
在室温下，将化合物Int 3(200mg，0.369mmol)溶于甲苯(4mL)，依次加入5-1(83mg，0.554mmol)，Pd(OAc) 2(9mg，0.037mmol)，xantphos(43mg，0.074mmol)和碳酸铯(361mg，1.11mmol)。N 2置换后将反应液密封，升温至120℃搅拌过夜。反应完全后，浓缩溶剂，柱层析分离纯化(PE/EA＝5:1-3:1)，得到黄色油状物100mg，产率47.19％，[M+H] +:574.7。 At room temperature, compound Int 3 (200 mg, 0.369 mmol) was dissolved in toluene (4 mL), and 5-1 (83 mg, 0.554 mmol), Pd(OAc) 2 (9 mg, 0.037 mmol), xantphos (43 mg, 0.074 mmol) and cesium carbonate (361 mg, 1.11 mmol). After N 2 replacement, the reaction solution was sealed, heated to 120°C and stirred overnight. After the reaction was complete, the solvent was concentrated and purified by column chromatography (PE/EA=5:1-3:1) to obtain 100 mg of yellow oil with a yield of 47.19%, [M+H] + : 574.7.
步骤2：合成1-(5-(2，4-二氟苯基)-1-((3-(四氢-1H-呋喃[3，4-c]吡咯-5(3H)-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺三氟乙酸盐(III-23)Step 2: Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzene Base)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine trifluoroacetate (III-23)
在室温下，将化合物23-1(100mg，0.262mmol)溶于1，4-二氧六环(3mL)中，加入4M盐酸/1，4-二氧六环(3mL)，室温反应1小时后，浓缩溶剂，粗品用反相柱分离纯化，得到无色油状物30mg，产率29.31％，纯度>95％，[M+H] +:474.5。 Dissolve compound 23-1 (100 mg, 0.262 mmol) in 1,4-dioxane (3 mL) at room temperature, add 4M hydrochloric acid/1,4-dioxane (3 mL), and react at room temperature for 1 hour Afterwards, the solvent was concentrated, and the crude product was separated and purified by a reverse-phase column to obtain 30 mg of a colorless oil, with a yield of 29.31%, a purity of >95%, and [M+H] + : 474.5.
1H NMR：(400MHz，DMSO-d 6)δ8.78(s，2H)，7.74(s，1H)，7.36-7.28(m，2H)，7.17-7.09(m，2H)，6.90-6.87(m，1H)，6.75-6.73(m，1H)，6.44-6.43(m，2H)，4.01-3.98(m，2H)，3.86-3.82(m，2H)，3.58-3.55(m，2H)，3.34-3.30(m，2H)，3.10-2.98(m，4H)，2.54-2.53(m，3H). 1 H NMR: (400MHz, DMSO-d 6 ) δ8.78(s, 2H), 7.74(s, 1H), 7.36-7.28(m, 2H), 7.17-7.09(m, 2H), 6.90-6.87( m, 1H), 6.75-6.73(m, 1H), 6.44-6.43(m, 2H), 4.01-3.98(m, 2H), 3.86-3.82(m, 2H), 3.58-3.55(m, 2H), 3.34-3.30(m, 2H), 3.10-2.98(m, 4H), 2.54-2.53(m, 3H).
实施例24Example 24
1-(5-(2-氟苯基)-1-((3-(呋喃-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺氯化氢盐(III-24)的合成1-(5-(2-fluorophenyl)-1-((3-(furan-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine hydrogen chloride salt Synthesis of (III-24)
Figure PCTCN2022104528-appb-000043
Figure PCTCN2022104528-appb-000043
步骤1：合成叔丁基((5-(2-氟苯基)-1-((3-(呋喃-3-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲 基)氨基甲酸酯(24-2)Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(furan-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl) (Methyl) carbamate (24-2)
在室温下，将化合物Int 1(200mg，0.38mmol)，24-1(64mg，0.57mmol)，Pd(dppf)Cl 2(28mg，0.04mmol)和碳酸钾(132mg，0.96mmol)溶解在1，4-二氧六环/水(5/1mL)中，在氮气保护下，110℃下搅拌4h。冷却到室温，加水(20mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到无色油状化合物150mg，产率76.89％，[M+H] +:511.2。 Compound Int 1 (200 mg, 0.38 mmol), 24-1 (64 mg, 0.57 mmol), Pd(dppf)Cl 2 (28 mg, 0.04 mmol) and potassium carbonate (132 mg, 0.96 mmol) were dissolved in 1 at room temperature. In 4-dioxane/water (5/1 mL), under nitrogen protection, stir at 110° C. for 4 h. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=3 : 1) Obtain 150 mg of colorless oily compound, yield 76.89%, [M+H] + : 511.2.
步骤2：合成1-(5-(2-氟苯基)-1-((3-(呋喃-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺氯化氢盐(III-24)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(furan-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methyl Methylamine Hydrochloride (III-24)
在室温下，将化合物24-2(150mg，0.29mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。析出白色固体，过滤得到目标化合物58mg，产率44.27％，纯度>95％，[M+H] +:412.2。 Compound 24-2 (150 mg, 0.29 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. A white solid was precipitated, and 58 mg of the target compound was obtained by filtration, with a yield of 44.27%, a purity of >95%, and [M+H] + : 412.2.
1H NMR：(400MHz，DMSO-d 6)δ9.15(br，2H)，8.28(s，1H)，7.98(d，J＝7.6Hz，1H)，7.87(s，1H)，7.81(s，1H)，7.60-7.56(m，2H)，7.52-7.50(m，1H)，7.33(d，J＝8.4Hz，1H)，7.24-7.18(m，2H)，7.07(t，J＝6.0Hz，1H)，6.93(s，1H)，6.53(s，1H)，3.99(s，2H)，2.49(s，3H). 1 H NMR: (400MHz, DMSO-d 6 )δ9.15(br, 2H), 8.28(s, 1H), 7.98(d, J=7.6Hz, 1H), 7.87(s, 1H), 7.81(s , 1H), 7.60-7.56(m, 2H), 7.52-7.50(m, 1H), 7.33(d, J=8.4Hz, 1H), 7.24-7.18(m, 2H), 7.07(t, J=6.0 Hz, 1H), 6.93(s, 1H), 6.53(s, 1H), 3.99(s, 2H), 2.49(s, 3H).
实施例25Example 25
1-(5-(2，4-二氟苯基)-1-((3-(呋喃-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-25)的合成1-(5-(2,4-difluorophenyl)-1-((3-(furan-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethyl Synthesis of Amine Hydrochloride (III-25)
Figure PCTCN2022104528-appb-000044
Figure PCTCN2022104528-appb-000044
步骤1：合成((5-(2，4-二氟苯基)-1-((3-(呋喃-3-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯(25-1)Step 1: Synthesis of ((5-(2,4-difluorophenyl)-1-((3-(furan-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl) (Methyl) tert-butyl carbamate (25-1)
在室温下，将化合物Int 3(200mg，0.37mmol)，24-1(62mg，0.56mmol)，Pd(dppf)Cl 2(27mg，0.04mmol)和碳酸钾(128mg，0.92mmol)溶解在1,4-二氧六环/水(5/1mL)中，在氮气保护下，110℃下搅拌4h。冷却到室温，加水(20mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/E A＝3:1)得到无色油状化合物150mg，产率76.82％，[M+H] +:529.1。 Compound Int 3 (200 mg, 0.37 mmol), 24-1 (62 mg, 0.56 mmol), Pd(dppf)Cl 2 (27 mg, 0.04 mmol) and potassium carbonate (128 mg, 0.92 mmol) were dissolved in 1, In 4-dioxane/water (5/1 mL), under nitrogen protection, stir at 110° C. for 4 h. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=3 : 1) 150 mg of colorless oily compound was obtained, yield 76.82%, [M+H] + : 529.1.
步骤2：合成1-(5-(2，4-二氟苯基)-1-((3-(呋喃-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-25)Step 2: Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(furan-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N -Methylmethylamine hydrochloride (III-25)
在室温下，将化合物25-1(150mg，0.28mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。析出白色固体，过滤得到目标化合物18mg，产率13.64％，纯度>95，[M+H] +:429.1。 Compound 25-1 (150 mg, 0.28 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. A white solid was precipitated, and 18 mg of the target compound was obtained by filtration, with a yield of 13.64%, a purity of >95, and [M+H] + : 429.1.
1H NMR：(400MHz，DMSO-d 6)δ9.10(br，2H)，8.31(s，1H)，7.99(d，J＝8.0Hz，1H)，7.88(s，1H)，7.82(s，1H)，7.62-7.58(m，2H)，7.33(d，J＝8.0Hz，1H)，7.07(t，J＝6.0Hz，1H)，7.12-7.09(m，2H)，6.95(s，1H)，6.53(s，1H)，3.99(s，2H)，2.49(s，3H). 1 H NMR: (400MHz, DMSO-d 6 )δ9.10(br, 2H), 8.31(s, 1H), 7.99(d, J=8.0Hz, 1H), 7.88(s, 1H), 7.82(s , 1H), 7.62-7.58(m, 2H), 7.33(d, J=8.0Hz, 1H), 7.07(t, J=6.0Hz, 1H), 7.12-7.09(m, 2H), 6.95(s, 1H), 6.53(s, 1H), 3.99(s, 2H), 2.49(s, 3H).
实施例26Example 26
1-(5-(2,4-二氟苯基)-1-((3-(5-甲氧基吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺三氟乙酸盐(III-26)的合成1-(5-(2,4-difluorophenyl)-1-((3-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)- Synthesis of N-Methylmethylamine Trifluoroacetate (III-26)
Figure PCTCN2022104528-appb-000045
Figure PCTCN2022104528-appb-000045
步骤1：合成((5-(2,4-二氟苯基)-1-((3-(5-甲氧基吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯(26-1)Step 1: Synthesis of ((5-(2,4-difluorophenyl)-1-((3-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrole-3- Base) methyl) (methyl) tert-butyl carbamate (26-1)
在室温下，将化合物Int 3(200mg，0.37mmol)，21-1(68mg，0.44mmol)，Pd(dppf)Cl 2(27mg，0.04mmol)和碳酸钾(128mg，0.92mmol)溶解在1,4-二氧六环/水(5/1mL)中，在氮气保护下，110℃下搅拌4h。冷却到室温，加水(20mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到无色油状化合物120mg，产率57.03％，[M+H] +:570.2。 Compound Int 3 (200 mg, 0.37 mmol), 21-1 (68 mg, 0.44 mmol), Pd(dppf)Cl 2 (27 mg, 0.04 mmol) and potassium carbonate (128 mg, 0.92 mmol) were dissolved in 1, In 4-dioxane/water (5/1 mL), under nitrogen protection, stir at 110° C. for 4 h. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=3 : 1) 120 mg of colorless oily compound was obtained, yield 57.03%, [M+H] + : 570.2.
步骤2：合成1-(5-(2,4-二氟苯基)-1-((3-(5-甲氧基吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺三氟乙酸盐(III-26)Step 2: Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrole-3 -yl)-N-methylmethylamine trifluoroacetate (III-26)
在室温下，将化合物26-1(150mg，0.28mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。浓缩，通过反相制备纯化得到26mg白色固体，产率21.31％，纯度>95％，[M+H] +:470.1。 Compound 26-1 (150 mg, 0.28 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. Concentrated and purified by reverse phase preparation to obtain 26 mg of white solid, yield 21.31%, purity >95%, [M+H] + : 470.1.
1HNMR：(400MHz，CD 3OD)δ8.64(br，2H)，8.19-8.12(m，2H)，7.89(s，1H)，7.82-7.80 (m，1H)，7.75(t，J＝8.0Hz，1H)，7.69(d，J＝7.6Hz，1H)，7.20-7.17(m，1H)，6.98-6.93(m，2H)，6.46(s，1H)，4.12(s，3H)，4.11(s，2H)，2.73(s，3H). 1 HNMR: (400MHz, CD 3 OD) δ8.64(br, 2H), 8.19-8.12(m, 2H), 7.89(s, 1H), 7.82-7.80 (m, 1H), 7.75(t, J= 8.0Hz, 1H), 7.69(d, J=7.6Hz, 1H), 7.20-7.17(m, 1H), 6.98-6.93(m, 2H), 6.46(s, 1H), 4.12(s, 3H), 4.11(s, 2H), 2.73(s, 3H).
实施例27Example 27
1-(1-((3-(2，3-二氢苯并呋喃-5-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-27)的合成1-(1-((3-(2,3-dihydrobenzofuran-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)- Synthesis of N-Methylmethylamine Hydrochloride (III-27)
Figure PCTCN2022104528-appb-000046
Figure PCTCN2022104528-appb-000046
步骤1：合成叔丁基((1-((3-(2，3-二氢苯并呋喃-5-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(27-2)Step 1: Synthesis of tert-butyl((1-((3-(2,3-dihydrobenzofuran-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole -3-yl)methyl)(methyl)carbamate (27-2)
在室温下，将化合物Int 1(200mg，0.38mmol)，27-1(75mg，0.46mmol)，Pd(dppf)Cl 2(27mg，0.04mmol)和碳酸钾(132mg，0.95mmol)溶解在1,4-二氧六环/水(5/1mL)中，在氮气保护下，110℃下搅拌4h。冷却到室温，加水(20mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到黄色油状化合物150mg，产率69.77％，[M+H] +:563.2。 Compound Int 1 (200 mg, 0.38 mmol), 27-1 (75 mg, 0.46 mmol), Pd(dppf)Cl 2 (27 mg, 0.04 mmol) and potassium carbonate (132 mg, 0.95 mmol) were dissolved in 1, In 4-dioxane/water (5/1 mL), under nitrogen protection, stir at 110° C. for 4 h. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=3 : 1) Obtain 150 mg of yellow oily compound, yield 69.77%, [M+H] + : 563.2.
步骤2：合成1-(1-((3-(2，3-二氢苯并呋喃-5-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-Step 2: Synthesis of 1-(1-((3-(2,3-dihydrobenzofuran-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3 -
基)-N-甲基甲胺盐酸盐(III-27)Base) -N-methylmethylamine hydrochloride (III-27)
在室温下，将化合物27-2(150mg，0.27mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。浓缩得到棕色化合物100mg，产率80.05％，纯度>95％，[M+H] +:463.2。 Compound 27-2 (150 mg, 0.27 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. Concentration gave 100 mg of brown compound, yield 80.05%, purity >95%, [M+H] + : 463.2.
1HNMR：(400MHz，CD 3OD)δ7.86(d，J＝8.0Hz，1H)，7.82(s，1H)，7.54-7.43(m，4H)，7.37(s，1H)，7.25(d，J＝8.0Hz，1H)，7.13-7.04(m，3H)，6.83(d，J＝8.0Hz，1H)，6.41(s，1H)，4.63(t，J＝8.8Hz，2H)，4.11(s，2H)，3.29(t，J＝8.8Hz，2H)，2.71(s，3H). 1 HNMR: (400MHz, CD 3 OD) δ7.86(d, J=8.0Hz, 1H), 7.82(s, 1H), 7.54-7.43(m, 4H), 7.37(s, 1H), 7.25(d , J=8.0Hz, 1H), 7.13-7.04(m, 3H), 6.83(d, J=8.0Hz, 1H), 6.41(s, 1H), 4.63(t, J=8.8Hz, 2H), 4.11 (s, 2H), 3.29(t, J=8.8Hz, 2H), 2.71(s, 3H).
实施例28Example 28
1-(1-((3-(1-(二氟甲基)-1H-吡唑-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-28)的合成1-(1-((3-(1-(Difluoromethyl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3 Synthesis of -yl)-N-methylmethylamine hydrochloride (III-28)
Figure PCTCN2022104528-appb-000047
Figure PCTCN2022104528-appb-000047
步骤1：合成叔丁基((1-((3-(1-(二氟甲基)-1H-吡唑-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(28-2)Step 1: Synthesis of tert-butyl((1-((3-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl) -1H-pyrrol-3-yl)methyl)(methyl)carbamate (28-2)
在室温下，将化合物Int 1(200mg，0.38mmol)，28-1(112mg，0.46mmol)，Pd(dppf)Cl 2(28mg，0.04mmol)和碳酸钾(132mg，0.95mmol)溶解在1,4-二氧六环/水(5/1mL)中，在氮气保护下，110℃下搅拌4h。冷却到室温，加水(20mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到无色油状化合物150mg，产率70.031％，[M+H] +:561.2。 Compound Int 1 (200 mg, 0.38 mmol), 28-1 (112 mg, 0.46 mmol), Pd(dppf)Cl 2 (28 mg, 0.04 mmol) and potassium carbonate (132 mg, 0.95 mmol) were dissolved in 1, In 4-dioxane/water (5/1 mL), under nitrogen protection, stir at 110° C. for 4 h. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=3 : 1) 150 mg of colorless oily compound was obtained, yield 70.031%, [M+H] + : 561.2.
步骤2：合成1-(1-((3-(1-(二氟甲基)-1H-吡唑-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-28)Step 2: Synthesis of 1-(1-((3-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H -pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-28)
在室温下，将化合物28-2(150mg，0.27mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。浓缩得到白色化合物100mg，产率75.19％，纯度>95％，[M+H] +:461.2。 Compound 28-2 (150 mg, 0.27 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. Concentration gave 100 mg of white compound, yield 75.19%, purity >95%, [M+H] + : 461.2.
1HNMR：(400MHz，CD 3OD)δ8.47(s，1H)，8.03(s，1H)，7.96(d，J＝8.0Hz，1H)，7.83(s，1H)，7.57(t，J＝82.8Hz，1H)，7.57-7.42(m，4H)，7.16-7.06(m，3H)，6.41(s，1H)，4.11(s，2H)，2.71(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ8.47(s, 1H), 8.03(s, 1H), 7.96(d, J=8.0Hz, 1H), 7.83(s, 1H), 7.57(t, J =82.8Hz, 1H), 7.57-7.42(m, 4H), 7.16-7.06(m, 3H), 6.41(s, 1H), 4.11(s, 2H), 2.71(s, 3H).
实施例29Example 29
1-(1-((3-(苯并呋喃-5-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-29)的合成1-(1-((3-(benzofuran-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine Synthesis of hydrochloride (III-29)
Figure PCTCN2022104528-appb-000048
Figure PCTCN2022104528-appb-000048
步骤1：合成叔丁基((1-((3-(苯并呋喃-5-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(29-2)Step 1: Synthesis of tert-butyl((1-((3-(benzofuran-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methanol base) (methyl) carbamate (29-2)
在室温下，将化合物Int 1(200mg，0.38mmol)，29-1(75mg，0.46mmol)，Pd(dppf)Cl 2(27mg，0.04mmol)和碳酸钾(132mg，0.95mmol)溶解在1,4-二氧六环/水(5/1mL)中，在氮气保护下，110℃下搅拌4h。冷却到室温，加水(20mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到黄色油状化合物150mg，产率69.77％，[M+H] +:561.1。 Compound Int 1 (200 mg, 0.38 mmol), 29-1 (75 mg, 0.46 mmol), Pd(dppf)Cl 2 (27 mg, 0.04 mmol) and potassium carbonate (132 mg, 0.95 mmol) were dissolved in 1, In 4-dioxane/water (5/1 mL), under nitrogen protection, stir at 110° C. for 4 h. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=3 : 1) Obtain 150 mg of yellow oily compound, yield 69.77%, [M+H] + : 561.1.
