CN109651297A - 一种n-苄基-n-芳基磺酰胺类衍生物及制备和应用 - Google Patents

一种n-苄基-n-芳基磺酰胺类衍生物及制备和应用 Download PDF

Info

Publication number
CN109651297A
CN109651297A CN201910058021.1A CN201910058021A CN109651297A CN 109651297 A CN109651297 A CN 109651297A CN 201910058021 A CN201910058021 A CN 201910058021A CN 109651297 A CN109651297 A CN 109651297A
Authority
CN
China
Prior art keywords
phenyl
benzyl
cyano
sulfoamido
piperazine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201910058021.1A
Other languages
English (en)
Other versions
CN109651297B (zh
Inventor
王晓路
胡永洲
叶青
胡秀爱
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hangzhou Yirui Pharmaceutical Technology Co Ltd
Original Assignee
Hangzhou Yirui Pharmaceutical Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hangzhou Yirui Pharmaceutical Technology Co Ltd filed Critical Hangzhou Yirui Pharmaceutical Technology Co Ltd
Priority to CN201910058021.1A priority Critical patent/CN109651297B/zh
Publication of CN109651297A publication Critical patent/CN109651297A/zh
Priority to EP20744951.3A priority patent/EP3915978A4/en
Priority to US17/424,292 priority patent/US11993576B2/en
Priority to PCT/CN2020/073367 priority patent/WO2020151687A1/zh
Application granted granted Critical
Publication of CN109651297B publication Critical patent/CN109651297B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/54—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/36—One oxygen atom with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/195—Radicals derived from nitrogen analogues of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/36—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Neurosurgery (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Dermatology (AREA)
  • Endocrinology (AREA)
  • Transplantation (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Emergency Medicine (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明提供一种N‑苄基‑N‑芳基磺酰胺类衍生物，所述衍生物包括其药学上可接受的盐和/或溶剂合物。通过取代硝基苯与含氮五元或六元脂杂环(B环)缩合，再将硝基还原成氨基,进而经还原胺化，磺酰胺化获得；或取代硝基苯先经硝基还原，再经还原胺化，磺酰胺化，最后与含氮五元或六元脂杂环(B环)缩合获得。本发明经实验证实，提供的N‑苄基‑N‑芳基磺酰胺类衍生物能够特异性结合并抑制或降低钾通道Kv1.3的活性，可应用于治疗人或动物由Kv1.3钾通道异常激活引起的自身免疫性疾病。本发明提供的抑制剂还包括该化合物的药物组合物。所述衍生物通式为：

Description

一种N-苄基-N-芳基磺酰胺类衍生物及制备和应用
技术领域
本发明属于医药领域，涉及一种作为Kv1.3钾通道抑制剂的N-苄基-N-芳基磺酰胺类衍生物，及其在制备治疗由Kv1.3介导的自身免疫性疾病抑制剂中的应用。
背景技术
Kv1.3(也称KCNA3)钾通道是电压门控型钾离子通道Kv1家族的一个重要亚型，其广泛分布在机体组织中，包括人类T淋巴细胞中。通过调控钾离子浓度参与细胞的增殖、迁移、凋亡等多种生理病理过程[Toldi G.et al.Immunol Res.,2016,64(2):627-631]。
自身免疫病相关研究发现，T淋巴细胞膜上的电压门控型钾离子通道Kv1.3在众多自身免疫疾病中扮演着重要角色[Kazama L.J Physiol Sci.,2015,65(1):25-35],在T淋巴细胞相关的免疫反应过程中，电压门控型钾离子通道Kv1.3和钙激活钾通道Kca共同调控T淋巴细胞的膜电势和Ca2+的信号，从而影响T淋巴细胞的激活、增殖及细胞因子分泌，其中Kv1.3钾通道就与机体异常的自身免疫特异性相关[胡明等.免疫学杂志，2010,26(4):356-361.]。如：在多发性硬化症患者大脑炎症浸润区域内，Kv1.3钾通道在T细胞上的表达量异常升高；在类凤湿性关节炎、银屑病、接触性皮炎、Ⅰ型糖尿病等自身免疫疾病中也己证实,效应记忆T淋巴细胞(TEM)的激活会伴随着Kv1.3钾通道表达量的显著上调,反之，阻断Kv1.3钾通道，可以阻断TEM的激活，减轻相应的免疫损伤。因此，Kv1.3钾通道已被视为是细胞相关众多自身免疫疾病治疗的重要靶点[Beeton C.,PNAS.,2006,103(46):17 414-17 419.][Koshy et al.J Biol chem 2014,289(18):12623-32]。
电压门控通道Kv1.3是由4个α亚基组成的4聚体，即由这些亚基组装成功能性通道，其中传导钾离子的孔穴位于4聚体的中心。每个亚基含有6个跨膜片段(S1-S6)、一个P环及膜内N-和C-末端。细胞膜的去极化由位于S4片段的4个精氨酸感应，然后导致通道被打开的构象改变。已知的Kv1.3肽类抑制剂均作用于膜外端的传导孔穴口，从而抑制其钾离子的传导功能[Chandy and Norton,Curr Opin Chen Biol,2017,38:97-107][Zhaoet.al.Toxins(Basel),2015,7:1749-1764]。
Kv1.3主要在T淋巴细胞表达，与钙激活的Kca3.1钾通道一起，防止细胞膜的去极化。当T细胞激活时，这些通道产生钾离子外流，并通过CRAC(Orai/Stim)通道，促进钙离子内流进入细胞质，以平衡抵消阳离子的留出。最终胞浆内钙离子的升高激活钙调磷酸酶(Calcineurin)，导致活化T细胞的转录因子(NFAT)去磷酸化后转位到核内，促成RNA转录而产生一系列免疫激活的生物效应。所以，T细胞中的Kv1.3和Kca3.1通道是细胞膜信号复合体的一部分，即将膜外刺激信号偶联到T细胞内的信号联级传导[Chandy and Norton,CurrOpin Chem Biol,2017,38:97-107]。
据文献报道，当处激活状态时，幼稚T细胞和中央记忆T细胞(TCM)上调Kca3.1表达水平而Kv1.3的数量无显著性变化。相反,处激活状态的已终端分化的效应器记忆T细胞(TEM)和表达CD-45RA的效应器记忆T细胞(TEMRA)上调Kv1.3表达水平而不影响Kca3.1的表达量。因此，选择性地阻断Kca3.1能抑制幼稚T细胞和中央记忆T细胞(TCM)的增殖从而抑制相应的细胞因子产生。另一方面，选择性地阻断Kv1.3能抑制效应器记忆T细胞(TEM和TEMRA)的增殖和所对应的细胞因子的产生，也抑制T细胞的体内迁移，但不影响被Kca3.1通道所保护的幼稚T细胞和中央记忆T细胞(TCM)的功能[Cahalan and Chandy,Immunol Rev,2009,231:59-87][Wulff et al.J Clin Invest,2003,111:1703-1713]。
在自身免疫性疾病中，如多发性硬化症、类风湿性关节炎、I型糖尿病和银屑病等，其自身抗原特异性的幼稚T细胞能逃避免疫调节。通过同源自身抗原的反复刺激，这些细胞最终被分化成TEM和TEMRA细胞。故这些与疾病相关的自身反应性T细胞主要为TEM和TEMR细胞。根据其产生的细胞因子的种类，具体可以分为Th1和/或Th17等细胞[Beeton et al.PNAS2006,103:17414-17418]。在动物模型中，选择性地阻断Kv1.3通道或敲除Kv1.3基因能预防和治疗多种自身免疫性疾病，同时不损害具保护作用的幼稚T细胞和中央记忆T细胞(TCM)的免疫应答功能。实验证明，当Kv1.3完整时，TEM细胞激活后被转化成效应细胞，而缺乏Kv1.3时，这些TEM细胞激活后可转变为起抗原特异性抑制效应的细胞。这种可塑性极大地支持了基于Kv1.3通道的靶向治疗，即抑制有害的自身反应性TEM细胞和TEMRA细胞，同时，通过诱导具有自身抗原特异性抑制效应的细胞的产生，促进长期的免疫耐受性[Chandy andNorton,Curr Opin Chem Biol,2017,38:97-107]。