步骤2：合成1-(1-((3-(苯并呋喃-5-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-29)Step 2: Synthesis of 1-(1-((3-(benzofuran-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N- Methylmethylamine hydrochloride (III-29)
在室温下，将化合物29-2(150mg，0.27mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。浓缩得到黄色化合物100mg，产率80.05％，纯度>95％，[M+H] +:461.1。 Compound 29-2 (150 mg, 0.27 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. Concentration gave 100 mg of the yellow compound with a yield of 80.05%, a purity of >95%, and [M+H] + : 461.1.
1H NMR：(400MHz，CD 3OD)δ7.97(d，J＝8.0Hz，1H)，7.86-7.83(m，2H)，7.77(s，1H)，7.64-7.57(m，3H)，7.50(d，J＝8.0Hz，1H)，7.46-7.39(m，2H)，7.13-7.11(m，2H)，7.03(t，J＝8.4Hz，1H)，6.96(s，1H)，6.41(s，1H)，4.11(s，2H)，2.70(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ7.97 (d, J=8.0Hz, 1H), 7.86-7.83 (m, 2H), 7.77 (s, 1H), 7.64-7.57 (m, 3H), 7.50(d, J=8.0Hz, 1H), 7.46-7.39(m, 2H), 7.13-7.11(m, 2H), 7.03(t, J=8.4Hz, 1H), 6.96(s, 1H), 6.41 (s, 1H), 4.11 (s, 2H), 2.70 (s, 3H).
实施例30Example 30
1-(5-(1H-吲哚-5-基)-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(III-30)的合成Synthesis of 1-(5-(1H-indol-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III-30)
Figure PCTCN2022104528-appb-000049
Figure PCTCN2022104528-appb-000049
步骤1：合成5-溴-1-(吡啶-3-基磺酰基)-1H-吡咯-3-甲醛(30-3)Step 1: Synthesis of 5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (30-3)
0℃下，将化合物30-1(500mg，2.87mmol)溶于DMF(10mL)，缓慢加入NaH(230 mg，5.75mmol)，搅拌10分钟后，加入30-2(766mg，4.31mmol)。将反应液升至室温继续反应1小时，反应完全后，用饱和氯化铵溶液(10mL)淬灭反应，然后用乙酸乙酯(20mL×2)萃取，合并有机相用饱和食盐水(20mL×1)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩，柱层析分离纯化(PE/EA＝5:1)，得到黄色固体500mg，产率55.40％，[M+H] +:316.1。 At 0°C, compound 30-1 (500 mg, 2.87 mmol) was dissolved in DMF (10 mL), NaH (230 mg, 5.75 mmol) was added slowly, and after stirring for 10 minutes, 30-2 (766 mg, 4.31 mmol) was added. The reaction solution was raised to room temperature and continued to react for 1 hour. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (10 mL), then extracted with ethyl acetate (20 mL×2), and the combined organic phases were washed with saturated brine (20 mL×2). 1) Wash, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, separate and purify by column chromatography (PE/EA=5:1), and obtain 500 mg of a yellow solid with a yield of 55.40%, [M+H] + :316.1.
步骤2：合成5-(1H-吲哚-5-基)-1-(吡啶-3-基磺酰基)-1H-吡咯-3-甲醛(30-5)Step 2: Synthesis of 5-(1H-indol-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (30-5)
在室温下，将化合物30-3(400mg，1.27mmol)，30-4(308mg，1.91mmol)，Pd(PPh 3) 4(147mg，0.127mmol)，K 2CO 3(528mg，3.82mmol)，DME(15mL)和水(1.5mL)依次加入单口瓶中，80℃搅拌3h。反应完全后，浓缩溶剂，柱层析分离纯化(PE/EA＝8:1-1:1)，得到黄色固体300mg，产率66.93％，[M+H] +:352.1。 At room temperature, compound 30-3 (400mg, 1.27mmol), 30-4 (308mg, 1.91mmol), Pd(PPh 3 ) 4 (147mg, 0.127mmol), K 2 CO 3 (528mg, 3.82mmol), DME (15 mL) and water (1.5 mL) were sequentially added into a one-necked flask, and stirred at 80° C. for 3 h. After the reaction was complete, the solvent was concentrated and purified by column chromatography (PE/EA=8:1-1:1) to obtain 300 mg of a yellow solid with a yield of 66.93%, [M+H] + : 352.1.
步骤3：合成1-(5-(1H-吲哚-5-基)-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(III-30)Step 3: Synthesis of 1-(5-(1H-indol-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III- 30)
在室温下，将化合物30-5(300mg，0.854mmol)溶于甲醇(3mL)，加入甲胺甲醇溶液(0.5mL)，30℃搅拌2小时后，加入NaBH 4(265mg，1.71mmol)，继续反应1小时。减压浓缩，反相柱分离纯化(0-100％ACN/H 2O)，得到黄色固体100mg，产率31.76％，纯度>95％，[M+H] +:365.2。 Compound 30-5 (300mg, 0.854mmol) was dissolved in methanol (3mL) at room temperature, methylamine methanol solution (0.5mL) was added, stirred at 30°C for 2 hours, NaBH 4 (265mg, 1.71mmol) was added, and React for 1 hour. Concentrate under reduced pressure, separate and purify by reverse phase column (0-100% ACN/H 2 O) to obtain 100 mg of yellow solid, yield 31.76%, purity >95%, [M+H] + : 365.2.
1H NMR：(400MHz，DMSO-d 6)δ11.30(s，1H)，8.81(d，J＝4.4Hz，1H)，8.72(s，2H)，7.72-7.70(m，2H)，7.53-7.50(m，1H)，7.42(s，1H)，7.35-7.33(m，1H)，7.28(s，1H)，6.82-6.80(m，1H)，6.43(s，1H)，6.34(s，1H)，4.01(s，2H)，2.55(m，3H). 1 H NMR: (400MHz, DMSO-d 6 ) δ11.30(s, 1H), 8.81(d, J=4.4Hz, 1H), 8.72(s, 2H), 7.72-7.70(m, 2H), 7.53 -7.50(m, 1H), 7.42(s, 1H), 7.35-7.33(m, 1H), 7.28(s, 1H), 6.82-6.80(m, 1H), 6.43(s, 1H), 6.34(s , 1H), 4.01(s, 2H), 2.55(m, 3H).
实施例31Example 31
1-(5-(2-氟苯基)-1-((3-(5-(2-甲氧基乙氧基)吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-31)的合成1-(5-(2-fluorophenyl)-1-((3-(5-(2-methoxyethoxy)pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrole-3 Synthesis of -yl)-N-methylmethylamine hydrochloride (III-31)
Figure PCTCN2022104528-appb-000050
Figure PCTCN2022104528-appb-000050
步骤1：合成3-溴-5-(2-甲氧基乙氧基)吡啶(31-3)Step 1: Synthesis of 3-bromo-5-(2-methoxyethoxy)pyridine (31-3)
在室温下，将化合物31-1(2.0g，11.49mmol)，31-2(1.6mL，17.24mmol)和K 2CO 3(3.9g，28.74mmol)溶解在DMF(20mL)中，40℃下搅拌过夜。反应结束后，加水(40mL)，用乙酸乙酯(20mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝5:1)得到白色固体化合物2.2g，其产率82.47％，[M+H] +: 232.0。 Compound 31-1 (2.0 g, 11.49 mmol), 31-2 (1.6 mL, 17.24 mmol) and K 2 CO 3 (3.9 g, 28.74 mmol) were dissolved in DMF (20 mL) at room temperature at 40° C. Stir overnight. After the reaction, add water (40mL), extract with ethyl acetate (20mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, and separate and purify by column chromatography (PE/EA=5 : 1) 2.2 g of white solid compound was obtained, the yield was 82.47%, [M+H] + : 232.0.
步骤2：合成叔丁基((5-(2-氟苯基)-1-((3-(5-(2-甲氧基乙氧基)吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(31-5)Step 2: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(5-(2-methoxyethoxy)pyridin-3-yl)phenyl)sulfonyl) -1H-pyrrol-3-yl)methyl)(methyl)carbamate (31-5)
在室温下，将化合物31-3(200mg，0.86mmol)，31-4(263mg，1.03mmol)，Pd(dppf)Cl 2DCM(71mg，0.09mmol)和醋酸钾(169mg，1.72mmol)溶解在1,4-二氧六环(10mL)中，在氮气保护下，110℃下搅拌2h。冷却到室温，向反应体系中加入化合物Int 1(200mg，0.38mmol)，Pd(dppf)Cl 2(28mg，0.04mmol)和碳酸钾(133mg，0.95mmol)和水(4mL)，在氮气保护下，110℃下搅拌2h。待反应结束后，加水(20mL)用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到黄色油状化合物150mg，产率65.90％，[M+H] +:596.2。 Compound 31-3 (200 mg, 0.86 mmol), 31-4 (263 mg, 1.03 mmol), Pd(dppf)Cl 2 DCM (71 mg, 0.09 mmol) and potassium acetate (169 mg, 1.72 mmol) were dissolved in 1,4-dioxane (10 mL), stirred at 110° C. for 2 h under nitrogen protection. Cool to room temperature, add compound Int 1 (200mg, 0.38mmol), Pd(dppf)Cl 2 (28mg, 0.04mmol) and potassium carbonate (133mg, 0.95mmol) and water (4mL) to the reaction system, under nitrogen protection , Stirring at 110°C for 2h. After the reaction was completed, add water (20 mL) and extract with ethyl acetate (15 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then separate and purify by column chromatography (PE/EA=3 : 1) Obtain 150 mg of yellow oily compound, yield 65.90%, [M+H] + : 596.2.
步骤3：合成1-(5-(2-氟苯基)-1-((3-(5-(2-甲氧基乙氧基)吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-31)Step 3: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-(2-methoxyethoxy)pyridin-3-yl)phenyl)sulfonyl)-1H -pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-31)
在室温下，将化合物31-5(150mg，0.25mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。浓缩得到白色化合物100mg，产率75.19％，纯度>95％，[M+H] +:461.1。 Compound 31-5 (150 mg, 0.25 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. Concentration gave 100 mg of white compound, yield 75.19%, purity >95%, [M+H] + : 461.1.
1H NMR：(400MHz，CD 3OD)δ8.71(s，2H)，8.36(s，1H)，8.14(s，1H)，7.90(s，1H)，7.82-7.69(m，3H)，7.47-7.45(m，1H)，7.17-7.15(m，2H)，7.07(t，J＝9.2Hz，1H)，6.47(s，1H)，4.52(t，J＝4.4Hz，2H)，4.13(s，2H)，3.88(t，J＝4.4Hz，2H)，3.44(s，3H)，2.73(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ8.71(s, 2H), 8.36(s, 1H), 8.14(s, 1H), 7.90(s, 1H), 7.82-7.69(m, 3H), 7.47-7.45(m, 1H), 7.17-7.15(m, 2H), 7.07(t, J=9.2Hz, 1H), 6.47(s, 1H), 4.52(t, J=4.4Hz, 2H), 4.13 (s, 2H), 3.88(t, J=4.4Hz, 2H), 3.44(s, 3H), 2.73(s, 3H).
实施例32Example 32
1-(1-((3-(1-环丙基-1H-吡唑-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-32)的合成1-(1-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl) Synthesis of -N-Methylmethylamine Hydrochloride (III-32)
Figure PCTCN2022104528-appb-000051
Figure PCTCN2022104528-appb-000051
步骤1：合成叔丁基((1-((3-(1H-吡唑-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(32-2)Step 1: Synthesis of tert-butyl ((1-((3-(1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl) Methyl)(methyl)carbamate (32-2)
在室温下，将化合物Int 1(500mg，0.96mmol)，32-1(214mg，1.91mmol)，Pd(dpp f)Cl 2(70mg，0.10mmol)和碳酸钾(330mg，2.39mmol)溶解在1,4-二氧六环/水(10/2mL)中，在氮气保护下，110℃下搅拌过夜。冷却到室温，加水(20mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝1:1)得到白色固体化合物150mg，产率30.80％，[M+H] +:511.2。 Compound Int 1 (500 mg, 0.96 mmol), 32-1 (214 mg, 1.91 mmol), Pd(dpp f)Cl 2 (70 mg, 0.10 mmol) and potassium carbonate (330 mg, 2.39 mmol) were dissolved in 1 , 4-dioxane/water (10/2mL), under nitrogen protection, stirred overnight at 110°C. Cool to room temperature, add water (20 mL), extract with ethyl acetate (15 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=1 : 1) 150 mg of white solid compound was obtained, yield 30.80%, [M+H] + : 511.2.
步骤2：合成叔丁基((1-((3-(1-环丙基-1H-吡唑-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(32-4)Step 2: Synthesis of tert-butyl((1-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H- Pyrrol-3-yl)methyl)(methyl)carbamate (32-4)
在室温下，将化合物32-2(150mg，0.29mmol)，32-3(76mg，0.88mmol)，Cu(OAc) 2(64mg，0.35mmol)，DMAP(72mg，0.59mmol)和吡啶(24mg，0.29mmol)溶解在1,4-二氧六环(8mL)中，100℃下搅拌两天。反应结束后，冷却到室温，加水(20mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到黄色油状化合物60mg，产率37.09％，[M+H] +:551.2 Compound 32-2 (150 mg, 0.29 mmol), 32-3 (76 mg, 0.88 mmol), Cu(OAc) 2 (64 mg, 0.35 mmol), DMAP (72 mg, 0.59 mmol) and pyridine (24 mg, 0.29 mmol) was dissolved in 1,4-dioxane (8 mL), and stirred at 100°C for two days. After the reaction, cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, and the filtrate is concentrated under reduced pressure, separated and purified by column chromatography (PE /EA=3:1) to obtain 60 mg of yellow oily compound, yield 37.09%, [M+H] + : 551.2
步骤3：合成1-(1-((3-(1-环丙基-1H-吡唑-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-Step 3: Synthesis of 1-(1-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole- 3-
基)-N-甲基甲胺盐酸盐(III-32)Base) -N-methylmethylamine hydrochloride (III-32)
在室温下，将化合物32-4(60mg，0.11mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。浓缩得到白色固体化合物32mg，产率60.38％，纯度>95％，[M+H] +:451.1。 Compound 32-4 (60 mg, 0.11 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. Concentration gave 32 mg of white solid compound, yield 60.38%, purity >95%, [M+H] + : 451.1.
1H NMR：(400MHz，DMSO-d 6)δ9.24(br，2H)，8.36(s，1H)，7.93(d，J＝8.0Hz，1H)，7.87-7.85(m，2H)，7.59(s，1H)，7.55-7.51(m，2H)，7.24-7.18(m，3H)，7.07(t，J＝7.6Hz，1H)，6.53(s，1H)，3.98(s，2H)，3.78-3.75(m，1H)，2.48(s，3H)，1.11-1.00(m，4H). 1 H NMR: (400MHz, DMSO-d 6 ) δ9.24 (br, 2H), 8.36 (s, 1H), 7.93 (d, J=8.0Hz, 1H), 7.87-7.85 (m, 2H), 7.59 (s, 1H), 7.55-7.51(m, 2H), 7.24-7.18(m, 3H), 7.07(t, J=7.6Hz, 1H), 6.53(s, 1H), 3.98(s, 2H), 3.78-3.75(m, 1H), 2.48(s, 3H), 1.11-1.00(m, 4H).
实施例33Example 33
1-(5-(2-氟苯基)-1-((3'-(三氟甲氧基)-[1，1'-联苯基]-3-基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-33)的合成1-(5-(2-fluorophenyl)-1-((3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)sulfonyl)-1H-pyrrole Synthesis of -3-yl)-N-methylmethylamine Hydrochloride (III-33)
Figure PCTCN2022104528-appb-000052
Figure PCTCN2022104528-appb-000052
步骤1：合成叔丁基((5-(2-氟苯基)-1-((3'-(三氟甲氧基)-[1，1'-联苯基]-3-基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(33-2)Step 1: Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)sulfonyl Acyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (33-2)
在室温下，将化合物Int 1(200mg，0.38mmol)，33-1(95mg，0.46mmol)，Pd(dppf) Cl 2(28mg，0.04mmol)和碳酸钾(132mg，0.95mmol)溶解在1，4-二氧六环/水(5/1mL)中，在氮气保护下，110℃下搅拌4h。冷却到室温，加水(20mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝5:1)得到黄色油状化合物100mg，产率43.48％，[M+H] +:605.2。 Compound Int 1 (200 mg, 0.38 mmol), 33-1 (95 mg, 0.46 mmol), Pd(dppf) Cl 2 (28 mg, 0.04 mmol) and potassium carbonate (132 mg, 0.95 mmol) were dissolved in 1, In 4-dioxane/water (5/1 mL), under nitrogen protection, stir at 110° C. for 4 h. Cool to room temperature, add water (20 mL), extract with ethyl acetate (15 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=5 : 1) Obtain 100 mg of yellow oily compound, yield 43.48%, [M+H] + : 605.2.
步骤2：合成1-(5-(2-氟苯基)-1-((3'-(三氟甲氧基)-[1，1'-联苯基]-3-基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-33)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)sulfonyl) -1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-33)
在室温下，将化合物33-2(100mg，0.17mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。浓缩得到棕色固体化合物51mg，产率57.30％，纯度>95％，[M+H] +:505.1。 Compound 33-2 (100 mg, 0.17 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. Concentration gave 51 mg of brown solid compound, yield 57.30%, purity >95%, [M+H] + : 505.1.
1H NMR：(400MHz，DMSO-d 6)δ9.06(br，2H)，8.10(d，J＝8.0Hz，1H)，7.87(s，1H)，7.72-7.63(m，3H)，7.59-7.56(m，3H)，7.49-7.44(m，2H)，7.20-7.10(m，3H)，6.54(s，1H)，3.99(s，2H)，2.49(s，3H). 1 H NMR: (400MHz, DMSO-d 6 ) δ9.06 (br, 2H), 8.10 (d, J=8.0Hz, 1H), 7.87 (s, 1H), 7.72-7.63 (m, 3H), 7.59 -7.56(m, 3H), 7.49-7.44(m, 2H), 7.20-7.10(m, 3H), 6.54(s, 1H), 3.99(s, 2H), 2.49(s, 3H).