近些年来，已报道发现了数个Kv1.3的特异性肽类抑制剂(如SHK-186等)或小分子抑制剂(如PAP-1等)，并用于治疗TEM细胞介导的自身免疫性疾病的动物模型的研究，如大鼠慢性多发性自身免疫性脑脊髓炎(EAE)、普利司坦诱导的关节炎、自发性自身免疫性糖尿病和肾小球肾炎。结果十分令人鼓舞。例如用SHK-186阻断Kv1.3能抵抗EAE的诱导发生并抑制IFN-γ和IL-17的产生，结果提示阻断Kv1.3可用于治疗多化性硬化症[Gocke et al,JImmunol 2012,188:5877-5886]。同样，在用卵清蛋白诱发的哮喘大鼠模型中，SHK-186能有效抑制Kv1.3高表达的Th2TEM细胞增殖和细胞因子的产生[Valverde et al,J Bone MinerRes2004,19:155-164]。在自身免疫性肾小球基底膜肾炎的大鼠模型中，给大鼠腹腔内注射一个小分子Kv1.3抑制剂Psora-4，能显著减少蛋白尿和新月体肾小球，提示了Psora-4在治疗快速发展性肾小球肾炎具有重要作用[Hyodo et al,Am J Physial Renal Physiol2010,299:F1258-69]。另一个Kv1.3小分子抑制剂PAP-1应用于大鼠局部皮肤模型时，能有效地抑制过敏性接触性皮炎(ACD)[Azam et al,J Invest Dermatal 2007,127(6):1419-1427]。进一步在SCID小鼠银屑病异种移植模型的实验中，注射或皮肤局部应用PAP-1能够将病变表皮增生的厚度减少约50％，并将所浸润的CD3+淋巴细胞减少了85％，显著性地改善了银屑病症状[Kun clu-Raychaudhuri et al,J Antoimmun 2014,55:63-72]。值得一提的是，据最新报道，Kv1.3肽类抑制剂SHK-186(Dalazatide)和小分子抑制剂PAP-1均已被用于治疗银屑病的I/II期临床试验，证明了其在人体内应用的安全性，统计学结果显示对银屑病症状的改善率高达90％以上[Tarch et al,PLoS ONE 2017,12(7):1-19][PressRelase by Circassia,13August 2018]。
发明内容
本发明的一个目的是提供一种N-苄基-N-芳基磺酰胺类衍生物，具有通式(Ⅰ)的化合物或其药学上可接受的盐或溶剂合物，
其中：
环A选自取代的苯基，所述取代的取代基选自和R3基团；其中环A优选下列取代苯环：
环B选自取代或无取代的包含1～3个选自O、N和S的五元或六元脂杂环基，所述取代的取代基选自Z和R4；其中环B优选下列含氧、氮的五元或六元脂杂环：
R选自无取代或取代的苯基或包含1-2个氮原子的无取代或取代的五元或六元芳杂环或C1-6直链、支链烷基或卤代的C1-6直链、支链烷基，苯基或芳杂环取代为单取代、双取代或三取代，所述的取代基选自Ra基团；
Ra任选自H、卤素、硝基、氰基、C1-3烷基、C1-3烷氧基、卤代的C1-3烷基、-C-O-C-；
R1选自无取代或取代的苯基或包含1～3个选自O、N和S的无取代或取代的五元或六元杂环芳基,取代为单取代、双取代或三取代，所述的取代基选自Rb基团；
Rb任选自H、卤素、硝基、氰基、C1-3烷基、C1-3烷氧基、卤代的C1-3烷基、-C-O-C-；
R2选自C1-3直链、支链烷基、环丙基、＝O；
R3选自卤素、硝基、氰基、三氟甲基、酰胺基、取代烷基酰胺基；
R4选自H、卤素、＝O、OH、NH2、甲酸酯基、氨基甲酸酯基、烷酰基、乙酸酯基、磺酰胺基、吡咯烷酮基、环丙基、氨基甲酰胺基,二甲基氨基乙氧基,烷酰氧基、烷酰胺基；
Z选自O、S、NH或缺失；
除非另有说明，本文所述被任选取代的成分可以在任何化学上可能的位置被取代。
本发明通式(Ⅰ)结构的优选化合物选自：
4-(4-(N-苄基苯基磺酰氨基)-2-氰基苯基)哌嗪-1-甲酸乙酯
4-(2-氰基-4-((4-氟-N-(4-氟苄基)苯基)磺酰氨基)苯基)哌嗪-1-甲酸乙酯
4-(2-氰基-4-((4-氟-N-(4-氟-3-甲氧基苄基)苯基)磺酰氨基)苯基)哌嗪-1-甲酸乙酯
4-(2-氰基-4-(N-(苯磺酰基)苯甲酰氨基)苯基)哌嗪-1-甲酸乙酯
N-苄基-N-(3-氰基-4-(4-氧代哌啶-1-基)苯基)苯磺酰胺
N-苄基-N-(3-氰基-4-(4-羟基哌啶-1-基)苯基)苯磺酰胺
N-苄基-N-(3-氰基-4-(4-乙酰氧基哌啶-1-基)苯基)苯磺酰胺
4-(2-氰基-4-((4-氟-N-丙基苯基)磺酰氨基)苯基)哌嗪-1-甲酸乙酯
4-(2-氰基-4-(N-(4-氟代苄基)丙磺酰氨基)苯基)哌嗪-1-甲酸乙酯
N-(3-氰基-4-吗啉基苯基)-N-(4-氟苄基)苯磺酰胺
4-(4-(N-苄基苯磺酰氨基)-2-氰基苯基)-N,N-二甲基哌嗪-1-甲酰胺
1-(4-(N-苄基苯磺酰氨基)-2-氰基苯基)-N,N-二甲基哌啶-4-磺酰胺
4-(2-氰基-4-(N-异丁基苯基磺酰胺基)苯基)哌嗪-1-甲酸乙酯
1-(4-(N-苄基苯磺酰氨基)-2-氰基苯基)哌啶-4-基氨基甲酸乙酯
N-(1-(4-(N-苄基苯磺酰胺基)-2-氰基苯基)吡咯烷-3-基)乙酰胺
N-苄基-N-(3-氰基-4-(2,6-二氧代哌啶-1-基)苯基)苯磺酰胺
N-苄基-N-(3-氰基-4-(3-甲基-2-氧代四氢嘧啶-1(2H)-基)苯基)苯磺酰胺
N-苄基-N-(3-氰基-4-(4-(2-(二甲基氨基)乙氧基)哌啶-1-基)苯基)苯磺酰胺