实施例34Example 34
1-(1-((3-(1H-吡唑-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-34)的合成1-(1-((3-(1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanol Synthesis of Amine Hydrochloride (III-34)
Figure PCTCN2022104528-appb-000053
Figure PCTCN2022104528-appb-000053
在室温下，将化合物32-2(150mg，0.27mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。浓缩得到白色固体化合物123mg，产率94.62％，纯度>95％，[M+H] +:411.1。 Compound 32-2 (150 mg, 0.27 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. Concentration gave 123 mg of white solid compound, yield 94.62%, purity >95%, [M+H] + : 411.1.
1H NMR：(400MHz，CD 3OD)δ8.17(s，2H)，7.93(d，J＝6.4Hz，1H)，7.83(s，1H)，7.58(s，1H)，7.55(t，J＝8.0Hz，1H)，7.48-7.40(m，2H)，7.16-7.04(m，3H)，6.41(s，1H)，4.12(s，2H)，2.71(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ8.17(s, 2H), 7.93(d, J=6.4Hz, 1H), 7.83(s, 1H), 7.58(s, 1H), 7.55(t, J=8.0Hz, 1H), 7.48-7.40(m, 2H), 7.16-7.04(m, 3H), 6.41(s, 1H), 4.12(s, 2H), 2.71(s, 3H).
实施例35Example 35
1-(5-(2-氟苯基)-1-((3-(5-(2，2，2-三氟乙氧基)吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-35)的合成1-(5-(2-fluorophenyl)-1-((3-(5-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)sulfonyl)-1H- Synthesis of pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-35)
Figure PCTCN2022104528-appb-000054
Figure PCTCN2022104528-appb-000054
步骤1：合成3-溴-5-(2，2，2-三氟乙氧基)吡啶(35-2)Step 1: Synthesis of 3-bromo-5-(2,2,2-trifluoroethoxy)pyridine (35-2)
在室温下，将化合物31-1(1.0g，5.75mmol)，35-1(2.0g，8.62mmol)和K 2CO 3(2.0g，14.37mmol)溶解在DMF(10mL)中，室温下搅拌过夜。反应结束后，加水(30mL)，用乙酸乙酯(20mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到黄色油状化合物1.1g，产率74.83％，[M+H] +:256.1。 Compound 31-1 (1.0 g, 5.75 mmol), 35-1 (2.0 g, 8.62 mmol) and K 2 CO 3 (2.0 g, 14.37 mmol) were dissolved in DMF (10 mL) at room temperature and stirred at room temperature overnight. After the reaction, add water (30mL), extract with ethyl acetate (20mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=3 : 1) 1.1 g of yellow oily compound was obtained, yield 74.83%, [M+H] + : 256.1.
步骤2：合成叔丁基((5-(2-氟苯基)-1-((3-(5-(2，2，2-三氟乙氧基)吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸甲酯(35-3)Step 2: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(5-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl) Sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (35-3)
在室温下，将化合物35-2(200mg，0.78mmol)，31-4(258mg，1.02mmol)，Pd(dppf)Cl 2·DCM(64mg，0.08mmol)和醋酸钾(154mg，1.56mmol)溶解在1,4-二氧六环(10mL)中，在氮气保护下，110℃下搅拌2h。冷却到室温，向反应体系中加入化合物Int 1(200mg，0.38mmol)，Pd(dppf)Cl 2(28mg，0.04mmol)和碳酸钾(133mg，0.95mmol)和水(2mL)，在氮气保护下，110℃下搅拌2h。待反应结束后，加水(20mL)用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到黄色油状化合物130mg，产率54.85％，[M+H] +:620.2。 Compound 35-2 (200 mg, 0.78 mmol), 31-4 (258 mg, 1.02 mmol), Pd(dppf)Cl 2 · DCM (64 mg, 0.08 mmol) and potassium acetate (154 mg, 1.56 mmol) were dissolved at room temperature In 1,4-dioxane (10 mL), stirred at 110° C. for 2 h under nitrogen protection. Cool to room temperature, add compound Int 1 (200mg, 0.38mmol), Pd(dppf)Cl 2 (28mg, 0.04mmol) and potassium carbonate (133mg, 0.95mmol) and water (2mL) to the reaction system, under nitrogen protection , Stirring at 110°C for 2h. After the reaction was completed, add water (20 mL) and extract with ethyl acetate (15 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then separate and purify by column chromatography (PE/EA=3 : 1) 130 mg of yellow oily compound was obtained, yield 54.85%, [M+H] + : 620.2.
步骤3：合成1-(5-(2-氟苯基)-1-((3-(5-(2，2，2-三氟乙氧基)吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-35)Step 3: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)sulfonyl )-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-35)
在室温下，将化合物35-3(130mg，0.21mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。浓缩得到黄色化合物73mg，产率62.93％，[M+H] +:520.1。 Compound 35-3 (130 mg, 0.21 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. Concentration gave 73 mg of the yellow compound with a yield of 62.93%, [M+H] + : 520.1.
1H NMR：(400MHz，DMSO-d 6)δ9.37(br，2H)，8.61(s，1H)，8.59(s，1H)，8.18(d，J＝7.6Hz，1H)，7.99(s，1H)，7.93(s，1H)，7.80(s，1H)，7.74(t，J＝8.0Hz，1H)，7.55(d，J＝8.0Hz，1H)，7.48-7.46(m，1H)，7.22-7.15(m，2H)，7.09(t，J＝7.6Hz，1H)，6.58(s，1H)，5.08(q，J＝8.8Hz，2H)，3.98(s，2H)，2.47(s，3H). 1 H NMR: (400MHz, DMSO-d 6 )δ9.37(br, 2H), 8.61(s, 1H), 8.59(s, 1H), 8.18(d, J=7.6Hz, 1H), 7.99(s , 1H), 7.93(s, 1H), 7.80(s, 1H), 7.74(t, J=8.0Hz, 1H), 7.55(d, J=8.0Hz, 1H), 7.48-7.46(m, 1H) , 7.22-7.15(m, 2H), 7.09(t, J=7.6Hz, 1H), 6.58(s, 1H), 5.08(q, J=8.8Hz, 2H), 3.98(s, 2H), 2.47( s, 3H).
实施例36Example 36
1-(1-((3-氟-5-(1-甲基-1H-吡唑-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-36)的合成1-(1-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3 Synthesis of -yl)-N-methylmethylamine hydrochloride (III-36)
Figure PCTCN2022104528-appb-000055
Figure PCTCN2022104528-appb-000055
步骤1：合成叔丁基((1-((3-氟-5-(1-甲基-1H-吡唑-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(36-1)Step 1: Synthesis of tert-butyl((1-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl) -1H-pyrrol-3-yl)methyl)(methyl)carbamate (36-1)
在室温下，将化合物Int 4(200mg，0.37mmol)，6-1(93mg，0.44mmol)，Pd(dppf)Cl 2(27mg，0.04mmol)和碳酸钾(130mg，0.95mmol)溶解在1,4-二氧六环/水(5/1mL)中，在氮气保护下，110℃下搅拌4h。冷却到室温，加水(20mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到黄色油状化合物150mg，产率74.89％，[M+H] +:543.2。 Compound Int 4 (200 mg, 0.37 mmol), 6-1 (93 mg, 0.44 mmol), Pd(dppf)Cl 2 (27 mg, 0.04 mmol) and potassium carbonate (130 mg, 0.95 mmol) were dissolved in 1, In 4-dioxane/water (5/1 mL), under nitrogen protection, stir at 110° C. for 4 h. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=3 : 1) Obtain 150 mg of yellow oily compound, yield 74.89%, [M+H] + : 543.2.
步骤2：合成1-(1-((3-氟-5-(1-甲基-1H-吡唑-4-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-36)Step 2: Synthesis of 1-(1-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H -pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-36)
在室温下，将化合物36-1(150mg，0.27mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。浓缩得到黄色化合物80mg，产率60.61％，纯度>95％，[M+H] +:443.1。 Compound 36-1 (150 mg, 0.27 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. Concentration gave 80 mg of the yellow compound, yield 60.61%, purity >95%, [M+H] + : 443.1.
1H NMR：(400MHz，CD 3OD)δ8.15(s，1H)，7.92(s，1H)，7.86(s，1H)，7.69(d，J＝9.6Hz，1H)，7.51-7.48(m，1H)，7.39(s，1H)，7.20-7.06(m，4H)，6.47(s，1H)，4.14(s，2H)，4.00(s，3H)，2.73(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ8.15(s, 1H), 7.92(s, 1H), 7.86(s, 1H), 7.69(d, J=9.6Hz, 1H), 7.51-7.48( m, 1H), 7.39(s, 1H), 7.20-7.06(m, 4H), 6.47(s, 1H), 4.14(s, 2H), 4.00(s, 3H), 2.73(s, 3H).
实施例37Example 37
1-(1-((3-氟-5-(5-甲氧基吡啶-3-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-37)的合成1-(1-((3-fluoro-5-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl) Synthesis of -N-Methylmethylamine Hydrochloride (III-37)
Figure PCTCN2022104528-appb-000056
Figure PCTCN2022104528-appb-000056
步骤1：合成叔丁基((1-((3-氟-5-(5-甲氧基吡啶-3-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(37-1)Step 1: Synthesis of tert-butyl((1-((3-fluoro-5-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H- Pyrrol-3-yl)methyl)(methyl)carbamate (37-1)
在室温下，将化合物Int 4(200mg，0.37mmol)，21-1(74mg，0.48mmol)，Pd(dppf)Cl 2(27mg，0.04mmol)和碳酸钾(130mg，0.95mmol)溶解在1,4-二氧六环/水(5/1mL)中，在氮气保护下，110℃下搅拌4h。冷却到室温，加水(20mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到黄色油状化合物100mg，产率47.62％，[M+H] +:570.2。 Compound Int 4 (200 mg, 0.37 mmol), 21-1 (74 mg, 0.48 mmol), Pd(dppf)Cl 2 (27 mg, 0.04 mmol) and potassium carbonate (130 mg, 0.95 mmol) were dissolved in 1, In 4-dioxane/water (5/1 mL), under nitrogen protection, stir at 110° C. for 4 h. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=3 : 1) Obtain 100 mg of yellow oily compound, yield 47.62%, [M+H] + : 570.2.
步骤2：合成1-(1-((3-氟-5-(5-甲氧基吡啶-3-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-Step 2: Synthesis of 1-(1-((3-fluoro-5-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole- 3-
基)-N-甲基甲胺盐酸盐(III-37)Base) -N-methylmethylamine hydrochloride (III-37)
在室温下，将化合物37-1(100mg，0.18mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。浓缩得到黄色化合物40mg，产率45.17％，纯度>95％，[M+H] +:470.2。 Compound 37-1 (100 mg, 0.18 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. Concentration gave 40 mg of the yellow compound with a yield of 45.17%, a purity of >95%, and [M+H] + : 470.2.
1H NMR：(400MHz，CD 3OD)δ8.74(s，1H)，8.71(s，1H)，8.36(s，1H)，8.03(d，J＝9.6Hz，1H)，7.92(s，1H)，7.74(s，1H)，7.50-7.45(m，1H)，7.40(d，J＝7.2Hz，1H)，7.21-7.19(m，2H)，7.10(t，J＝9.2Hz，1H)，6.50(s，1H)，4.16(s，3H)，4.14(s，2H)，2.74(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ8.74(s, 1H), 8.71(s, 1H), 8.36(s, 1H), 8.03(d, J=9.6Hz, 1H), 7.92(s, 1H), 7.74(s, 1H), 7.50-7.45(m, 1H), 7.40(d, J=7.2Hz, 1H), 7.21-7.19(m, 2H), 7.10(t, J=9.2Hz, 1H ), 6.50(s, 1H), 4.16(s, 3H), 4.14(s, 2H), 2.74(s, 3H).
实施例38Example 38
1-(5-(2-氟苯基)-1-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-38)的合成1-(5-(2-fluorophenyl)-1-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrole Synthesis of -3-yl)-N-methylmethylamine Hydrochloride (III-38)
Figure PCTCN2022104528-appb-000057
Figure PCTCN2022104528-appb-000057
步骤1：合成叔丁基((5-(2-氟苯基)-1-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)磺酰基)-1H-吡咯-3-基)甲基))(甲基)氨基甲酸酯(38-1)Step 1: Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl) Acyl)-1H-pyrrol-3-yl)methyl))(methyl)carbamate (38-1)
在室温下，将化合物Int 5(200mg，0.36mmol)，6-1(90mg，0.43mmol)，Pd(dppf)Cl 2(8.0mg，0.01mmol)溶解在1,4-二氧六环(10mL)中，再加入碳酸钠(76mg，0.72mmol)和水(2mL)，在氮气保护下，105℃下加热反应过夜。待反应结束后，加水(20mL)用乙酸乙酯(30mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝1:2)得到黄色油状化合物180mg，产率89.81％，[M+H] +:499.2。 Compounds Int 5 (200 mg, 0.36 mmol), 6-1 (90 mg, 0.43 mmol), Pd(dppf)Cl 2 (8.0 mg, 0.01 mmol) were dissolved in 1,4-dioxane (10 mL) at room temperature ), sodium carbonate (76mg, 0.72mmol) and water (2mL) were added, and the reaction was heated at 105°C overnight under the protection of nitrogen. After the reaction was completed, add water (20 mL) and extract with ethyl acetate (30 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then separate and purify by column chromatography (PE/EA=1 :2) Obtain 180 mg of yellow oily compound, yield 89.81%, [M+H] + : 499.2.
步骤2：合成1-(5-(2-氟苯基)-1-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-38)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl) -1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-38)
在室温下，将化合物38-1(180mg，0.33mmol)溶解在DCM(3mL)溶液中，然后加入4M盐酸/1，4-二氧六环(5mL)室温搅拌2h。浓缩得到粉色固体化合物148mg，放置一会儿后变为灰色固体。产率92.96％，纯度>95％，[M+H] +:455.2。 Compound 38-1 (180 mg, 0.33 mmol) was dissolved in DCM (3 mL) solution at room temperature, then added 4M hydrochloric acid/1,4-dioxane (5 mL) and stirred at room temperature for 2 h. Concentration gave 148 mg of the compound as a pink solid, which turned into a gray solid after standing for a while. Yield 92.96%, purity>95%, [M+H] + : 455.2.
1H NMR：(400MHz，CD 3OD)δ7.96-7.92(m，1H)，7.84-7.80(m，1H)，7.80(s，2H)，7.26-7.20(m，2H)，7.18(d，J＝8.7Hz，1H)，7.03-6.95(m，2H)，6.80(d，J＝8.4Hz，1H)，6.37(d，J＝2.0Hz，1H)，4.15(s，2H)，4.00(s，3H)，3.82(s，3H)，2.74(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ7.96-7.92(m, 1H), 7.84-7.80(m, 1H), 7.80(s, 2H), 7.26-7.20(m, 2H), 7.18(d , J=8.7Hz, 1H), 7.03-6.95(m, 2H), 6.80(d, J=8.4Hz, 1H), 6.37(d, J=2.0Hz, 1H), 4.15(s, 2H), 4.00 (s, 3H), 3.82(s, 3H), 2.74(s, 3H).
实施例39Example 39
1-(5-(2-氟苯基)-1-((2-甲氧基-5-(5-甲氧基吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-39)的合成1-(5-(2-fluorophenyl)-1-((2-methoxy-5-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrole-3- Synthesis of -N-methylmethylamine hydrochloride (III-39)
Figure PCTCN2022104528-appb-000058
Figure PCTCN2022104528-appb-000058
步骤1：合成叔丁基((5-(2-氟苯基)-1-((2-甲氧基-5-(5-甲氧基吡啶-3-基))苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(39-1)Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((2-methoxy-5-(5-methoxypyridin-3-yl))phenyl)sulfonyl) -1H-pyrrol-3-yl)methyl)(methyl)carbamate (39-1)
在室温下，将化合物Int 5(200mg，0.36mmol)，21-1(66mg，0.43mmol)，Pd(dppf)Cl 2(8.0mg，0.01mmol)溶解在1,4-二氧六环(10mL)中，再加入碳酸钾(100mg，0.72mmol)和水(2mL)，在氮气保护下，105℃下加热反应过夜。待反应结束后，加水(5 mL)，用DCM(10mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝1:1)得到黄色油状化合物82mg，产率39.23％，[M+H] +:582.1。 Compound Int 5 (200 mg, 0.36 mmol), 21-1 (66 mg, 0.43 mmol), Pd(dppf)Cl 2 (8.0 mg, 0.01 mmol) was dissolved in 1,4-dioxane (10 mL) at room temperature ), potassium carbonate (100mg, 0.72mmol) and water (2mL) were added, and the reaction was heated at 105°C overnight under the protection of nitrogen. After the reaction was completed, add water (5 mL), extract with DCM (10 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then separate and purify by column chromatography (PE/EA=1 : 1) Obtain 82 mg of yellow oily compound, yield 39.23%, [M+H] + : 582.1.
步骤2：合成1-(5-(2-氟苯基)-1-((2-甲氧基-5-(5-甲氧基吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-39)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((2-methoxy-5-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H- Pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-39)
在室温下，将化合物39-1(82mg，0.14mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(5mL)室温搅拌2h。浓缩得到灰黑色固体化合物24mg。产率33.09％，纯度>95％，[M+H] +:482.2。 Compound 39-1 (82 mg, 0.14 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added 4M hydrochloric acid/1,4-dioxane (5 mL) and stirred at room temperature for 2 h. Concentration gave 24 mg of gray-black solid compound. Yield 33.09%, purity >95%, [M+H] + : 482.2.
1H NMR：(400MHz，CD 3OD)δ8.10(s，3H)，7.96(s，1H)，7.85(s，1H)，7.53(d，J＝9.2Hz，2H)，7.39(d，J＝8.2Hz，1H)，7.24(s，1H)，7.11–6.79(m，2H)，6.41(s，1H)， 1 H NMR: (400MHz, CD 3 OD) δ8.10(s, 3H), 7.96(s, 1H), 7.85(s, 1H), 7.53(d, J=9.2Hz, 2H), 7.39(d, J=8.2Hz, 1H), 7.24(s, 1H), 7.11–6.79(m, 2H), 6.41(s, 1H),
4.17(s，2H)，4.13(s，3H)，3.91(s，3H)，2.75(s，3H).4.17(s, 2H), 4.13(s, 3H), 3.91(s, 3H), 2.75(s, 3H).