N-(3-氰基-4-(4-羟基哌啶-1-基)苯基)-N-(4-氟苄基)丙烷-1-磺酰胺
N-(3-氰基-4-(4-羟基哌啶-1-基)苯基)-N-(4-氟苄基)苯磺酰胺
4-(2-氰基-4-(N-(4-氟苄基)丙基)苯基)-N,N-二甲基哌嗪-1-甲酰胺
4-(4-(N-苄基丙磺酰胺基)2-腈基苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(3-氟苄基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(4-(4-(N-(4-氯苄基)丙磺酰胺基)2-腈基苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(2-氟苄基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(3-甲氧基苄基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(4-甲氧基苄基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(3,4-二甲氧基苄基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(2-氟-4-甲氧基苄基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(4-氟-2-甲氧基苄基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(嘧啶-4-基甲基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(吡啶-2-基甲基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(呋喃-2-基甲基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(噻唑-4-基甲基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-((1-甲基-1H-咪唑-5-基)甲基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-((1-甲基-1H-吡唑-5-基)甲基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-((N-(4-氟苄基)-2-甲基丙基)磺酰胺基)苯基)-N,N-二甲基哌嗪-1-甲酰胺
4-(2-腈基-4-(N-(4-氟苄基)丁磺酰胺基)苯基)-N,N-二甲基哌嗪-1-甲酰胺
4-(2-腈基-4-((N-(4-氟苄基)-3-甲基丁基)磺酰胺基)苯基)-N,N-二甲基哌嗪-1-甲酰胺
4-(2-腈基-4-((N-(4-氟苄基)-2,2-二甲基丙基)磺酰胺基)苯基)-N,N-二甲基哌嗪-1-甲酰胺
4-(2-腈基-4-(N-(吡啶-4-基甲基)丙磺酰胺基)苯基)-N,N-二甲基哌嗪-1-甲酰胺
4-(2-腈基-4-(N-(嘧啶-4-基甲基)丙磺酰胺基)苯基)-N,N-二甲基哌嗪-1-甲酰胺
4-(2-腈基-4-(N-(4-氟苄基)乙磺酰胺基)苯基)-N,N-二甲基哌嗪-1-磺酰胺
4-(4-(N-(4-氯苄基)丙磺酰胺基)-2-腈基苯基)-N,N-二甲基哌嗪-1-磺酰胺
4-(2-腈基-4-(N-(4-甲氧基苄基)丙磺酰胺基)苯基)-N,N-二甲基哌嗪-1-磺酰胺
4-(2-腈基-4-((4-氟-N-((1-甲基-1H-吡唑-5-基)甲基)苯基)磺酰胺基)苯基)-N,N-二甲基哌嗪-1-磺酰胺
4-(2-腈基-4-((1-环丙基-N-(2,4-二氟苄基)甲基)磺酰胺基)苯基)-N,N-二甲基哌嗪-1-磺酰胺
4-(2-腈基-4-(-N-(4-氟苯基)吡啶-3-磺酰胺基)苯基)-N,N-二甲基哌嗪-1-磺酰胺4-(4-(N-(4-氟苯基)丙磺酰胺基)-2-(三氟甲基)苯基)哌嗪-1-甲酸乙酯
4-(2-氰基-4-((4-氟-N-(4-氟苄基)苯基)磺酰氨基)苯基)哌嗪-1-甲酸乙酯
N-(3-氰基-4-(哌啶-4-基硫)苯基)-N-(4-氟苄基)丙磺酰胺
N-(3-氰基-4-(哌啶-4-基氨)苯基)-N-(4-氟苄基)丙磺酰胺
N-(4-((1-乙酰基哌啶-4-基)氧)-3-腈基苯基)-N-(4-氟苄基)丙磺酰胺
N-(4-((1-乙酰基哌啶-4-基)硫)-3-腈基苯基)-N-(4-氟苄基)丙磺酰胺
N-(4-((1-乙酰基哌啶-4-基)氨)-3-腈基苯基)-N-(4-氟苄基)丙磺酰胺
N-(4-((1-甲酰基哌啶-4-基)氧)-3-腈基苯基)-N-(4-氟苄基)丙磺酰胺
N-(4-((1-甲酰基哌啶-4-基)硫)-3-腈基苯基)-N-(4-氟苄基)丙磺酰胺
N-(4-((1-乙酰基哌啶-4-基)氧)-3-腈基苯基)-N-苄基苯磺酰胺
N-(4-((1-甲酰基哌啶-4-基)氧)-3-腈基苯基)-N-苄基苯磺酰胺
N-(4-((1-甲酰基哌啶-4-基)氨)-3-腈基苯基)-N-(4-氟苄基)丙磺酰胺及其上述化合物的药学上可接受的盐或溶剂合物。
本发明的另一个目的是提供具有通式(Ⅰ)的化合物的制备方法，通过以下步骤实现：