实施例40Example 40
1-(1-((3-氟-5-(四氢-1H-呋喃[3，4-c]吡咯-5(3H)-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-40)的合成1-(1-((3-fluoro-5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonyl)-5-(2-fluorobenzene Synthesis of -1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-40)
Figure PCTCN2022104528-appb-000059
Figure PCTCN2022104528-appb-000059
步骤1：合成叔丁基((1-((3-氟-5-(四氢-1H-呋喃[3，4-c]吡咯-5(3H)-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(40-1)Step 1: Synthesis of tert-butyl((1-((3-fluoro-5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonyl)-5 -(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (40-1)
在室温下，将化合物Int 5(200mg，0.37mmol)，5-1(83mg，0.55mmol)，Pd(OAc) 2(9mg，0.04mmol)和碳酸铯(422mg，1.29mmol)溶解在甲苯(10mL)中，在氮气保护下，110℃下搅拌过夜。冷却到室温，加水(20mL)，用乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到黄色油状化合物150mg，产率69.77％，[M+H] +:574.2。 Compounds Int 5 (200 mg, 0.37 mmol), 5-1 (83 mg, 0.55 mmol), Pd(OAc) 2 (9 mg, 0.04 mmol) and cesium carbonate (422 mg, 1.29 mmol) were dissolved in toluene (10 mL) at room temperature ), stirred overnight at 110°C under nitrogen protection. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=3 : 1) Obtain 150 mg of yellow oily compound, yield 69.77%, [M+H] + : 574.2.
步骤2：合成1-(1-((3-氟-5-(四氢-1H-呋喃[3，4-c]吡咯-5(3H)-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-40)Step 2: Synthesis of 1-(1-((3-fluoro-5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonyl)-5-( 2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-40)
在室温下，将化合物40-1(150mg，0.26mmol)溶解在DCM(2mL)溶液中，然后 加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。浓缩得到白色化合物112mg，产率84.21％，纯度>95％，[M+H] +:475.2。 Compound 40-1 (150 mg, 0.26 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. Concentration gave 112 mg of white compound, yield 84.21%, purity >95%, [M+H] + : 475.2.
1H NMR：(400MHz，CD 3OD)δ7.77(s，1H)，7.51-7.49(m，1H)，7.20-7.08(m，3H)，6.57(d，J＝12.0Hz，1H)，6.48(d，J＝7.6Hz，1H)，6.43(s，1H)，6.32(s，1H)，4.12(s，2H)，3.97-3.94(m，2H)，3.72-3.67(m，2H)，3.39-3.37(m，2H)，3.13-3.11(m，2H)，3.13-3.11(m，4H)，2.71(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ7.77(s, 1H), 7.51-7.49(m, 1H), 7.20-7.08(m, 3H), 6.57(d, J=12.0Hz, 1H), 6.48(d, J=7.6Hz, 1H), 6.43(s, 1H), 6.32(s, 1H), 4.12(s, 2H), 3.97-3.94(m, 2H), 3.72-3.67(m, 2H) , 3.39-3.37(m, 2H), 3.13-3.11(m, 2H), 3.13-3.11(m, 4H), 2.71(s, 3H).
实施例41Example 41
1-(1-((3-(3，4-二甲氧基噻吩-2-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-41)的合成1-(1-((3-(3,4-dimethoxythiophen-2-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)- Synthesis of N-Methylmethylamine Hydrochloride (III-41)
Figure PCTCN2022104528-appb-000060
Figure PCTCN2022104528-appb-000060
步骤1：合成叔丁基((1-((3-(3，4-二甲氧基噻吩-2-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(41-2)Step 1: Synthesis of tert-butyl((1-((3-(3,4-dimethoxythiophen-2-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole -3-yl)methyl)(methyl)carbamate (41-2)
在室温下，将化合物Int1(500mg，0.96mmol)，41-1(276mg，1.92mmol)，Pd(OAc) 2(22mg，0.10mmol)，三环己基膦四氟硼酸盐(71mg，0.19mmol)，特戊酸(49mg，0.48mmol)和碳酸钾(265mg，1.95mmol)溶解在甲苯(15mL)中，在氮气保护下，110℃下搅拌2天。冷却到室温，加水(30mL)，用乙酸乙酯(20mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(PE/EA＝3:1)得到黄色油状化合物250mg，产率44.56％，[M+H] +:587.2。 At room temperature, compound Int1 (500mg, 0.96mmol), 41-1 (276mg, 1.92mmol), Pd(OAc) 2 (22mg, 0.10mmol), tricyclohexylphosphine tetrafluoroborate (71mg, 0.19mmol ), pivalic acid (49mg, 0.48mmol) and potassium carbonate (265mg, 1.95mmol) were dissolved in toluene (15mL), and stirred at 110°C for 2 days under nitrogen protection. Cool to room temperature, add water (30mL), extract with ethyl acetate (20mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, separate and purify by column chromatography (PE/EA=3 : 1) Obtain 250 mg of yellow oily compound, yield 44.56%, [M+H] + : 587.2.
步骤2：合成1-(1-((3-(3，4-二甲氧基噻吩-2-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-41)Step 2: Synthesis of 1-(1-((3-(3,4-dimethoxythiophen-2-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3 -yl)-N-methylmethylamine hydrochloride (III-41)
在室温下，将化合物41-2(250mg，0.43mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。浓缩，通过反相制备得到黄色化合物50mg，产率22.52％，纯度>95％，[M+H] +:487.1。 Compound 41-2 (250 mg, 0.43 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. Concentrate, and prepare 50 mg of yellow compound by reverse phase preparation, the yield is 22.52%, the purity is >95%, [M+H] + : 487.1.
1H NMR：(400MHz，CD 3OD)δ7.94(s，1H)，7.81(s，1H)，7.75(s，1H)，7.51-7.39(m，3H)，7.15-7.05(m，3H)，6.56(s，1H)，6.42(s，1H)，4.13(s，2H)，3.91(s，3H)，3.81(s，3H)，2.73(s，3H). 1 H NMR: (400MHz, CD 3 OD) δ7.94(s, 1H), 7.81(s, 1H), 7.75(s, 1H), 7.51-7.39(m, 3H), 7.15-7.05(m, 3H ), 6.56(s, 1H), 6.42(s, 1H), 4.13(s, 2H), 3.91(s, 3H), 3.81(s, 3H), 2.73(s, 3H).
实施例42Example 42
1-(1-((3-(5，6-二甲氧基吡啶-3-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺1-(1-((3-(5,6-dimethoxypyridin-3-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)- N-Methylmethylamine
(III-42)的合成Synthesis of (III-42)
Figure PCTCN2022104528-appb-000061
Figure PCTCN2022104528-appb-000061
步骤1：合成2，3-二甲氧基-5-(4，4，5，5-四甲基-1，3，2-二氧硼烷-2-基)吡啶(42-2)Step 1: Synthesis of 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (42-2)
在室温下，将化合物42-1(200mg，0.92mmol)，31-4(350mg，1.38mmol)，Pd(dppf)Cl 2DCM(75.2mg，0.09mmol)，乙酸钾(270mg，2.76mmol)加入1，4-二氧六环(8mL)中，氮气置换三次，氮气保护下，升温至90℃，搅拌过夜。TLC监控(PE/EA＝10:1)原料反应完全，有新点生成，直接进行下一步反应。 Compound 42-1 (200 mg, 0.92 mmol), 31-4 (350 mg, 1.38 mmol), Pd(dppf)Cl 2 DCM (75.2 mg, 0.09 mmol), potassium acetate (270 mg, 2.76 mmol) were added at room temperature 1,4-Dioxane (8 mL) was replaced with nitrogen three times, under the protection of nitrogen, the temperature was raised to 90° C., and stirred overnight. TLC monitors (PE/EA=10:1) that the reaction of the raw materials is complete, and new spots are formed, and the next reaction is directly carried out.
步骤2：合成叔丁基((1-((3-(5，6-二甲氧基吡啶-3-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(42-3)Step 2: Synthesis of tert-butyl((1-((3-(5,6-dimethoxypyridin-3-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole -3-yl)methyl)(methyl)carbamate (42-3)
在室温下，将化合物42-2(244mg，0.92mmol)，Int 1(401mg，0.77mmol)，Pd(dppf)Cl 2(56mg，0.077mmol)，K 2CO 3(212.8mg，1.54mmol)，加入到1，4-二氧六环(8mL)中，加入水(4mL)，置换三次，氮气保护下，升温至95℃，搅拌过夜，反应结束后，将反应体系减压浓缩，柱层析(PE/EA＝2:1)得到黄色油状物300mg，产率39.74％，[M+H] +:582.3。 At room temperature, compound 42-2 (244 mg, 0.92 mmol), Int 1 (401 mg, 0.77 mmol), Pd(dppf)Cl 2 (56 mg, 0.077 mmol), K 2 CO 3 (212.8 mg, 1.54 mmol), Added to 1,4-dioxane (8mL), added water (4mL), replaced three times, under the protection of nitrogen, raised the temperature to 95 ° C, stirred overnight, after the reaction was completed, the reaction system was concentrated under reduced pressure, column chromatography (PE/EA=2:1) 300 mg of yellow oil was obtained, the yield was 39.74%, [M+H] + : 582.3.
步骤3：1-(1-((3-(5，6-二甲氧基吡啶-3-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺(III-42)Step 3: 1-(1-((3-(5,6-dimethoxypyridin-3-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3- base)-N-methylmethylamine (III-42)
在室温下，将化合物42-3(300mg，0.52mmol)，溶解在DCM(5mL)溶液中，然后加入4M盐酸/1，4-二氧六环(0.65mL)室温搅拌2h。反应结束后，加入DCM(10mL)，水(5mL)，加入碳酸钾水溶液，调节pH＝8左右，分液得有机相，水相用20mLDCM萃取，合并有机相，旋干，柱层析(DCM/MeOH＝40:1)得黄色固体90mg，产率36％，[M+H] +:482.2。 Compound 42-3 (300mg, 0.52mmol) was dissolved in DCM (5mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (0.65mL) and stirred at room temperature for 2h. After the reaction, add DCM (10mL), water (5mL), add potassium carbonate aqueous solution, adjust pH=8 left and right, separate liquid to obtain organic phase, aqueous phase is extracted with 20mL DCM, combine organic phase, spin dry, column chromatography (DCM /MeOH=40:1) to obtain 90 mg of yellow solid with a yield of 36%, [M+H] + : 482.2.
1HNMR：(400MHz，CD 3OD)δ7.95(s，1H)，7.83(s，1H)，7.77(s，1H)，7.60(t，J＝7.6Hz，1H)，7.56-7.51(m，2H)，7.48-7.43(m，1H)，7.35(s，1H)，7.16-7.10(m，2H)，7.08-7.02(m，1H)，6.40(s，1H)，4.03(s，3H)，4.02(s，2H)，3.95(s，3H)，2.65(s，3H). 1 HNMR: (400MHz, CD 3 OD) δ7.95(s, 1H), 7.83(s, 1H), 7.77(s, 1H), 7.60(t, J=7.6Hz, 1H), 7.56-7.51(m , 2H), 7.48-7.43(m, 1H), 7.35(s, 1H), 7.16-7.10(m, 2H), 7.08-7.02(m, 1H), 6.40(s, 1H), 4.03(s, 3H ), 4.02(s, 2H), 3.95(s, 3H), 2.65(s, 3H).
实施例43Example 43
1-(5-(2-氟苯基)-1-((3-(5-(甲基磺酰基)吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺 (III-43)的合成1-(5-(2-fluorophenyl)-1-((3-(5-(methylsulfonyl)pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)- Synthesis of N-methylmethylamine (III-43)
Figure PCTCN2022104528-appb-000062
Figure PCTCN2022104528-appb-000062
步骤1：合成(5-(甲基磺酰基)吡啶-3-基)硼酸酯(43-2)Step 1: Synthesis of (5-(methylsulfonyl)pyridin-3-yl)boronate (43-2)
在室温下，将化合物43-1(200mg，0.85mmol)，31-4(324mg，1.30mmol)，Pd(dppf)Cl 2DCM(70mg，0.09mmol)，乙酸钾(250mg，2.55mmol)加入1，4-二氧六环(8mL)中，氮气置换三次，升温至90℃，搅拌过夜。TLC监控(PE/EA＝10/1)原料反应完全，有新点生成，直接进行下一步反应，[M+H]+:202.1。 Compound 43-1 (200 mg, 0.85 mmol), 31-4 (324 mg, 1.30 mmol), Pd(dppf)Cl 2 DCM (70 mg, 0.09 mmol), potassium acetate (250 mg, 2.55 mmol) were added at room temperature in 1 , 4-dioxane (8 mL), replaced with nitrogen three times, heated to 90°C, and stirred overnight. TLC monitors (PE/EA=10/1) raw material reaction is complete, and new point is formed, directly carries out next step reaction, [M+H]+: 202.1.
步骤2：合成叔丁基((5-(2-氟苯基)-1-((3-(5-(甲基磺酰基)吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(43-3)Step 2: Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-(5-(methylsulfonyl)pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrole -3-yl)methyl)(methyl)carbamate (43-3)
在室温下，将化合物43-2(171mg，0.85mmol)，Int 1(371mg，0.71mmol)，Pd(dppf)Cl 2(52mg，0.071mmol)，K 2CO 3(196mg，1.42mmol)，加入到1，4-二氧六环(8mL)中，加入水(4mL)，氮气置换三次保护下，升温至110℃，搅拌过夜，反应结束后，将反应体系减压浓缩，柱层析(PE/EA＝5:1)得到黄色油状物280mg，产率65.7％，[M+H] +:544.1。 At room temperature, compound 43-2 (171 mg, 0.85 mmol), Int 1 (371 mg, 0.71 mmol), Pd(dppf)Cl 2 (52 mg, 0.071 mmol), K 2 CO 3 (196 mg, 1.42 mmol), were added Add water (4mL) to 1,4-dioxane (8mL), under the protection of nitrogen replacement three times, raise the temperature to 110°C, stir overnight, after the reaction, the reaction system is concentrated under reduced pressure, column chromatography (PE /EA=5:1) to obtain 280 mg of a yellow oily product, the yield was 65.7%, [M+H] + : 544.1.
步骤3：合成1-(5-(2-氟苯基)-1-((3-(5-(甲基磺酰基)吡啶-3-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(III-43)Step 3: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-(methylsulfonyl)pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrole-3 -yl)-N-methylmethylamine (III-43)
在室温下，将化合物43-3(230mg，0.38mmol)，溶解在DCM(5mL)溶液中，然后加入4M盐酸/1，4-二氧六环(1.0mL)室温搅拌2h。反应结束后，加入DCM(10mL)，水(5mL)，加入碳酸氢钠水溶液，调节pH＝8左右，分液得有机相，水相用20mLDCM萃取两次，合并有机相，旋干，薄层色谱纯化得黄色固体130mg，产率68.4％，[M+H] +:500.08。 Compound 43-3 (230mg, 0.38mmol) was dissolved in DCM (5mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (1.0mL) and stirred at room temperature for 2h. After the reaction, add DCM (10mL), water (5mL), add sodium bicarbonate aqueous solution, adjust pH = about 8, separate the liquid to obtain the organic phase, extract the aqueous phase with 20mL DCM twice, combine the organic phase, spin dry, thin layer Purified by chromatography to obtain 130 mg of a yellow solid with a yield of 68.4%, [M+H] + : 500.08.
1H NMR：(400MHz，Chloroform-d)δ9.18(s，1H)，8.96(s，1H)，8.26(s，1H)，7.81-7.78(m，1H)，7.62-7.55(m，3H)，7.43(s，1H)，7.41-7.35(m，1H)，7.22(d，J＝7.6，1H)，7.14(t，J＝7.6Hz，1H)，7.01(t，J＝8.8Hz，1H)，6.27(s，1H)，3.65(s，2H)，3.19(s，3H)，2.46(s，3H). 1 H NMR: (400MHz, Chloroform-d) δ9.18(s, 1H), 8.96(s, 1H), 8.26(s, 1H), 7.81-7.78(m, 1H), 7.62-7.55(m, 3H ), 7.43(s, 1H), 7.41-7.35(m, 1H), 7.22(d, J=7.6, 1H), 7.14(t, J=7.6Hz, 1H), 7.01(t, J=8.8Hz, 1H), 6.27(s, 1H), 3.65(s, 2H), 3.19(s, 3H), 2.46(s, 3H).
实施例44Example 44
(S)-1-(3-((2-(2-氟苯基)-4-((甲氨基)甲基)-1H-吡咯-1-基)磺酰基)苯基)-N，N-二甲基吡咯烷-2-甲酰胺(III-44)的合成(S)-1-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)-N,N -Synthesis of dimethylpyrrolidine-2-carboxamide (III-44)
Figure PCTCN2022104528-appb-000063
Figure PCTCN2022104528-appb-000063
步骤1：合成叔丁基(S)-((1-((3-(2-(二甲基氨基甲酰基)吡咯烷-1-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(44-2)Step 1: Synthesis of tert-butyl(S)-((1-((3-(2-(dimethylcarbamoyl)pyrrolidin-1-yl)phenyl)sulfonyl)-5-(2-fluoro Phenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (44-2)
将化合物Int 1(200mg，0.38mmol)44-1(82mg，0.58mmol)Pd(OAc) 2(10mg，0.04mmol)和碳酸铯(311mg，0.95mmol)溶解在甲苯(10mL)中，120℃下搅拌过夜。待反应结束后，用乙酸乙酯(20mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩。通过柱层析(PE/EA＝11:1)纯化得到100mg黄色油状化合物，产率44.85％，[M+H] +:585.2。 Compound Int 1 (200 mg, 0.38 mmol) 44-1 (82 mg, 0.58 mmol) Pd(OAc) 2 (10 mg, 0.04 mmol) and cesium carbonate (311 mg, 0.95 mmol) were dissolved in toluene (10 mL) at 120 °C Stir overnight. After the reaction was completed, it was extracted with ethyl acetate (20 mL×2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Purified by column chromatography (PE/EA=11:1) to obtain 100 mg of a yellow oily compound with a yield of 44.85%, [M+H] + : 585.2.
步骤2：合成(S)-1-(3-((2-(2-氟苯基)-4-((甲氨基)甲基)-1H-吡咯-1-基)磺酰基)苯基)-N，N-二甲基吡咯烷-2-甲酰胺(III-44)Step 2: Synthesis of (S)-1-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl) -N,N-Dimethylpyrrolidine-2-carboxamide (III-44)
在室温下，将化合物44-2(100mg，0.17mmol)溶解在DCM(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。调节溶液的pH值为7，DCM萃取，浓缩得到棕色化合物38mg，产率46.34％，[M+H] +:485.2。 Compound 44-2 (100 mg, 0.17 mmol) was dissolved in DCM (2 mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (2 mL) and stirred at room temperature for 2 h. The pH of the solution was adjusted to 7, extracted with DCM, and concentrated to obtain 38 mg of a brown compound with a yield of 46.34%, [M+H] + : 485.2.
1H NMR：(400MHz，DMSO-d 6)δ9.02(br，1H)，7.72(s，1H)，7.53-7.51(m，1H)，7.29-7.20(m，3H)，7.07(t，J＝8.0Hz，1H)，6.68(d，J＝7.6Hz，1H)，6.57(d，J＝8.0Hz，1H)，6.48(s，1H)，6.31(s，1H)，4.61(d，J＝9.2Hz，1H)，3.98(s，2H)，3.29-3.23(m，2H)，3.07(s，3H)，2.79(s，3H)，2.49(s，3H)，2.32-2.27(m，1H)，2.00-1.89(m，3H). 1 H NMR: (400MHz, DMSO-d 6 )δ9.02(br, 1H), 7.72(s, 1H), 7.53-7.51(m, 1H), 7.29-7.20(m, 3H), 7.07(t, J=8.0Hz, 1H), 6.68(d, J=7.6Hz, 1H), 6.57(d, J=8.0Hz, 1H), 6.48(s, 1H), 6.31(s, 1H), 4.61(d, J=9.2Hz, 1H), 3.98(s, 2H), 3.29-3.23(m, 2H), 3.07(s, 3H), 2.79(s, 3H), 2.49(s, 3H), 2.32-2.27(m , 1H), 2.00-1.89(m, 3H).
实施例45Example 45
1-(5-(2-氟苯基)-1-((3-(1-(2-甲氧基乙基)-1H-吡唑-4-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲胺盐酸盐(III-45)的合成1-(5-(2-fluorophenyl)-1-((3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H- Synthesis of pyrrol-3-yl)-N-methylamine hydrochloride (III-45)
Figure PCTCN2022104528-appb-000064
Figure PCTCN2022104528-appb-000064
步骤1：合成叔丁基((5-(2-氟苯基)-1-((3-(1-(2-甲氧基乙基)-1H-吡唑-4-基)苯基)磺酰基)-1H-吡咯-3-基)甲基))(甲基)氨基甲酸酯(45-2)Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)phenyl)) Sulfonyl)-1H-pyrrol-3-yl)methyl))(methyl)carbamate (45-2)
将化合物32-2(150mg，0.29mmol)，45-1(82mg,0.59mmol)和碳酸钾(122mg，0.88mmol)溶解在DMF(5mL)中，室温搅拌过夜。待反应完成，加入乙酸乙酯(20mL)，用饱和食盐水洗涤(20mL×3)，将有机相用无水硫酸钠干燥，过滤。滤液浓缩，通过柱层析(PE/EA＝2:1)纯化得到120mg黄色油状化合物，产率71.85％，[M+H] +:569.2。 Compound 32-2 (150 mg, 0.29 mmol), 45-1 (82 mg, 0.59 mmol) and potassium carbonate (122 mg, 0.88 mmol) were dissolved in DMF (5 mL), and stirred overnight at room temperature. After the reaction was complete, ethyl acetate (20 mL) was added, washed with saturated brine (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by column chromatography (PE/EA=2:1) to obtain 120 mg of yellow oily compound, yield 71.85%, [M+H] + : 569.2.
步骤2：合成1-(5-(2-氟苯基)-1-((3-(1-(2-甲氧基乙基)-1H-吡唑-4-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲胺盐酸盐(III-45)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)phenyl)sulfonyl )-1H-pyrrol-3-yl)-N-methylamine hydrochloride (III-45)
在室温下，将化合物45-2(120mg,0.21mmol)溶解在1，4-二氧六环(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2mL)室温搅拌2h。将反应液浓缩得到白色固体化合物92mg，产率86.79％，[M+H] +:469.2。 Dissolve compound 45-2 (120mg, 0.21mmol) in 1,4-dioxane (2mL) solution at room temperature, then add 4M hydrochloric acid/1,4-dioxane (2mL) and stir at room temperature for 2h . The reaction liquid was concentrated to obtain 92 mg of white solid compound, the yield was 86.79%, [M+H] + : 469.2.
1H NMR(400MHz,CD 3OD)δ8.04(s,1H),7.86(d,J＝8.0Hz,1H),7.82(s,2H),7.51-7.46(m,3H),7.38(d,J＝7.6Hz,1H),7.18-7.04(m,3H),6.42(s,1H),4.37(t,J＝4.8Hz,2H),4.11(s,2H),3.81(t,J＝4.8Hz,2H),3.38(s,3H),2.71(s,3H). 1 H NMR (400MHz, CD 3 OD) δ8.04(s, 1H), 7.86(d, J=8.0Hz, 1H), 7.82(s, 2H), 7.51-7.46(m, 3H), 7.38(d ,J=7.6Hz,1H),7.18-7.04(m,3H),6.42(s,1H),4.37(t,J=4.8Hz,2H),4.11(s,2H),3.81(t,J= 4.8Hz,2H),3.38(s,3H),2.71(s,3H).
实施例46Example 46
1-(1-((3-(2,3-二氢噻吩并[3,4-b][1,4]二恶英-5-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-46)的合成1-(1-((3-(2,3-Dihydrothieno[3,4-b][1,4]dioxin-5-yl)phenyl)sulfonyl)-5-(2- Synthesis of Fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine Hydrochloride (III-46)
Figure PCTCN2022104528-appb-000065
Figure PCTCN2022104528-appb-000065
步骤1：合成叔丁基((1-((3-(2,3-二氢噻吩并[3,4-b][1,4]二恶英-5-基)苯基)磺酰基)-5-(2-氟 苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸(46-2)Step 1: Synthesis of tert-butyl ((1-((3-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)phenyl)sulfonyl) -5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (46-2)
在50ml单口瓶中加入化合物Int 1(300mg,0.573mmol)，46-1(225mg,0.85mmol)，Pd(OAc) 2(13mg,0.057mmol)，PCy 3.HBF 4(42mg,0.115mmol)，PivOH(30mg,0.287mmol)和K 2CO 3(159mg,1.146mmol)，加入甲苯(10mL)溶解，氮气保护下在110℃下反应过夜。反应结束后，加水(20mL)，用乙酸乙酯(40mL×2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸镁干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(hex/EA＝1:1)得到黄色油状物92mg，产率27.46％，[M-100+H] +:485.13。 Add compound Int 1 (300mg, 0.573mmol), 46-1 (225mg, 0.85mmol), Pd(OAc) 2 (13mg, 0.057mmol), PCy 3 .HBF 4 (42mg, 0.115mmol) in a 50ml one-port bottle, PivOH (30mg, 0.287mmol) and K 2 CO 3 (159mg, 1.146mmol) were dissolved in toluene (10mL) and reacted overnight at 110°C under nitrogen protection. After the reaction, add water (20mL), extract with ethyl acetate (40mL×2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate the filtrate under reduced pressure, and separate by column chromatography Purification (hex/EA=1:1) gave 92 mg of yellow oil, yield 27.46%, [M-100+H] + : 485.13.
步骤2：合成1-(1-((3-(2,3-二氢噻吩并[3,4-b][1,4]二恶英-5-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-46)Step 2: Synthesis of 1-(1-((3-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)phenyl)sulfonyl)-5 -(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-46)
在室温下，将化合物46-2(92mg,0.157mmol)溶解在二氯甲烷(2mL)溶液中，然后加入4M盐酸/1,4-二氧六环(1mL)室温搅拌2h。浓缩得到黑灰色固体化合物86mg。产率95.68％，[M+H] +:483.0。 Compound 46-2 (92mg, 0.157mmol) was dissolved in dichloromethane (2mL) at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (1mL) and stirred at room temperature for 2h. Concentration gave 86 mg of dark gray solid compound. Yield 95.68%, [M+H] + : 483.0.
1H NMR(400MHz,CD 3OD)δ7.97(d,J＝8.4Hz,1H),7.75(s,1H),7.61(s,1H),7.47(d,J＝8.0Hz,1H),7.40–7.28(m,3H),7.10–7.06(m,2H),6.99(t,J＝8.8Hz,1H),6.38(,1H),4.35–4.08(m,4H),4.08(s,2H),2.68(s,3H). 1 H NMR (400MHz, CD 3 OD) δ7.97(d, J=8.4Hz, 1H), 7.75(s, 1H), 7.61(s, 1H), 7.47(d, J=8.0Hz, 1H), 7.40–7.28(m,3H),7.10–7.06(m,2H),6.99(t,J＝8.8Hz,1H),6.38(,1H),4.35–4.08(m,4H),4.08(s,2H ),2.68(s,3H).
实施例47Example 47
1-(5-(2-氟苯基)-1-((3'-甲氧基-[1,1'-联苯基]-3-基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-47)的合成1-(5-(2-fluorophenyl)-1-((3'-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-1H-pyrrol-3-yl Synthesis of )-N-methylmethylamine hydrochloride (III-47)
Figure PCTCN2022104528-appb-000066
Figure PCTCN2022104528-appb-000066
步骤1：合成叔丁基((5-(2-氟苯基)-1-((3'-甲氧基-[1,1'-联苯基]-3-基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(47-2)Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3'-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-1H -pyrrol-3-yl)methyl)(methyl)carbamate (47-2)
在室温下，将化合物Int 1(200mg,0.38mmol),化合物47-1(69.7mg,0.46mmol)，碳酸钾(105mg,0.76mmol)，Pd(dppf)Cl 2(27.8mg,0.04mmol)加入1,4-二氧六环(8mL)中，加入水(2mL)，氮气置换3次，升温至100℃搅拌过夜。反应结束，向反应体系加入水(10mL)，用二氯甲烷(20mL×3)萃取，合并有机相，用无水硫酸钠干燥。过滤，将滤液浓缩，通过柱层析(PE/EA＝10:1)纯化得粉红色油状物化合物200mg，产率95.24％，[M+H] +:451.28。 At room temperature, compound Int 1 (200mg, 0.38mmol), compound 47-1 (69.7mg, 0.46mmol), potassium carbonate (105mg, 0.76mmol), Pd(dppf)Cl 2 (27.8mg, 0.04mmol) were added Add water (2 mL) to 1,4-dioxane (8 mL), replace with nitrogen three times, heat up to 100° C. and stir overnight. After the reaction was completed, water (10 mL) was added to the reaction system, extracted with dichloromethane (20 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and purified by column chromatography (PE/EA=10:1) to obtain 200 mg of the pink oily compound, with a yield of 95.24%, [M+H] + : 451.28.
步骤2：合成1-(5-(2-氟苯基)-1-((3'-甲氧基-[1,1'-联苯基]-3-基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-47)Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3'-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-1H-pyrrole -3-yl)-N-methylmethylamine hydrochloride (III-47)
在室温下，将化合物47-2(200mg,0.36mmol)溶解在二氯甲烷(5mL)溶液中，然后加入4M盐酸/1，4-二氧六环(1.5mL)室温搅拌过夜。减压浓缩，得到紫色固体156mg，产率89.14，[M+H] +:451.21。 Compound 47-2 (200 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (1.5 mL) and stirred overnight at room temperature. Concentration under reduced pressure gave 156 mg of purple solid, yield 89.14, [M+H] + : 451.21.
1H NMR(400MHz,CD3OD)δ7.94(d,J＝7.6Hz,1H),7.82(d,J＝2.0Hz,1H),7.59(d,J＝7.6Hz,1H),7.57-7.52(m,2H),7.45-7.39(m,2H),7.14-7.00(m,6H),6.41(d,J＝2.0Hz,1H),4.11(s,2H),3.89(s,3H),2.71(s,3H). 1 H NMR (400MHz, CD3OD) δ7.94(d, J=7.6Hz, 1H), 7.82(d, J=2.0Hz, 1H), 7.59(d, J=7.6Hz, 1H), 7.57-7.52( m,2H),7.45-7.39(m,2H),7.14-7.00(m,6H),6.41(d,J=2.0Hz,1H),4.11(s,2H),3.89(s,3H),2.71 (s,3H).
实施例48Example 48
1-(1-((3'-氟-5'-甲氧基-[1,1'-联苯基]-3-基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-48)的合成1-(1-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H- Synthesis of pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-48)
Figure PCTCN2022104528-appb-000067
Figure PCTCN2022104528-appb-000067
步骤1：合成叔丁基((1-((3'-氟-5'-甲氧基-[1,1'-联苯基]-3-基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(48-2)Step 1: Synthesis of tert-butyl((1-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(2-fluoro Phenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (48-2)
在室温下，将化合物Int 1(200mg,0.38mmol),化合物48-1(77.5mg,0.46mmol)，碳酸钾(105mg,0.76mmol)，Pd(dppf)Cl 2(27.8mg,0.04mmol)加入1,4-二氧六环(8mL)中，加入水(2mL)，氮气置换3次，氮气保护下，升温至100℃搅拌过夜。反应结束，向反应体系加入水(10mL)，用二氯甲烷(20mL×3)萃取，合并有机相，用无水硫酸钠干燥。过滤，将滤液浓缩，通过柱层析(PE/EA＝10:1)纯化得黄色油状物化合物200mg，产率92.56％，[M+H] +:469.24。 At room temperature, compound Int 1 (200mg, 0.38mmol), compound 48-1 (77.5mg, 0.46mmol), potassium carbonate (105mg, 0.76mmol), Pd(dppf)Cl 2 (27.8mg, 0.04mmol) were added Add water (2 mL) to 1,4-dioxane (8 mL), replace with nitrogen three times, and raise the temperature to 100° C. and stir overnight under the protection of nitrogen. After the reaction was completed, water (10 mL) was added to the reaction system, extracted with dichloromethane (20 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and purified by column chromatography (PE/EA=10:1) to obtain 200 mg of yellow oil compound, with a yield of 92.56%, [M+H] + : 469.24.
步骤2：合成1-(1-((3'-氟-5'-甲氧基-[1,1'-联苯基]-3-基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-48)Step 2: Synthesis of 1-(1-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(2-fluorophenyl )-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-48)
在室温下，将化合物48-2(200mg,0.36mmol)溶解在二氯甲烷(5mL)溶液中，然后加入4M盐酸/1，4-二氧六环(2.0mL)室温搅拌过夜。减压浓缩，得到紫色固体160mg，产率90.52％，[M+H] +:469.33。 Compound 48-2 (200 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (2.0 mL) and stirred overnight at room temperature. Concentrate under reduced pressure to obtain 160 mg of purple solid with a yield of 90.52%, [M+H] + : 469.33.
1H NMR(400MHz,CD 3OD)δ7.95(d,J＝7.6Hz,1H),7.83(d,J＝2.0Hz,1H),7.60(t,J＝7.6Hz,1H),7.56(d,J＝7.6Hz,1H),7.53(t,J＝2.0Hz,1H),7.47-7.41(m,1H),7.13(d,J＝5.6Hz,2H),7.05(t,J＝8.8Hz,1H),6.88(s,1H),6.83(m,2H),6.42(d,J＝2.0Hz,1H),4.12(s,2H),3.89(s,3H),2.72(s,3H). 1 H NMR (400MHz, CD 3 OD) δ7.95(d, J=7.6Hz, 1H), 7.83(d, J=2.0Hz, 1H), 7.60(t, J=7.6Hz, 1H), 7.56( d, J=7.6Hz, 1H), 7.53(t, J=2.0Hz, 1H), 7.47-7.41(m, 1H), 7.13(d, J=5.6Hz, 2H), 7.05(t, J=8.8 Hz,1H),6.88(s,1H),6.83(m,2H),6.42(d,J=2.0Hz,1H),4.12(s,2H),3.89(s,3H),2.72(s,3H ).
实施例49Example 49
1-(1-((3',5'-二甲氧基-[1,1'-联苯基]-3-基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(III-49)的合成1-(1-((3',5'-dimethoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole Synthesis of -3-yl)-N-methylmethylamine Hydrochloride (III-49)
Figure PCTCN2022104528-appb-000068
Figure PCTCN2022104528-appb-000068
步骤1：合成叔丁基((1-((3',5'-二甲氧基-[1,1'-联苯基]-3-基)磺酰基)-5-(2-氟邻苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸甲酯(49-2)Step 1: Synthesis of tert-butyl ((1-((3',5'-dimethoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(2-fluoro-o Phenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (49-2)
在50ml单口瓶中加入化合物Int 1(200mg,0.38mmol)，49-1(91mg,0.50mmol)，Pd(dppf)Cl 2(14mg,0.02mmol)和K 2CO 3(106mg,0.76mmol)，加入1,4-二氧六环(10mL)和H 2O(2mL)溶解，氮气保护下在105℃下回流反应过夜。反应结束后，加水(20mL)，用乙酸乙酯(50mL×2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸镁干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(hex/EA＝3:1)得到淡粉色油状物125mg，产率56.35％，[M-100+H] +:481.4。 Add compound Int 1 (200mg, 0.38mmol), 49-1 (91mg, 0.50mmol), Pd(dppf)Cl 2 (14mg, 0.02mmol) and K 2 CO 3 (106mg, 0.76mmol) in a 50ml one-port bottle, Add 1,4-dioxane (10 mL) and H 2 O (2 mL) to dissolve, and react under reflux at 105° C. under nitrogen protection overnight. After the reaction, add water (20mL), extract with ethyl acetate (50mL×2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate the filtrate under reduced pressure, and separate by column chromatography Purification (hex/EA=3:1) gave 125mg of a light pink oily substance, with a yield of 56.35%, [M-100+H] + : 481.4.
步骤2：合成1-(1-((3',5'-二甲氧基-[1,1'-联苯基]-3-基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺氯化氢盐(III-49)Step 2: Synthesis of 1-(1-((3',5'-dimethoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(2-fluorophenyl) -1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (III-49)
在室温下，将化合物49-2(125mg,0.22mmol)溶解在二氯甲烷(2mL)溶液中，然后加入4M盐酸/1，4-二氧六环(5mL)室温搅拌2h。浓缩，加入少量正己烷，旋干，得到黄白色固体化合物112mg。产率100％，[M+H] +:481.27。 Compound 49-2 (125mg, 0.22mmol) was dissolved in dichloromethane (2mL) solution at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (5mL) and stirred at room temperature for 2h. Concentrate, add a small amount of n-hexane, and spin dry to obtain 112 mg of yellow-white solid compound. Yield 100%, [M+H] + : 481.27.
1H NMR(400MHz,CD 3OD)δ7.90(d,J＝7.6Hz,1H),7.81(d,J＝2.0Hz,1H),7.587.49(m,3H),7.41(d,J＝8.4Hz,1H),7.13–7.06(m,2H),7.02(d,J＝9.6Hz,1H),6.60(d,J＝2.4Hz,2H), 6.56(t,J＝2.4Hz,1H),6.41(d,J＝1.6Hz,1H),4.09(s,2H),3.84(s,6H),2.69(s,3H). 1 H NMR (400MHz, CD 3 OD) δ7.90(d, J=7.6Hz, 1H), 7.81(d, J=2.0Hz, 1H), 7.587.49(m, 3H), 7.41(d, J ＝8.4Hz, 1H), 7.13–7.06(m, 2H), 7.02(d, J＝9.6Hz, 1H), 6.60(d, J＝2.4Hz, 2H), 6.56(t, J＝2.4Hz, 1H ), 6.41(d, J=1.6Hz, 1H), 4.09(s, 2H), 3.84(s, 6H), 2.69(s, 3H).