1.当通式(I)的化合物中，环A为取代苯环，同时Z缺失时：
1-卤代-2-R3-4-硝基苯在碱性条件下与含氮五元或六元脂杂环(B环)缩合，再将硝基还原成氨基,进而经还原胺化，磺酰胺化，必要时经脱保护基得到目标化合物；也可以采用1-卤代-2-R3-4-硝基苯先经硝基还原，进而经还原胺化，磺酰胺化，所得中间体再在碱性条件下与含氮五元或六元脂杂环(B环)缩合，最后必要时经脱保护基得到目标化合物。
化合物1-49,61按照下列合成路线制备：
2.当通式(I)的化合物中，环A为苯环，环B为哌啶，Z选自O、S、NH时：
1-卤代-2-R3-4-硝基苯在碱性条件下与4-羟基或4-巯基或4-氨基哌啶反应，再将硝基还原成氨基,进而经还原胺化，磺酰胺化得目标分子；亦可以采用N-苄基/烷基-N-(3-R3-4-氟苯基)磺酰胺与N-Boc保护的4-羟基或4-巯基或4-氨基哌啶反应，进而脱Boc保护基,再经哌啶N取代得目标分子。
化合物50-60按照下列合成路线制备：
本发明的再一个目的是提供N-苄基-N-芳基磺酰胺类衍生物在制备治疗由Kv1.3介导的自身免疫性疾病抑制剂中的应用。本发明提供的N-苄基-N-芳基磺酰胺类衍生物能够特异性结合并抑制或降低钾通道Kv1.3的活性。
所述抑制剂包含至少一种活性组分以及一种或多种药学上可接受的载体或赋形剂，所述的活性组分可以是本发明的N-苄基-N-芳基磺酰胺类化合物及其在药学上可接受的盐、所述化合物的溶剂合物中的任意一种或任意多种。
所述载体或赋形剂包括药学领域的常规稀释剂，填充剂，粘合剂，湿润剂，崩解剂，吸收促进剂，表面活性剂，吸附载体，润滑剂等，必要时还可以加入香味剂，甜味剂等。本发明药物可以制成片剂、胶囊、贴剂、乳剂、混悬剂、凝胶剂,粉剂、颗粒剂、口服液及注射剂等多种形式，上述各剂型的药物均可以按照药学领域的常规方法制备。
本发明采用本领域技术人员所熟知的方法可以制备本发明所述的N-苄基-N-芳基磺酰胺类化合物的盐。所述的盐可以是无机酸盐、有机酸盐等，所述的无机酸盐包括与氢卤酸(如氢氟酸、氢溴酸、氢碘酸、盐酸)，硝酸，碳酸，硫酸，磷酸等形成相应的盐；所述的有机酸盐包括与苹果酸、L-苹果酸、D-苹果酸、枸橼酸、富马酸、草酸、乳酸、樟脑磺酸、L-樟脑磺酸、D-樟脑磺酸、对甲苯磺酸、甲磺酸、苯甲酸等形成相应的盐。
本发明还提供通式(Ⅰ)所述的任一项化合物、及其药学上可接受的盐或溶剂合物单独和/或与其他药物联合使用在制备治疗由Kv1.3介导的自身免疫性疾病抑制剂中的应用。
Kv1.3钾通道已被视为是细胞自身免疫性疾病治疗的重要靶点，因此，选择性Kv1.3钾通道抑制剂可用于治疗自身免疫性疾病。所述的自身免疫性疾病包括银屑病、银屑病性关节炎、变应性以及刺激性接触性皮炎、特应性皮炎、白癜风、类风湿性关节炎、Ⅰ型糖尿病、多发性硬化、哮喘、肾小球肾炎、牙周疾病、睫状体扁平部炎、移植排斥、神经退行性变、肥胖症、高血压。
本发明通过实验证实，本发明中的大部分化合物可选择性抑制Kv1.3钾通道活性，可应用于治疗人或动物由Kv1.3钾通道异常激活引起的自身免疫性疾病。本发明提供的抑制剂还包括该化合物的药物组合物。
具体实施方式
本发明结合实施例作进一步的说明，以下实施例仅是说明本发明，而不是以任何方式限制本发明。
制备实施例1：4-(4-(N-苄基苯基磺酰氨基)-2-氰基苯基)哌嗪-1-甲酸乙酯(化合物1)的合成：
步骤1. 4-(2-氰基-4-硝基苯基)哌嗪-1-甲酸乙酯(中间体1a)的合成：
在反应瓶中加入2-氯-5-硝基苯甲腈(0.91g,5.0mmol)，哌嗪-1-甲酸乙酯(0.84g,5.3mmol)，三乙胺(1.1g,10.9mmol)和乙腈20mL，回流反应4.5h，反应完后将反应液冷却至室温，加水稀释，乙酸乙酯萃取，有机层用无水硫酸钠干燥，过滤，浓缩，残留物用乙酸乙酯重结晶得1a，收率71.7％；ESI-MS：m/z＝305[M+1]+。
步骤2. 4-(4-氨基-2-氰基苯基)哌嗪-1-甲酸乙酯(中间体1b)的合成：
在反应瓶中加入1a(2.76g,9.0mmol)，二水合氯化亚锡(11.12g,49.3mmol)和无水乙醇130mL，回流反应2h，反应完后将反应液冷却至室温，加入碳酸钠溶液碱化，抽滤，滤液用乙酸乙酯萃取，有机层用无水硫酸钠干燥，过滤，浓缩，残留物用乙酸乙酯重结晶得1b，收率71.3％；ESI-MS：m/z＝275[M+1]+。
步骤3. 4-(4-苄基氨基-2-氰基苯基)哌嗪-1-甲酸乙酯(1c)的合成：
将1b(0.27g,1.0mmol)溶于醋酸1mL中，加入苯甲醛(0.14g,1.3mmol)，室温搅拌1h，将反应液冷却至10-15℃，向其中加入硼氢化钠(0.04g,1.1mmol)，保温反应10min，然后将反应液用碳酸钠溶液碱化，乙酸乙酯萃取，有机层用无水硫酸钠干燥，过滤，浓缩，残留物用乙酸乙酯重结晶得到1c，收率86.0％；ESI-MS：m/z＝365[M+1]+。
步骤4. 4-(4-(N-苄基苯磺酰氨基)-2-氰基苯基)哌嗪-1-甲酸乙酯(化合物1)的合成：