实施例50Example 50
1-(3-((2-(2-氟苯基)-4-((甲氨基)甲基)-1H-吡咯-1-基)磺酰基)苯基)氮杂环丁烷-2-酮盐酸盐(III-50)的合成1-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)azetidine-2- Synthesis of Ketone Hydrochloride (III-50)
Figure PCTCN2022104528-appb-000069
Figure PCTCN2022104528-appb-000069
步骤1：合成叔丁基((5-(2-氟苯基)-1-((3-(2-氧氮杂环丁烷-1-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(50-2)Step 1: Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-(2-oxazetidin-1-yl)phenyl)sulfonyl)-1H-pyrrole- 3-yl)methyl)(methyl)carbamate (50-2)
在50ml单口瓶中加入化合物Int 1(100mg,0.19mmol)，50-1(71mg,0.29mmol)，xantphos(28mg,0.05mmol)，Pd(OAc)2(43mg,0.19mmol)和Cs 2CO 3(125mg,0.38mmol)，加入甲苯(6mL)溶解，氮气保护下在110℃下反应过夜。反应结束后，加水(10mL)洗涤，用乙酸乙酯(20mL×2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸镁干燥，过滤，滤液通过减压浓缩，柱层析分离纯化(hex/EA＝2:1)得到淡黄色油状物50mg，产率50.97％，[M-100+H] +:414.26。 Add compound Int 1 (100mg, 0.19mmol), 50-1 (71mg, 0.29mmol), xantphos (28mg, 0.05mmol), Pd(OAc) 2 (43mg, 0.19mmol) and Cs 2 CO 3 in a 50ml one-port bottle (125mg, 0.38mmol), add toluene (6mL) to dissolve, and react overnight at 110°C under nitrogen protection. After the reaction, add water (10mL) to wash, extract with ethyl acetate (20mL×2), combine the organic phases, wash the organic phase with saturated brine, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure, column chromatography Separation and purification (hex/EA=2:1) gave 50 mg of light yellow oil, yield 50.97%, [M-100+H] + : 414.26.
步骤2：合成1-(3-((2-(2-氟苯基)-4-((甲氨基)甲基)-1H-吡咯-1-基)磺酰基)苯基)氮杂环丁烷-2-酮盐酸盐(III-50)Step 2: Synthesis of 1-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)azetidine Alkan-2-one hydrochloride (III-50)
在室温下，将化合物50-2(50mg,0.10mmol)溶解在二氯甲烷(1mL)溶液中，然后加入4M盐酸/1,4-二氧六环(3mL)室温搅拌3h。浓缩，加入少量正己烷，旋干，得到棕黄色固体化合物30mg。产率68.74％，[M+H] +:414.25。 Compound 50-2 (50 mg, 0.10 mmol) was dissolved in dichloromethane (1 mL) at room temperature, then added with 4M hydrochloric acid/1,4-dioxane (3 mL) and stirred at room temperature for 3 h. Concentrate, add a small amount of n-hexane, and spin dry to obtain 30 mg of brown-yellow solid compound. Yield 68.74%, [M+H] + : 414.25.
1H NMR(400MHz,CD 3OD)δ7.77(d,J＝2.0Hz,1H),7.55–7.52(m,1H),7.47(d,J＝5.2Hz,2H),7.20–7.14(m,2H),7.12–7.04(m,3H),6.40(d,J＝2.0Hz,1H),4.11(s,2H),3.65(t,J＝4.8Hz,2H),3.16(t,J＝4.8Hz,2H),2.71(s,3H). 1 H NMR (400MHz, CD 3 OD) δ7.77(d, J=2.0Hz, 1H), 7.55–7.52(m, 1H), 7.47(d, J=5.2Hz, 2H), 7.20–7.14(m ,2H),7.12–7.04(m,3H),6.40(d,J=2.0Hz,1H),4.11(s,2H),3.65(t,J=4.8Hz,2H),3.16(t,J= 4.8Hz,2H),2.71(s,3H).
实施例51Example 51
1-(1-((3-(1,4-二氧杂-8-氮杂螺环[4.5]癸-8-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺(III-51)的合成1-(1-((3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)- Synthesis of 1H-pyrrol-3-yl)-N-methylmethylamine (III-51)
Figure PCTCN2022104528-appb-000070
Figure PCTCN2022104528-appb-000070
步骤1：合成叔丁基((1-((3-(1,4-二氧杂-8-氮杂螺环[4.5]癸-8-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(51-2)Step 1: Synthesis of tert-butyl ((1-((3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)sulfonyl)-5-(2 -Fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (51-2)
在室温下，将化合物Int 1(200mg,0.38mmol),化合物51-1(61mg,0.42mmol)，Pd(OAc) 2(8.5mg,0.04mmol)，xantphos(26.4mg,0.05mmol),碳酸铯(248mg,0.76mmol)加入甲苯(5mL)中，氮气置换3次，升温至100℃，搅拌过夜。反应结束，将反应体系减压浓缩，通过柱层析(PE/EA＝10:1),得到油状物化合物150mg，产率67.38％，[M+H] +:529.19。 At room temperature, compound Int 1 (200mg, 0.38mmol), compound 51-1 (61mg, 0.42mmol), Pd(OAc) 2 (8.5mg, 0.04mmol), xantphos (26.4mg, 0.05mmol), cesium carbonate (248mg, 0.76mmol) was added to toluene (5mL), replaced with nitrogen three times, heated to 100°C, and stirred overnight. After the reaction was completed, the reaction system was concentrated under reduced pressure, and 150 mg of oily compound was obtained by column chromatography (PE/EA=10:1), with a yield of 67.38%, [M+H] + : 529.19.
步骤2：合成1-(1-((3-(1,4-二氧杂-8-氮杂螺环[4.5]癸-8-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺(III-51)Step 2: Synthesis of 1-(1-((3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)sulfonyl)-5-(2-fluoro Phenyl)-1H-pyrrol-3-yl)-N-methylmethylamine (III-51)
在室温下，将化合物51-2(150mg,0.26mmol)溶解在二氯甲烷(5mL)溶液中，然后加入三氟乙酸(1.5mL)，室温搅拌2h，加入水(5mL)，加入碳酸钾水溶液，调节pH＝8，分液得有机相，水相用二氯甲烷(10mL)萃取一次，合并有机相，用无水硫酸钠干燥，过滤，得滤液，将滤液45℃减压浓缩，得到黄色油状物100mg，产率79.21％，[M+H] +:486.27。 Dissolve compound 51-2 (150mg, 0.26mmol) in dichloromethane (5mL) solution at room temperature, then add trifluoroacetic acid (1.5mL), stir at room temperature for 2h, add water (5mL), add potassium carbonate aqueous solution , adjusted to pH=8, separated to obtain an organic phase, the aqueous phase was extracted once with dichloromethane (10mL), the organic phases were combined, dried with anhydrous sodium sulfate, filtered to obtain a filtrate, and the filtrate was concentrated under reduced pressure at 45°C to obtain a yellow Oil 100 mg, yield 79.21%, [M+H] + : 486.27.
1H NMR(400MHz,CD 3OD)δ7.51(s,1H),7.45(t,J＝7.2Hz,1H),7.32-7.26(m,1H),7.19(d,J＝8.4Hz,1H),7.16(d,J＝7.4Hz,1H),7.13-7.06(m,2H),6.89(d,J＝7.6Hz,1H),6.82(t,J＝2.4Hz,1H),6.30(d,J＝2.0Hz,1H),4.01(s,4H),3.68(s,2H),3.30-3.26(m,4H),2.43(s,3H),1.79-1.70(m,4H). 1 H NMR (400MHz, CD 3 OD) δ7.51(s, 1H), 7.45(t, J=7.2Hz, 1H), 7.32-7.26(m, 1H), 7.19(d, J=8.4Hz, 1H ), 7.16(d, J=7.4Hz, 1H), 7.13-7.06(m, 2H), 6.89(d, J=7.6Hz, 1H), 6.82(t, J=2.4Hz, 1H), 6.30(d ,J＝2.0Hz,1H),4.01(s,4H),3.68(s,2H),3.30-3.26(m,4H),2.43(s,3H),1.79-1.70(m,4H).
实施例52Example 52
1-(1-((3-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺(III-52)的合成1-(1-((3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H- Synthesis of pyrrol-3-yl)-N-methylmethylamine (III-52)
Figure PCTCN2022104528-appb-000071
Figure PCTCN2022104528-appb-000071
步骤1：合成(3-溴苯磺酰基)-5-(2-氟苯基)-1H-吡咯-3-甲醛(52-1)Step 1: Synthesis of (3-bromobenzenesulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (52-1)
在冰浴下，将化合物Int 1-1(2.0g，10.58mmol)溶解在DMF(15mL)中，加入氢化钠(635mg，15.87mmol)，搅拌30分钟，然后向反应体系中加入化合物Int 3-6(3.3g，12.69mmol)，继续搅拌2h。待反应完成后，加入饱和氯化铵的水溶液淬灭反应，用乙酸乙酯(30mL×2)萃取，合并有机相用饱和食盐水(50mL×1)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩，通过柱层析(PE/EA＝3:1)纯化得到3.8g棕色油状化合物Under ice bath, compound Int 1-1 (2.0g, 10.58mmol) was dissolved in DMF (15mL), sodium hydride (635mg, 15.87mmol) was added, stirred for 30 minutes, then compound Int 3- was added to the reaction system 6 (3.3g, 12.69mmol), stirring was continued for 2h. After the reaction was completed, the aqueous solution of saturated ammonium chloride was added to quench the reaction, extracted with ethyl acetate (30mL×2), the combined organic phase was washed with saturated brine (50mL×1), and the organic phase was dried over anhydrous sodium sulfate. Filtration, concentration under reduced pressure, and purification by column chromatography (PE/EA=3:1) gave 3.8g of brown oily compound
步骤2：合成1-((3-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-甲醛(52-3)Step 2: Synthesis of 1-((3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H -Pyrrole-3-carbaldehyde (52-3)
在50mL单口瓶中加入化合物52-1(300mg,0.74mmol)，52-2(235mg,0.88mmol)，K 2CO 3(203mg,1.48mmol)，Pd(dppf)Cl 2(27mg,0.04mmol)，用1,4-二氧六环(15mL)和水(3mL)溶解，氮气保护下85℃加热搅拌反应过夜。反应结束后，冷却至室温，加水(20mL)洗涤，乙酸乙酯(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸镁干燥，过滤，旋干，硅胶柱层析(hex/EA＝2:1)得到淡黄色油状物322mg，产率93.71％，[M+H] +:468.20。 Add compound 52-1 (300mg, 0.74mmol), 52-2 (235mg, 0.88mmol), K 2 CO 3 (203mg, 1.48mmol), Pd(dppf)Cl 2 (27mg, 0.04mmol) into a 50mL one-port bottle , dissolved in 1,4-dioxane (15 mL) and water (3 mL), heated and stirred at 85° C. under nitrogen protection overnight. After the reaction, cool to room temperature, wash with water (20mL), extract with ethyl acetate (50mL×2), wash the organic phase with saturated brine, dry over anhydrous magnesium sulfate, filter, spin dry, silica gel column chromatography (hex/ EA=2:1) to obtain 322mg of light yellow oil, yield 93.71%, [M+H] + : 468.20.
步骤3：合成1-(1-((3-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺(III-52)Step 3: Synthesis of 1-(1-((3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl )-1H-pyrrol-3-yl)-N-methylmethylamine (III-52)
在50mL单口瓶中将化合物52-3(135mg,0.29mmol)，甲胺(120mg,1.16mmol，30％wt)，用二氯甲烷(4mL)溶解，室温搅拌30min，冰浴条件下加入三乙酰氧基硼氢化钠(245mg,1.16mmol)，氮气保护下升至室温反应过夜。反应完毕，加水10mL淬灭反应，用DCM(30mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸镁干燥，过滤，旋干，TLC制备(DCM/MeOH＝8:1)得到淡紫色固体88mg。产率63.10％，[M+H] +:483.26。 Dissolve compound 52-3 (135mg, 0.29mmol), methylamine (120mg, 1.16mmol, 30%wt) in dichloromethane (4mL) in a 50mL single-necked bottle, stir at room temperature for 30min, and add triacetyl Sodium oxyborohydride (245mg, 1.16mmol) was reacted overnight at room temperature under nitrogen protection. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with DCM (30 mL×2), the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and spin-dried, prepared by TLC (DCM/MeOH=8:1) to obtain light Purple solid 88mg. Yield 63.10%, [M+H] + : 483.26.
1H NMR(400MHz,DMSO)δ7.75(d,J＝8.0Hz,1H),7.60(s,1H),7.55-7.45(m,2H),7.40–7.35(m,1H),7.27(t,J＝2.0Hz,1H),7.23–7.17(m,2H),7.10-7.02(m,1H),6.40(s,1H),6.01(s,1H),3.94(s,4H),3.69(s,2H),2.45–2.41(m,2H),2.40–2.37(m,2H),2.33(s,3H),1.81(t,J＝6.4Hz,2H). 1 H NMR (400MHz, DMSO) δ7.75(d, J=8.0Hz, 1H), 7.60(s, 1H), 7.55-7.45(m, 2H), 7.40–7.35(m, 1H), 7.27(t ,J＝2.0Hz,1H),7.23–7.17(m,2H),7.10-7.02(m,1H),6.40(s,1H),6.01(s,1H),3.94(s,4H),3.69( s,2H),2.45–2.41(m,2H),2.40–2.37(m,2H),2.33(s,3H),1.81(t,J＝6.4Hz,2H).
实施例53Example 53
1-(1-((3-(1,4-二氧杂螺[4.5]癸烷-8-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺(III-53)的合成1-(1-((3-(1,4-dioxaspiro[4.5]decane-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3 Synthesis of -yl)-N-methylmethylamine (III-53)
Figure PCTCN2022104528-appb-000072
Figure PCTCN2022104528-appb-000072
步骤1：合成1-((3-(1,4-二氧杂螺[4.5]癸烷-8-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-甲醛(53-1)Step 1: Synthesis of 1-((3-(1,4-dioxaspiro[4.5]decane-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole- 3-Formaldehyde (53-1)
在25mL单口瓶中将化合物52-3(60mg,0.13mmol)，用乙酸乙酯(5mL)溶解，加入Pd/C(15mg,10％wt)，氢气保护下室温搅拌反应过夜。反应完毕，抽滤，EA多次洗涤滤饼，有机相旋干，得到淡黄色油状物60mg。产率99.18％，[M+H] +:470.26。 Compound 52-3 (60mg, 0.13mmol) was dissolved in ethyl acetate (5mL) in a 25mL single-necked bottle, Pd/C (15mg, 10%wt) was added, and the reaction was stirred overnight at room temperature under the protection of hydrogen. After the reaction was completed, suction filtered, EA washed the filter cake several times, and the organic phase was spin-dried to obtain 60 mg of light yellow oil. Yield 99.18%, [M+H] + : 470.26.
步骤2：合成1-(1-((3-(1,4-二氧杂螺[4.5]癸烷-8-基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺(III-53)Step 2: Synthesis of 1-(1-((3-(1,4-dioxaspiro[4.5]decane-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H -pyrrol-3-yl)-N-methylmethylamine (III-53)
在50mL单口瓶中加入化合物53-1(60mg,0.13mmol)，甲胺(53mg,0.52mmol,30％wt)，用DCM(5mL)溶解，室温搅拌30min，冰浴条件下加入三乙酰氧基硼氢化钠(109mg,0.52mmol)和一滴冰醋酸，自然升至室温反应6h。反应结束后，加水10mL淬灭，DCM(20mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸镁干燥，过滤，旋干，TLC制备(DCM/MeOH＝8:1)得到黄白色固体35mg，产率56.45％，[M+H] +:485.23。 Add compound 53-1 (60mg, 0.13mmol), methylamine (53mg, 0.52mmol, 30%wt) into a 50mL single-necked bottle, dissolve with DCM (5mL), stir at room temperature for 30min, add triacetoxy Sodium borohydride (109mg, 0.52mmol) and a drop of glacial acetic acid were reacted at room temperature for 6h naturally. After the reaction, add 10 mL of water to quench, extract with DCM (20 mL×2), wash the organic phase with saturated brine, dry over anhydrous magnesium sulfate, filter, spin dry, prepare by TLC (DCM/MeOH=8:1) to obtain yellow-white Solid 35 mg, yield 56.45%, [M+H] + : 485.23.
1H NMR(400MHz,DMSO-d 6)δ7.56(d,J＝7.6Hz,1H),7.51–7.44(m,3H),7.36(d,J＝7.8Hz,1H),7.23–7.18(m,2H),7.14(d,J＝2.0Hz,1H),7.10-7.05(m,1H),6.33(d,J＝2.0Hz,1H), 1 H NMR (400MHz, DMSO-d 6 ) δ7.56 (d, J=7.6Hz, 1H), 7.51–7.44 (m, 3H), 7.36 (d, J=7.8Hz, 1H), 7.23–7.18( m,2H),7.14(d,J=2.0Hz,1H),7.10-7.05(m,1H),6.33(d,J=2.0Hz,1H),
4.01-3.95(m,4H),3.53(s,2H),2.62-2.54(m,1H),2.24(s,3H),1.77–1.67(m,4H),1.63–1.51(m,4H).4.01-3.95(m,4H),3.53(s,2H),2.62-2.54(m,1H),2.24(s,3H),1.77–1.67(m,4H),1.63–1.51(m,4H).
H +/K +-ATPase生物学评价 Biological evaluation of H + /K + -ATPase
下面的体外筛选试验是用来测定本发明化合物对于H +/K +-ATPase酶活性的抑制作用。 The following in vitro screening test is used to determine the inhibitory effect of the compounds of the present invention on the enzymatic activity of H + /K + -ATPase.
实验材料及仪器：Experimental materials and instruments:
ATP、孔雀石绿、缬氨霉素、钼酸铵ATP, malachite green, valinomycin, ammonium molybdate
无K +缓冲液：50mM Tris-HCl pH 6.5，5mM magnesium chloride，10μM valinomycin K + -free buffer: 50mM Tris-HCl pH 6.5, 5mM magnesium chloride, 10μM valinomycin
含K +缓冲液：50mM Tris-HCl pH 6.5，5mM magnesium chloride，10μM valinomycin，20mM KCl MLG显色液：0.1％w/v孔雀石绿，1.5％w/v钼酸铵，0.2％v/v Tween-20 兔胃黏膜微粒体(富含H +/K +-ATPase)，提取方法为蔗糖梯度离心：把兔胃用分别自来水，3MNaCl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％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100000g离心90min，收集沉淀；利用匀浆液悬浮沉淀，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。 K + containing buffer: 50mM Tris-HCl pH 6.5, 5mM magnesium chloride, 10μM valinomycin, 20mM KCl MLG chromogenic solution: 0.1% w/v malachite green, 1.5% w/v ammonium molybdate, 0.2% v/v Tween-20 rabbit gastric mucosal microsomes (rich in H + /K + -ATPase), the extraction method is sucrose gradient centrifugation: the rabbit stomach is washed with tap water and 3M NaCl solution, and then the surface water is removed with filter paper. Add pre-cooled homogenization buffer (4ml/g tissue), and homogenize in a tissue homogenizer for 2-5min. 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 at 100,000g for 90min to collect the precipitate; use the homogenate to suspend the precipitate, blow it evenly, measure the protein concentration by the Bradford method, adjust the concentration to 10mg/ml; (H + /K + -ATPaseenriched gastric membranes) were collected in a clean centrifuge tube, diluted 4-5 times with the homogenate, and centrifuged at 100,000 g for 90 minutes to collect the precipitate; the homogenate was used to suspend the sediment, homogenate evenly, and the protein was measured by the Bradford method Concentration, adjust the concentration to 22.5mg/ml. Freeze at -80°C for later use.
实验过程：experiment procedure:
45μL缓冲液(含K +缓冲液：50mM Tris-HCl pH 6.5，5mM magnesium chloride，10μM valinomycin，20mM KCl)中加入5μL的胃粘膜微粒体(H +/K +-ATPase)，再加入5μL的化合物溶液，然后加入5μL 5mM的ATP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。 Add 5 μL of gastric mucosal microsomes (H + /K + -ATPase) to 45 μL of buffer (containing K + buffer: 50 mM Tris-HCl pH 6.5, 5 mM magnesium chloride, 10 μM valinomycin, 20 mM KCl), and then add 5 μL of the compound solution, and then add 5 μL of 5mM ATP to start the reaction, and pre-react at 37°C for 30min. Add 15 μL malachite green solution to terminate the reaction, equilibrate at room temperature for 20 min, and read the absorbance value at 620 nm.
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。At the same time, the same volume was carried out without adding potassium chloride as the background, which was subtracted when calculating the enzyme activity.
化合物IC 50值通过不同浓度下的抑制率计算得到，本发明的化合物对对H +/K +-ATPase具有明显的抑制活性，IC 50为20至100nM，优选的为20至50nM。其中对照组1选自Vonoprazan(沃诺拉赞)，其制备方法参照专利CN101300229A；对照组2选自具有如下结构式。 The IC 50 value of the compound is calculated by the inhibition rate at different concentrations. The compound of the present invention has obvious inhibitory activity on H + /K + -ATPase, and the IC 50 is 20 to 100 nM, preferably 20 to 50 nM. Wherein the control group 1 is selected from Vonoprazan (Vonoprazan), and its preparation method refers to the patent CN101300229A; the control group 2 is selected from the group with the following structural formula.
Figure PCTCN2022104528-appb-000073
Figure PCTCN2022104528-appb-000073
本发明的部分化合物的IC 50值(H +/K +-ATPase)示于下表1中； The IC 50 values (H + /K + -ATPase) of some compounds of the present invention are shown in Table 1 below;
表1：Table 1:
Figure PCTCN2022104528-appb-000074
Figure PCTCN2022104528-appb-000074
Figure PCTCN2022104528-appb-000075
Figure PCTCN2022104528-appb-000075
本发明化合物对H +/K +-ATPase具有明显的抑制活性。 The compound of the present invention has obvious inhibitory activity on H + /K + -ATPase.
体外细胞毒实验In vitro cytotoxicity test
利用Dulbecco的改进Eagle培养基(DMEM；Invitrogen)，将源于人肝癌的细胞系HepG2在5％和37℃下培养和传代，收集对数生长期细胞，计数，用完全培养基重新悬浮细胞，调整细胞浓度至合适浓度(依照细胞密度优化试验结果确定)，接种96孔板，按照以下platemap加75μL/well细胞悬液。用培养基将待测化合物稀释至所设置的相应作用浓度，按照platemap25μL/well加入细胞。待测化合物的作用浓度均从100μM开始，4倍梯度稀释，共9个浓度，2个复孔。细胞置于37℃，100％相对湿度，5％CO 2培养箱中孵育24h。加入50μL/well CellTiter Glo RT避光孵育30min。轻轻震荡后在Envision进行检测，计算抑制率。 Using Dulbecco's modified Eagle medium (DMEM; Invitrogen), the cell line HepG2 derived from human liver cancer was cultured and subcultured at 5% and 37°C, and the cells in the logarithmic growth phase were collected, counted, and the cells were resuspended with complete medium, Adjust the cell concentration to an appropriate concentration (determined according to the results of the cell density optimization test), inoculate a 96-well plate, and add 75 μL/well cell suspension according to the following platemap. Dilute the compound to be tested with the culture medium to the corresponding effect concentration set, and add 25 μL/well to the cells according to the platemap. The concentration of the compounds to be tested starts from 100 μM, and is serially diluted 4 times, with a total of 9 concentrations and 2 duplicate wells. Cells were incubated at 37°C, 100% relative humidity, 5% CO 2 incubator for 24h. Add 50μL/well CellTiter Glo RT and incubate for 30min in the dark. After shaking gently, detect in Envision and calculate the inhibition rate.
按下式计算药物对各细胞生长的抑制率：细胞生长抑制率％＝(1-As/Ac)×100。The inhibition rate of the drug on each cell growth was calculated according to the formula: cell growth inhibition rate%=(1-As/Ac)×100.
As:样品的OA(细胞+CTG+待测化合物)，As: OA of the sample (cell+CTG+test compound),
Ac:正常生长细胞对照的OA(细胞+CTG+DMSO)。Ac: OA of normal growing cell control (cell+CTG+DMSO).
运用软件Graphpad Prism 6并采用计算公式XY-analysis/Nonlinear regression(curvefit)/Dose response-Inhibition/log(inhibitor)vs.response-Variable slope(four parameters)进行IC 50曲线拟合并计算出IC 50值，实验发现本发明化合物IC 50大于20μM，具有低细胞毒性。 Use the software Graphpad Prism 6 and use the calculation formula XY-analysis/Nonlinear regression (curvefit)/Dose response-Inhibition/log (inhibitor) vs. response-Variable slope (four parameters) to perform IC 50 curve fitting and calculate the IC 50 value , the experiment found that the IC 50 of the compound of the present invention is greater than 20 μM, and has low cytotoxicity.
本发明部分化合物对细胞生长具有低毒性，具体见下表2；Some compounds of the present invention have low toxicity to cell growth, see Table 2 below for details;
表2：Table 2:
化合物编号Compound number IC 50 IC50
III-5III-5 ++++++
III-6III-6 ++++++
III-9III-9 ++++++
III-20III-20 ++++++
III-41III-41 ++++++
对照组1Control group 1 ++++++
注：IC 50>20μM为+++，20μM>IC 50>10μM为++,10μM>IC 50为+。 Note: IC 50 >20μM is +++, 20μM>IC 50 >10μM is ++, 10μM>IC 50 is +.
肝微粒稳定性实验Liver Microparticle Stability Test
制备获取所需的种属肝微粒体(例如小鼠、大鼠、犬、猴子或者人)。以DMSO为稀释剂，配制10mM浓度的试样原液和阳性对照原液。然后用70％乙腈将所有原液稀释至0.25mM的工作浓度。本研究使用的辅助因子为NADPH再生体系，该体系由6.5mM NADP、16.5mM G-6-P、3U/mL G-6-P D组成。淬火试剂为含甲苯磺丁脲和心得安的乙腈溶液。Prepare liver microsomes from the desired species (eg, mouse, rat, dog, monkey, or human). Using DMSO as diluent, prepare 10mM sample stock solution and positive control stock solution. All stocks were then diluted to a working concentration of 0.25 mM with 70% acetonitrile. The cofactor used in this study is the NADPH regeneration system, which consists of 6.5mM NADP, 16.5mM G-6-P, and 3U/mL G-6-PD. The quenching reagent was a solution of tolbutamide and propranolol in acetonitrile.
本研究使用的缓冲液100mM磷酸钾缓冲液。含0.2mg/mL肝微粒体蛋白和1μM试验品/阳性对照的混合物在100mM磷酸钾缓冲液中孵育。The buffer used in this study was 100 mM potassium phosphate buffer. A mixture containing 0.2 mg/mL liver microsomal protein and 1 μM test article/positive control was incubated in 100 mM potassium phosphate buffer.
每一种孵育液取80μL加入300μL淬火试剂中沉淀蛋白，制备0分钟的样品。样品涡旋后，加入20μL的NADPH再生体系。每个孵育液520μL加入130μL的NADPH再生体系引发反应。650μL的最终孵育条件为:0.2mg/mL微粒体蛋白、1μM条带/阳性对照、1.3mM NADP、3.3mM葡萄糖6磷酸、0.6U/mL葡萄糖6磷酸脱氢酶。将混合物放入37℃的水浴中，轻轻摇晃。分别于0、5、10、30、60分钟取100μL的混合物，置于包含300μL淬火试剂沉淀蛋白的96孔板上，离心(5000×g，10分钟)。取80μL上清液加入预先添加160μL超纯水的96孔检测板，用LC-MS/MS进行分析。数据处理获得消除半衰期(T 1/2，T 1/2＝0.693/K)和体外清除率(Cl int)。 Take 80 μL of each incubation solution and add 300 μL quenching reagent to precipitate protein to prepare 0-minute samples. After the sample was vortexed, 20 μL of NADPH regeneration system was added. Add 130 μL of NADPH regeneration system to 520 μL of each incubation solution to initiate the reaction. The final incubation conditions for 650 µL are: 0.2 mg/mL microsomal protein, 1 µM band/positive control, 1.3 mM NADP, 3.3 mM glucose 6 phosphate, 0.6 U/mL glucose 6 phosphate dehydrogenase. Place the mixture in a 37 °C water bath and shake gently. At 0, 5, 10, 30, and 60 minutes, 100 μL of the mixture was taken, placed on a 96-well plate containing 300 μL of quenching reagent to precipitate protein, and centrifuged (5000×g, 10 minutes). Take 80 μL of supernatant and add 160 μL of ultrapure water to a 96-well detection plate, and analyze by LC-MS/MS. Data processing was used to obtain the elimination half-life (T 1/2 , T 1/2 =0.693/K) and in vitro clearance (Cl int ).
本发明的部分化合物在SD大鼠肝微粒体稳定性结果具体见下表3；The stability results of some compounds of the present invention in SD rat liver microsomes are shown in Table 3 below;
表3：table 3:
Figure PCTCN2022104528-appb-000076
Figure PCTCN2022104528-appb-000076
实验发现本发明化合物在肝微粒体中T 1/2(min)>80min，优选的T 1/2(min)>100min，具有良好的肝微粒代谢稳定性。 Experiments have found that the compound of the present invention has T 1/2 (min)>80min, preferably T 1/2 (min)>100min in liver microsomes, and has good metabolic stability of liver microsomes.
药代动力学实验Pharmacokinetic experiment
被研究化合物单次口服或者静脉给药(溶媒5％DMSO+10％Solutol(HS-15)+85％saline)于动物(例如小鼠、大鼠、犬或者猴子)，在固定的时间点取血。血样采集后，立即温和地颠 倒试管至少5次，保证混合充分后放置于冰上。血液用肝素抗凝，然后8000pm离心5分钟，将血清与红细胞分离。用移液器吸岀血清转移至2mL的聚丙烯管，标明化合物的名称和时间点，在进行LC-MS分析前保存在-40℃冰箱，待测。髙浓度样品用空白血浆稀释测定时。样品处理后，用LCMS/MS对血浆中的物质进行定量分析。通过进行了验证的药动学计算机程序，用以这种方式获得的血浆浓度/时曲线来计算药动学参数。实验发现本发明化合物具有较好的药代动力学性质。Single oral or intravenous administration (vehicle 5% DMSO + 10% Solutol (HS-15) + 85% saline) of the compound under study was given to animals (such as mice, rats, dogs or monkeys), and taken at fixed time points Blood. Immediately after blood sample collection, gently invert the tube at least 5 times to ensure thorough mixing and place on ice. The blood was anticoagulated with heparin, and then centrifuged at 8000pm for 5 minutes to separate the serum from the red blood cells. Aspirate the serum with a pipette and transfer it to a 2mL polypropylene tube, mark the name and time point of the compound, and store it in a -40°C refrigerator before LC-MS analysis for testing. When high concentration samples are diluted with blank plasma for determination. After sample processing, the substances in the plasma were quantified by LCMS/MS. The plasma concentration/time curves obtained in this way were used to calculate the pharmacokinetic parameters by means of a validated pharmacokinetic computer program. Experiments have found that the compound of the present invention has better pharmacokinetic properties.
SD雄性大鼠以表4组别剂量口服给药后(各组为等摩尔剂量给药，溶媒为5％DMSO+10％Solutol(HS-15)+85％saline，每组3只)，在固定的时间点取血检测。本发明的部分化合物的在大鼠血浆中的原型游离分子药代动力学参数如下表4；SD male rats were orally administered with the doses of groups in Table 4 (each group was administered with an equimolar dose, and the vehicle was 5% DMSO+10% Solutol (HS-15)+85% saline, 3 rats in each group). Blood testing at fixed time points. The pharmacokinetic parameters of the prototype free molecules in rat plasma of some compounds of the present invention are shown in Table 4 below;
表4：Table 4:
Figure PCTCN2022104528-appb-000077
Figure PCTCN2022104528-appb-000077
实验发现本发明化合物在大鼠血浆中的原型游离分子的AUC相比对照组在血浆中的原型游离分子的AUC提高了50％以上，具有良好的药代动力学性质。Experiments have found that the AUC of the prototype free molecule of the compound in rat plasma is increased by more than 50% compared with the AUC of the prototype free molecule in plasma of the control group, and has good pharmacokinetic properties.
雄性比格犬以表5组别剂量口服给药后(各组为等摩尔剂量给药，溶媒为5％DMSO+10％Solutol(HS-15)+85％saline，每组3只)，在固定的时间点取血检测。本发明的部分化合物的在比格犬血浆中的原型游离分子药代动力学参数如下表5；After oral administration of male Beagle dogs with table 5 group doses (each group is an equimolar dose administration, vehicle is 5%DMSO+10%Solutol (HS-15)+85%saline, every group 3), in Blood testing at fixed time points. The prototype free molecular pharmacokinetic parameters of some compounds of the present invention in beagle dog plasma are as follows in Table 5;
表5：table 5:
Figure PCTCN2022104528-appb-000078
Figure PCTCN2022104528-appb-000078
Figure PCTCN2022104528-appb-000079
Figure PCTCN2022104528-appb-000079
实验发现本发明化合物在比格犬血浆中的原型游离分子的AUC相比对照组在血浆中的原型游离分子的AUC提高了20％以上，半衰期有显著延长，具有良好的药代动力学性质。Experiments have found that the AUC of the prototype free molecule of the compound in beagle dog plasma has increased by more than 20% compared with the AUC of the prototype free molecule in the plasma of the control group, the half-life is significantly prolonged, and has good pharmacokinetic properties.
急性毒性实验Acute Toxicity Test
化合物单次静脉给药(溶媒5％DMSO+10％Solutol(HS-15)+85％saline)于SD大鼠(每个化合物设置4-6剂量组，每剂量组10只，雌性各半)，给药后后进行临床观察。临床观察第一天两次，第二天开始一天一次，连续14天。包括行为学观察、自主活动和神经系统行为和死亡情况等，得到化合物的最大耐受量(MTD值)和半数致死量(LD 50值)。实验结果下表6； Single intravenous administration of the compound (vehicle 5% DMSO+10% Solutol (HS-15)+85% saline) in SD rats (4-6 dose groups for each compound, 10 rats in each dose group, half female) , clinical observation after administration. The clinical observation was performed twice on the first day, once a day from the second day, for 14 consecutive days. The maximum tolerated dose (MTD value) and median lethal dose (LD 50 value) of the compound were obtained by including behavioral observation, autonomic activity, nervous system behavior and death conditions. The experimental results are shown in Table 6 below;
表6：Table 6:
编号Numbering MTD值(mg/kg)MTD value (mg/kg) LD 50值(mg/kg) LD50 value (mg/kg)
对照组1Control group 1 3.753.75 21.8821.88
III-20III-20 27.3127.31 44.2344.23
实验发现本发明化合物在大鼠单次静脉给药的MTD值和LD 50值相比对照组有显著提高，MTD值提高了7倍，LD 50值提高了2倍，具有良好的安全性。 Experiments have found that the MTD value and LD 50 value of the compound of the present invention in a single intravenous administration to rats are significantly improved compared with the control group, the MTD value is increased by 7 times, and the LD 50 value is increased by 2 times, which has good safety.
hERG钾离子通道作用的研究Study on the Function of hERG Potassium Ion Channel
试验系统test system
细胞：中国仓鼠卵巢(CHO)细胞系，CHO-hERG细胞用于本试验。Cells: Chinese hamster ovary (CHO) cell line, CHO-hERG cells were used in this experiment.
细胞培养液及培养条件：完全培养基为F12培养基，补充加入10％胎牛血清，1％
Figure PCTCN2022104528-appb-000080
选择性抗生素(G418)，89μg/mL潮霉素B(HB)。复苏培养基为F12培养基补充加入10％胎牛血清。CHO-hERG细胞生长在37℃(±2℃)、5％CO 2(4％至8％)的高湿度培养箱中。细胞用复苏培养基复苏，完全培养基传代，用于膜片钳试验的细胞在最后一次传代 时换成复苏培养基。 Cell culture medium and culture conditions: the complete medium is F12 medium, supplemented with 10% fetal bovine serum, 1%
Figure PCTCN2022104528-appb-000080
Selective antibiotic (G418), 89 μg/mL hygromycin B (HB). The recovery medium is F12 medium supplemented with 10% fetal bovine serum. CHO-hERG cells were grown in a high humidity incubator at 37°C (±2°C), 5% CO 2 (4% to 8%). Cells were revived with recovery medium, passaged in complete medium, and cells used for patch clamp experiments were replaced with recovery medium at the last passage.
细胞外液及内液成分：Extracellular and intracellular fluid components:
试剂Reagent 外液(mM)External fluid (mM) 内液(mM)Internal fluid (mM)
CaCl2CaCl2 22 5.375.37
MgCl2MgCl2 11 1.751.75
KClKCl 44 120120
NaClNaCl 145145 --
GlucoseGlucose 1010 --
HEPESHEPES 1010 1010
EGTAEGTA -- 55
Na2ATPNa2ATP -- 44
pHpH 7.3-7.47.3-7.4 7.2-7.37.2-7.3
试验方法experiment method
(1)将处于指数生长期的CHO-hERG细胞收集并重悬在ECS中备用。(1) CHO-hERG cells in exponential growth phase were collected and resuspended in ECS for later use.