将1c(0.31g,0.86mmol)溶于二氯甲烷3.0mL中，向其中加入吡啶(0.37g,4.7mmol)和苯磺酰氯(0.18g,1.0mmol)，室温搅拌5h后，反应液用稀盐酸酸化，二氯甲烷萃取，有机层用无水硫酸钠干燥，过滤，浓缩，残留物用乙酸乙酯重结晶得到1，收率77.4％。1H NMR(500MHz,Chloroform-d):δ7.71-7.63(m,3H),7.56(t,J＝7.8Hz,2H),7.27-7.23(m,3H),7.22-7.19(m,2H),7.16(dd,J＝7.9,2.6Hz,1H),7.09(d,J＝2.6Hz,1H),6.81(d,J＝7.9Hz,1H),4.68(s,2H),4.18(q,J＝7.1Hz,2H),3.70-3.62(m,4H),3.18-3.10(m,4H),1.29(t,J＝7.0Hz,3H)；ESI-MS:m/z＝505[M+1]+。
制备实施例2.4-(2-氰基-4-((4-氟-N-(4-氟苄基)苯基)磺酰氨基)苯基)哌嗪-1-甲酸乙酯(化合物2)的合成：
步骤1. 4-(2-氰基-4-((4-氟苄基)氨基)苯基)哌嗪-1-甲酸乙酯(2a)的合成：
合成步骤参考实施案例1步骤3,只是用中间体1b和对氟苯甲醛为原料制备化合物2a；ESI-MS：m/z＝384[M+1]+。
步骤2. 4-(2-氰基-4-((4-氟-N-(4-氟苄基)苯基)磺酰氨基)苯基)哌嗪-1-甲酸乙酯(化合物2)的合成：
合成步骤参考实施案例1步骤4,只是用2a和对氟苯磺酰氯为原料制备化合物2，收率50.2％。1H NMR(500MHz,Chloroform-d):δ7.72-7.65(m,2H),7.22(t,J＝8.5Hz,2H),7.19-7.16(m,2H),7.12-7.10(m,2H),6.95(t,J＝8.6Hz,2H),6.83(d,J＝9.6Hz,1H),4.63(s,2H),4.17(q,J＝7.1Hz,2H),3.70-3.60(m,4H),3.20-3.11(m,4H),1.28(t,J＝7.1Hz,3H)；ESI-MS:m/z＝541[M+1]+。
制备实施例3.4-(2-氰基-4-((4-氟-N-(4-氟-3-甲氧基苄基)苯基)磺酰氨基)苯基)哌嗪-1-甲酸乙酯(化合物3)的合成：
步骤1. 4-(2-氰基-4-((4-氟-3-甲氧基苄基)氨基)苯基)哌嗪-1-甲酸乙酯(3a)的合成
合成步骤参考实施案例1步骤3.只是用中间体1b和4-氟-3-甲氧基苯甲醛为原料制备化合物3a，收率73.0％；ESI-MS：m/z＝413[M+1]+。
步骤2. 4-(2-氰基-4-((4-氟-N-(4-氟-3-甲氧基苄基)苯基)磺酰氨基)苯基)哌嗪-1-甲酸乙酯(化合物3)的合成：
合成步骤参考实施案例1步骤4,只是用3a和对氟苯磺酰氯为原料制备化合物3，收率53.2％。1H NMR(500MHz,Chloroform-d):δ7.98(m,2H),7.40(dd,J＝8.0,7.5Hz,2H),7.23(dd,J＝8.0,7.5Hz,1H),7.06(d,J＝7.5Hz,1H),6.95(dd,J＝5.0,1.5Hz,1H),6.81(d,J＝7.5H,1H),6.77(dd,J＝7.5,1.5Hz,1H),6.74(s,1H),4.53(s,2H),4.14(q,J＝7.2Hz,2H),3.83(s,3H),3.32-3.29(m,8H),1.22(t,J＝7.2Hz,3H)；ESI-MS:m/z＝571[M+1]+。
制备实施例4.4-(2-氰基-4-(N-(苯磺酰基)苯甲酰氨基)苯基)哌嗪-1-甲酸乙酯(化合物4)的合成：
步骤1. 4-(4-苯甲酰氨基-2-氰基苯基)哌嗪-1-甲酸乙酯(4a)的合成：
将化合物1b(0.5g,1.82mmol)和4-DMAP(0.025g，0.2mmol)溶于吡啶3.0mL中，再向其中加入苯甲酰氯(0.31g,2.19mmol)，室温搅拌2h，稀盐酸酸化，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝2:1,v/v)得到化合物4a,收率88.0％；ESI-MS:m/z＝379[M+1]+。
步骤2. 4-(2-氰基-4-(N-(苯磺酰基)苯甲酰氨基)苯基)哌嗪-1-甲酸乙酯(化合物4)的合成：
将4a(0.3g,0.79mmol)溶于无水THF15mL中，降温至0℃，向其中加入60％氢化钠(0.034g,0.85mmol),保温反应0.5h，再向反应液中加入苯磺酰氯(0.14g,0.79mmol)，加完后升至室温反应2h，过滤，滤液减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝1:2,v/v)，得到4，收率61.0％。1H NMR(500MHz,Chloroform-d):δ7.97-7.94(m，2H),7.70(t,J＝7.5Hz,1H),7.61-7.55(m,2H),7.47-7.42(m,2H),7.37(t,J＝7.5Hz,1H),7.34(dd,J＝7.8,2.6Hz,1H),7.29-7.27(m,1H),7.25-7.22(m,2H),6.89(d,J＝7.8Hz,1H),4.18(q,J＝7.1Hz,2H),3.70-3.65(m,4H),3.25-3.17(m,4H),1.29(t,J＝7.1Hz,3H)；ESI-MS:m/z＝519[M+1]+。
制备实施例5.N-苄基-N-(3-氰基-4-(4-氧代哌啶-1-基)苯基)苯磺酰胺(化合物5)的合成：
步骤1. 5-(苄基氨基)-2-氟苄腈(5a)的合成：
将5-氨基-2-氟苯腈(1.50g,11.0mmol)溶于醋酸10mL中，向其中加入苯甲醛(1.50g,14.1mmol)，室温搅拌1h，将反应液冷却至10-15℃，向其中加入硼氢化钠(0.44g,11.6mmol)，保温搅拌10min，然后用碳酸钠溶液碱化，乙酸乙酯萃取，有机层用无水硫酸钠干燥，过滤并减压浓缩，残留物用乙酸乙酯重结晶得到5a，收率80.2％；ESI-MS:m/z＝227[M+1]+。
步骤2.N-苄基-N-(3-氰基-4-氟苯基)苯磺酰胺(5b)的合成：
将5a(1.54g,6.8mmol)溶于二氯甲烷20mL中，加入吡啶(2.96g,37.4mmol)和苯磺酰氯(1.44g,8.2mmol)，室温搅拌5h，稀盐酸酸化，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用乙酸乙酯重结晶得到5b,收率87.8％；ESI-MS:m/z＝337[M+1]+。
步骤3.N-苄基-N-(3-氰基-4-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)苯基)苯磺酰胺(5c)的合成：
在反应瓶中加入5b(0.20g,0.55mmol)，4-哌啶酮缩乙二醇盐酸盐(0.11g,0.62mmol)，无水碳酸钾(0.22g,1.61mmol)和DMSO 2mL，120℃反应6h，反应完后冷却至室温，加水稀释，乙酸乙酯萃取，饱和食盐水洗涤，有机层用无水硫酸钠干燥，过滤并减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝2:1,v/v)，得到5c，收率86.7％；ESI-MS:m/z＝490[M+1]+。
步骤4.N-苄基-N-(3-氰基-4-(4-氧代哌啶-1-基)苯基)苯磺酰胺(化合物5)的合成：
将5c(0.20g,0.41mmol)溶于THF3mL中，加入10％的稀硫酸溶液3mL，室温搅拌5h，用碳酸钠溶液碱化，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤并减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝1:1,v/v)，得到50，收率87.9％。1H NMR(500MHz,Chloroform-d):δ7.71-7.65(m,3H),7.57(t,J＝7.5Hz,2H),7.25-7.23(m,3H),7.22-7.20(m,2H),7.18(dd,J＝7.8,2.6Hz,1H),7.12(d,J＝2.6Hz,1H),6.87(d,J＝7.8Hz,1H),4.69(s,2H),3.50(t,J＝6.0Hz,4H),2.66(t,J＝6.0Hz,4H)；ESI-MS:m/z＝446[M+1]+。
制备实施例6.N-苄基-N-(3-氰基-4-(4-羟基哌啶-1-基)苯基)苯磺酰胺(化合物6)的合成：
步骤:将5b(0.50g,1.36mol),4-哌啶醇(1.58g,1.56mmol)和碳酸钾(0.54g,3.9mmol)溶于DMF5mL中,升温至100℃反应2h，反应毕后冷却至室温，加水稀释，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤并减压浓缩，残留物用硅胶柱层析纯化(DCM:EA＝10:1,v/v)，得到6，收率70.4％。1H NMR(500MHz,Chloroform-d)：δ7.71-7.63(m,3H),7.55(t,J＝7.5Hz,2H),7.25(m,1H),7.24-7.21(m,2H),7.20-7.18(m,2H),7.12(dd,J＝7.9,2.6Hz,1H),7.04(d,J＝2.6Hz,1H),6.82(d,J＝7.9Hz,1H),4.67(s,2H),4.03-3.84(m,1H),3.52-3.40(m,2H),3.09-2.93(m,2H),2.15-1.97(m,2H),1.84-1.67(m,2H)；ESI-MS:m/z＝448[M+1]+。
制备实施例7.N-苄基-N-(3-氰基-4-(4-乙酰氧基哌啶-1-基)苯基)苯磺酰胺(化合物7)的合成：
步骤:将化合物6(0.25g,0.56mmol)溶于二氯甲烷20mL中,加入三乙胺(0.084g,0.83mmol)和乙酰氯(0.052g,0.67mmol)，室温搅拌1h。反应结束后，有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝2:1,v/v)，得7，收率51.2％。1H NMR(500MHz,Chloroform-d):δ7.70-7.64(m,3H),7.55(t,J＝7.8Hz,2H),7.25-7.21(m,3H),7.20-7.17(m,2H),7.13(dd,J＝7.9,2.6Hz,1H),7.05(d,J＝2.6Hz,1H),6.83(d,J＝7.9Hz,1H),5.00-4.91(m,1H),4.67(s,2H),3.44-3.30(m,2H),3.12-3.04(m,2H),2.08(s,3H),2.07-2.02(m,2H),1.92-1.81(m,2H)；ESI-MS:m/z＝490[M+1]+。