(2)手动膜片钳试验(2) Manual patch clamp test
全细胞膜片钳技术下记录hERG电流，记录温度为室温。膜片钳放大器输出信号通过数模转换以及2.9KHz低通滤波。数据记录用Patchmaster Pro软件采集。The hERG current was recorded under the whole-cell patch clamp technique, and the recording temperature was room temperature. The output signal of the patch clamp amplifier is converted by digital to analog and filtered by 2.9KHz low pass. Data records were collected with Patchmaster Pro software.
细胞种在细胞记录槽中放置在倒置显微镜载物台上，随机选择记录槽中的一个细胞进行试验。灌流系统固定在倒置显微镜载物台上用ECS持续灌流细胞。The cell species is placed on the inverted microscope stage in the cell recording tank, and a cell in the recording tank is randomly selected for the experiment. The perfusion system was fixed on the inverted microscope stage and cells were continuously perfused with ECS.
用毛细玻璃管制备手动膜片钳试验记录微电极，其中充灌细胞內液。在膜片钳试验当天，使用硼硅酸盐玻璃管(BF150-117-10,SUTTER INSTRUMENT USA)制备电极。电极充灌ICS后电阻在2-5MΩ之间。Microelectrodes for manual patch clamp experiments were prepared from capillary glass tubes filled with intracellular fluid. On the day of the patch clamp test, electrodes were prepared using borosilicate glass tubes (BF150-117-10, SUTTER INSTRUMENT USA). After the electrode is filled with ICS, the resistance is between 2-5MΩ.
钳制电压为-80mV，第一步去极化至+60mV并维持850ms开放hERG通道。然后，电压设置为-50mV并维持1275ms，产生反弹电流或者称为尾电流，尾电流的峰值将被测量并用于分析。最后，电压恢复到钳制电压(-80mV)。试验过程中，这个指令电压程序每间隔15s重复一次。The clamping voltage was -80mV, the first step depolarized to +60mV and maintained for 850ms to open the hERG channel. Then, the voltage is set to -50mV and maintained for 1275ms, resulting in rebound current or tail current, the peak value of tail current will be measured and used for analysis. Finally, the voltage returns to the clamping voltage (-80mV). During the test, this command voltage program is repeated every 15s.
Figure PCTCN2022104528-appb-000081
Figure PCTCN2022104528-appb-000081
手动膜片钳hERG电流测试指令电压程序Manual patch clamp hERG current test command voltage program
在溶媒对照工作溶液灌流的记录开始阶段，监测尾电流峰值直至稳定3条以上扫描曲线 后则可以灌流待测试的供试品/阳性对照工作溶液，直到供试品/阳性对照工作溶液对hERG电流峰值的抑制作用达到稳定状态。一般以最近的连续3个电流曲线峰值基本重合作为判断是否稳定状态的标准。达到稳定态势以后继续灌流下一浓度供试品。一个细胞上可以测试一个或多个供试品/阳性对照，或者同一种药物的多个浓度，不同供试品/阳性对照之间需用溶媒对照工作液冲洗直到hERG电流回复到加药物之前80％以上的大小。同一浓度下各记录细胞抑制率的标准差不超过15％。At the beginning of the recording of the perfusion of the vehicle control working solution, monitor the peak value of the tail current until more than 3 scanning curves are stabilized, then perfuse the test product/positive control working solution to be tested until the test product/positive control working solution has a positive effect on the hERG current. Inhibition of the peak reaches a steady state. Generally, the basic coincidence of the peak values of the latest three consecutive current curves is used as the criterion for judging whether it is in a stable state. After reaching a steady state, continue to perfuse the next concentration of the test product. One or more test articles/positive controls, or multiple concentrations of the same drug can be tested on one cell. Different test articles/positive controls need to be washed with a solvent control working solution until the hERG current returns to 80% before adding the drug. % above the size. The standard deviation of the inhibition rate of each recorded cell under the same concentration is not more than 15%.
阳性对照西沙必利的测试浓度为0.1μM，重复测定两个细胞。根据科学文献报道，0.1μM的西沙必利抑制hERG电流超过50％。(Milnes,J.T.,et al.)。The positive control cisapride was tested at a concentration of 0.1 [mu]M in duplicates of the cells. According to scientific literature reports, cisapride at 0.1 μM inhibits hERG current by more than 50%. (Milnes, J.T., et al.).
(3)手动膜片钳数据接受标准(3) Manual patch clamp data acceptance criteria
封接标准：全细胞模式形成后，施加钳制电压(-80mV)，可以记录到细胞膜相关参数(Cm，Rm以及Ra)。一个好的的全细胞记录应该满足以下条件：路径电阻(Rs)小于10MΩ；膜电阻(Rm)大于500MΩ和膜电容(Cm)小于100pF。Sealing standard: After the whole cell pattern is formed, apply a clamping voltage (-80mV), and the relevant parameters of the cell membrane (Cm, Rm and Ra) can be recorded. A good whole-cell recording should meet the following conditions: path resistance (Rs) less than 10MΩ; membrane resistance (Rm) greater than 500MΩ and membrane capacitance (Cm) less than 100pF.
电流大小：供试品/阳性对照品作用前峰电流幅度在400pA和5000pA之间。否则，放弃该细胞。Current magnitude: The peak current amplitude before the test product/positive control product is acted is between 400pA and 5000pA. Otherwise, discard the cell.
漏电流：在-80mV的钳制电压下，漏电流绝对值应该小于200pA。电流幅度将会用-80mV下的漏电流校正。漏电流绝对值大于200pA的扫描曲线不能用于分析。Leakage current: Under the clamping voltage of -80mV, the absolute value of the leakage current should be less than 200pA. The current amplitude will be corrected for the leakage current at -80mV. Scanning curves whose absolute value of leakage current is greater than 200pA cannot be used for analysis.
数据分析data analysis
对于每个细胞，每一个浓度的供试品及阳性对照的抑制百分比由记录到的电流反应用以下公式算出：(1-供试品/阳性对照灌流后记录到的尾峰值电流/溶媒对照灌流记录到的尾峰值电流(起始电流))×100％。For each cell, the percentage inhibition of each concentration of the test product and the positive control was calculated from the recorded current response using the following formula: (1- tail peak current recorded after perfusion of the test product/positive control/vehicle control perfusion Recorded tail peak current (initial current)) x 100%.
对于每一个浓度记录到所有的细胞抑制百分比取均值，IC 50值由Hill拟合的方法由浓度效应曲线中得出。 For each concentration, all cell inhibition percentages were averaged, and IC50 values were obtained from concentration-effect curves by Hill's method of fitting.
试验结果test results
本发明部分化合物对hERG电流的抑制结果，具体见下表7；The results of inhibition of hERG current by some compounds of the present invention are shown in Table 7 below;
表7：Table 7:
编号Numbering hERGIC 50 hERGIC 50
III-5III-5 ++++++
III-9III-9 ++
III-14III-14 ++
III-15III-15 ++++++
III-20III-20 ++++
III-21III-21 ++++++
III-22III-22 ++++
III-47III-47 ++++++
对照组1Control group 1 ++
注：IC 50>20μM为+++，20μM>IC 50>10μM为++,10μM>IC 50>1μM为+。 Note: IC 50 >20μM is +++, 20μM>IC 50 >10μM is ++, 10μM>IC 50 >1μM is +.
实验发现本发明化合物具有较高的hERG IC 50值，说明本发明化合物心脏毒性风险较低。 Experiments have found that the compound of the present invention has a higher hERG IC 50 value, indicating that the compound of the present invention has a lower risk of cardiotoxicity.
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，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，这些简单变型均属于本发明的保护范围。The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention. These simple modifications All belong to the protection scope of the present invention.
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。In addition, it should be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable way if there is no contradiction. The combination method will not be described separately.

Claims (10)

  1. 一种吡咯磺酰类衍生物、其互变异构体或其立体异构体，及其药学上可接受的盐，其特征在于，所述吡咯磺酰类衍生物的结构如式(I)所示：A pyrrolesulfonyl derivative, its tautomer or its stereoisomer, and a pharmaceutically acceptable salt thereof, characterized in that the structure of the pyrrolesulfonyl derivative is as shown in formula (I) Shown:
    Figure PCTCN2022104528-appb-100001
    Figure PCTCN2022104528-appb-100001
    其中：in:
    环A选自苯基或吡啶基，所述苯基或吡啶基任选被1、2或3个R 1所取代； Ring A is selected from phenyl or pyridyl, which is optionally substituted by 1, 2 or 3 R 1 ;
    环B选自3-12元的杂环基、5-8元的芳基、5-8元的杂芳基、3-12元的环烷基、7-12元的螺环基、7-12元的并环基、7-12元的桥环基，其中，所述环B任选地被1、2或3个R 2所取代或氧代； Ring B is selected from 3-12 membered heterocyclic group, 5-8 membered aryl group, 5-8 membered heteroaryl group, 3-12 membered cycloalkyl group, 7-12 membered spirocyclic group, 7- A 12-membered ring group, a 7-12-membered bridged ring group, wherein the ring B is optionally substituted or oxo by 1, 2 or 3 R 2 ;
    或者环A和环B一起形成稠环芳基；Or ring A and ring B together form a condensed ring aryl;
    R 1选自C 1-6的烷基、C 1-6烷氧基、卤素、氰基、C 2-6炔基、C 2-6烯基、-O-C 1-6烷基-O-C 1-6烷基、NR aR b； R 1 is selected from C 1-6 alkyl, C 1-6 alkoxy, halogen, cyano, C 2-6 alkynyl, C 2-6 alkenyl, -OC 1-6 alkyl-OC 1- 6 alkyl, NR a R b ;
    R 2选自H、C 1-6的烷基、C 1-6烷氧基、卤素、氰基、C 2-6炔基、C 2-6烯基、3-12元的环烷基、-NH 2、-C(＝O)R c、-O-C 1-6烷基-O-C 1-6烷基、-C 1-6烷基-O-C 1-6烷基、-O-C 1-6烷基-C(＝O)NHR d、-S(＝O) m-C 1-6烷基，其中，所述烷基、烷氧基、环烷基任选进一步被1、2或3个氯素所取代； R 2 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, halogen, cyano, C 2-6 alkynyl, C 2-6 alkenyl, 3-12 membered cycloalkyl, -NH 2 , -C(=O)R c , -OC 1-6 alkyl-OC 1-6 alkyl, -C 1-6 alkyl-OC 1-6 alkyl, -OC 1-6 alkyl -C(=O)NHR d , -S(=O) m -C 1-6 alkyl, wherein the alkyl, alkoxy and cycloalkyl are optionally further replaced by 1, 2 or 3 chlorine replaced by
    R 3选自卤素、5-8元的芳基、5-8元的杂芳基；或者两个R 3连同它们连接的碳原子一起形成稠环芳基；其中所述芳基、杂芳基和稠环芳基可任选地进一步被1、2或3个C 1-6烷基、C 1-6烷氧基、卤素所取代； R 3 is selected from halogen, 5-8 membered aryl, 5-8 membered heteroaryl; or two R 3 together with their connected carbon atoms form a condensed ring aryl; wherein the aryl, heteroaryl And the condensed ring aryl can be optionally further substituted by 1, 2 or 3 C 1-6 alkyl, C 1-6 alkoxy, halogen;
    R 4选自C 1-6的烷基；其中所述烷基可任选地进一步被1、2或3个氘、卤素所取代； R 4 is selected from the alkyl group of C 1-6 ; Wherein the alkyl group may be optionally further substituted by 1, 2 or 3 deuterium, halogen;
    R a、R b、R c、R d各自独立的选自H、C 1-6的烷基、3-12元的环烷基； R a , R b , R c , R d are each independently selected from H, C 1-6 alkyl, 3-12 membered cycloalkyl;
    n选自0、1、2、3；n is selected from 0, 1, 2, 3;
    m选自0、1、2。m is selected from 0,1,2.
  2. 如权利要求1所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体，及其药学上可接受的盐，其特征在于，The pyrrolesulfonyl derivatives, their tautomers or their stereoisomers, and pharmaceutically acceptable salts thereof according to claim 1, wherein:
    环B选自3-8元单杂环基、7-12元的桥环基、7-12元的螺杂环基、3-8元杂环基并3-8元杂环基、3-8元单杂环基并3-8元单环烷基、3-8元单杂环基并苯基。Ring B is selected from 3-8 membered monoheterocyclic group, 7-12 membered bridging ring group, 7-12 membered spiroheterocyclic group, 3-8 membered heterocyclic group and 3-8 membered heterocyclic group, 3- 8-membered monoheterocyclic group and 3-8 membered monocycloalkyl group, 3-8 membered monoheterocyclic group and phenyl group.
  3. 如权利要求1所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体，及其药学上可接受的盐，其特征在于，The pyrrolesulfonyl derivatives, their tautomers or their stereoisomers, and pharmaceutically acceptable salts thereof according to claim 1, wherein:
    环B选自：Ring B is selected from:
    Figure PCTCN2022104528-appb-100002
    Figure PCTCN2022104528-appb-100002
    Z 1、Z 2、Z 3各自独立的选自C、O、S、S(＝O)、S(＝O) 2、NR e；R e选自H、C 1-6的烷基、多卤代C 1-6烷基、-C 1-6烷基-O-C 1-6烷基、3-12元的环烷基、-C(＝O)C 1-6烷基； Z 1 , Z 2 , and Z 3 are each independently selected from C, O, S, S(=O), S(=O) 2 , NR e ; R e is selected from H, C 1-6 alkyl, poly Halogenated C 1-6 alkyl, -C 1-6 alkyl-OC 1-6 alkyl, 3-12 membered cycloalkyl, -C(=O)C 1-6 alkyl;
    Z 4、Z 5、Z 6各自独立的选自N、C； Z 4 , Z 5 , and Z 6 are independently selected from N and C;
    L、P各自独立的选自1、2、3、4；L and P are independently selected from 1, 2, 3, 4;
    所述环B任选地被1、2或3个R 2所取代。 The ring B is optionally substituted with 1, 2 or 3 R 2 .
  4. 如权利要求1-2任一项所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体，及其药学上可接受的盐，其特征在于，The pyrrolesulfonyl derivatives, their tautomers or their stereoisomers, and pharmaceutically acceptable salts thereof according to any one of claims 1-2, wherein,
    环B选自：Ring B is selected from:
    Figure PCTCN2022104528-appb-100003
    Figure PCTCN2022104528-appb-100003
    Figure PCTCN2022104528-appb-100004
    Figure PCTCN2022104528-appb-100004
    其中，Z 1选自O、S、NR e；R e选自H、C 1-3的烷基、多卤代C 1-3烷基、3-6元的环烷基、-C(＝O)C 1-6烷基； Wherein, Z 1 is selected from O, S, NR e ; R e is selected from H, C 1-3 alkyl, polyhalogenated C 1-3 alkyl, 3-6 membered cycloalkyl, -C(= O) C 1-6 alkyl;
    所述环B任选地被1、2或3个R 2所取代。 The ring B is optionally substituted with 1, 2 or 3 R 2 .
  5. 如权利要求4任一项所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体，及其药学上可接受的盐，其特征在于，The pyrrolesulfonyl derivatives, their tautomers or their stereoisomers, and pharmaceutically acceptable salts thereof according to any one of claim 4, wherein:
    环B选自：Ring B is selected from:
    Figure PCTCN2022104528-appb-100005
    Figure PCTCN2022104528-appb-100005
  6. 如权利要求1-3任一项所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体，及其药学上可接受的盐，其特征在于，所述R 2选自H、C 1-6烷氧基、卤素；R 3选自卤素；R 4为C 1-6烷基。 The pyrrolesulfonyl derivatives, tautomers or stereoisomers thereof, and pharmaceutically acceptable salts thereof according to any one of claims 1-3, wherein said R is selected from from H, C 1-6 alkoxy, halogen; R 3 is selected from halogen; R 4 is C 1-6 alkyl.
  7. 如权利要求1所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体，及其药学上可接受的盐，其特征在于，所述吡咯磺酰类衍生物选自如下结构的任意一种：The pyrrolesulfonyl derivatives, their tautomers or their stereoisomers, and pharmaceutically acceptable salts thereof according to claim 1, wherein the pyrrolesulfonyl derivatives are selected from Any of the following structures:
    Figure PCTCN2022104528-appb-100006
    Figure PCTCN2022104528-appb-100006
    Figure PCTCN2022104528-appb-100007
    Figure PCTCN2022104528-appb-100007
    Figure PCTCN2022104528-appb-100008
    Figure PCTCN2022104528-appb-100008
    Figure PCTCN2022104528-appb-100009
    Figure PCTCN2022104528-appb-100009
  8. 一种药物组合物，其特征在于，所述药物组合物包括如权利要求1-7中任一项所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体、及其药学上可接受的盐和药用载体和/或赋形剂。A pharmaceutical composition, characterized in that the pharmaceutical composition comprises the pyrrolesulfonyl derivatives, tautomers or stereoisomers thereof as claimed in any one of claims 1-7, and Its pharmaceutically acceptable salts and pharmaceutically acceptable carriers and/or excipients.
  9. 如权利要求1-7中任一项所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体、及其药学上可接受的盐或如权利要求8所述的药物组合物在制备胃酸分泌抑制剂、H +/K +-ATPase抑制剂或钾离子竞争性酸阻滞剂中的用途。 The pyrrolesulfonyl derivatives as described in any one of claims 1-7, its tautomers or stereoisomers thereof, and pharmaceutically acceptable salts thereof, or the medicine as claimed in claim 8 Use of the composition in preparing gastric acid secretion inhibitor, H + /K + -ATPase inhibitor or potassium ion competitive acid blocker.
  10. 如权利要求1-7中任一项所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体、及其药学上可接受的盐或如权利要求8所述的药物组合物在制备治疗或预防如下疾病用药物中的用途：消化性溃疡、卓-艾综合征、胃糜烂性食管炎、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、幽门螺旋杄菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡、手术后应激导致的胃酸过多或手术后应激导致的溃疡的药物中的用途；或者在制备抑制消化性溃疡、急应激性溃疡、出血性胃炎或侵入性应激造成的上消化道出血的药物中的用途。The pyrrolesulfonyl derivatives as described in any one of claims 1-7, its tautomers or stereoisomers thereof, and pharmaceutically acceptable salts thereof, or the medicine as claimed in claim 8 Use of the composition in preparing medicines for treating or preventing the following diseases: peptic ulcer, Zoller-Ellison syndrome, gastric erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagitis , functional dyspepsia, Helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, ulcers caused by non-steroidal anti-inflammatory drugs, hyperacidity caused by postoperative stress, or ulcers caused by postoperative stress purposes; or in the preparation of medicines for inhibiting peptic ulcer, acute stress ulcer, hemorrhagic gastritis or upper gastrointestinal bleeding caused by invasive stress.
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