制备实施例8.4-(2-氰基-4-((4-氟-N-丙基苯基)磺酰氨基)苯基)哌嗪-1-甲酸乙酯(化合物8)的合成：
步骤1. 4-(2-氰基-4-(丙氨基)苯基)哌嗪-1-甲酸乙酯(8a)的合成：
将1b(0.3g,1.1mmol)溶于无水乙醇30mL中，加入丙醛(0.095g,1.6mmol)，分子筛0.3g,回流反应4h，然后将反应液冷却至室温，加入硼氢化钠(0.05g,1.3mmol)，室温反应1h。反应液加水稀释，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析纯化(DCM:EA＝5:1,v/v)，得到8a，收率38.1％；ESI-MS:m/z＝317[M+1]+。
步骤2. 4-(2-氰基-4-((4-氟-N-丙基苯基)磺酰氨基)苯基)哌嗪-1-甲酸乙酯(化合物8)的合成：
合成步骤参考实施案例1步骤4，只是用8a和对氟苯磺酰氯为原料制备化合物8,收率49.3％。1H NMR(500MHz,Chloroform-d):δ7.65-7.60(m,2H),7.25(dd,J＝8.8,2.6Hz,1H),7.22-7.16(m,3H),6.94(d,J＝8.8Hz,1H),4.19(q,J＝7.1Hz,2H),3.73-3.67(m,4H),3.45(t,J＝7.1Hz,2H),3.24-3.18(m,4H),1.50-1.38(m,2H),1.30(t,J＝7.1Hz,3H),0.91(t,J＝7.4Hz,3H)；ESI-MS:m/z＝475[M+1]+。
制备实施例9.4-(2-氰基-4-(N-(4-氟代苄基)丙磺酰氨基)苯基)哌嗪-1-甲酸乙酯(化合物9)的合成：
合成步骤参考实施案例1步骤4,只是用2a和丙磺酰氯为原料制备化合物9,所得粗品用硅胶柱层析纯化(PE:EA＝2:1,v/v)，收率45.1％。1H NMR(500MHz,Chloroform-d):δ7.43(d,J＝2.6Hz,1H),7.31(dd,J＝7.8,2.6Hz,1H),7.23-7.18(m,2H),6.97-6.94(m,2H),6.89(d,J＝8.9Hz,1H),4.77(s,2H),4.17(q,J＝7.1Hz,2H),3.69-3.63(m,4H),3.19-3.14(m,4H),3.05-2.99(m,2H),1.98-1.85(m,2H),1.28(t,J＝7.1Hz,3H),1.08(t,J＝7.4Hz,3H)；ESI-MS:m/z＝489[M+1]+。
制备实施例10.N-(3-氰基-4-吗啉基苯基)-N-(4-氟苄基)苯磺酰胺(化合物10)的合成：
步骤1. 2-吗啉基-5-硝基苯甲腈(10a)的合成：
将2-溴-5-硝基苯甲腈(1.0g,4.4mmol)溶于四氢呋喃20mL中，再加入碳酸钾(1.22g,8.8mmol)和吗啉(0.58g,6.6mmol)，加热回流4h。反应结束后冷却至室温，过滤，滤液浓缩后用硅胶柱层析纯化(PE:EA＝4:1,v/v)，得到10a，收率96.3％；ESI-MS:m/z＝234[M+1]+。
步骤2. 2-吗啉基-5-氨基苯甲腈(10b)的合成：
将10a(1.0g,4.29mmol)溶于无水乙醇10mL中，加入二水合氯化亚锡(4.84g,21.4mmol)，加热回流6h。反应完后冷却至室温，反应混合物用碳酸氢钠溶液碱化,过滤，滤液用乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，并减压浓缩，残留物用乙酸乙酯重结晶，得到10b，收率51.6％；ESI-MS:m/z＝204[M+1]+。
步骤3. 5-((4-氟苄基)氨基)-2-吗啉基苯甲腈(10c)的合成：
将10b(0.48g,2.36mol)溶于醋酸10mL中，加入对氟苯甲醛(0.35g,2.83mmol)，室温搅拌1h，在10～15℃下加入硼氢化钠(0.134g,3.54mmol)，保温反应0.5h。反应结束后将反应液倒入水中，用碳酸氢钠溶液碱化，乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，并减压浓缩，残留物用乙酸乙酯重结晶，得到10c，收率27.2％；ESI-MS:m/z＝312[M+1]+。
步骤4.N-(3-氰基-4-吗啉基苯基)-N-(4-氟苄基)苯磺酰胺(化合物10)的合成：
将10c(0.2g,0.64mmol)溶于二氯甲烷10mL中，再加入吡啶(0.25g,3.2mmol)和丙磺酰氯(0.15g,0.82mmol)，室温反应6h。反应结束后倒入水中，用稀盐酸溶液洗涤有机相，二氯甲烷萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱层析纯化(PE:EA＝4:1,v/v)，得到10，收率74.7％。1H NMR(500MHz,Chloroform-d):δ7.70-7.64(m,3H),7.56(t,J＝7.8Hz,2H),7.21-7.16(m,2H),7.14(dd,J＝7.9,2.6Hz,1H),7.05(d,J＝2.6Hz,1H),6.99-6.92(m,2H),6.83(d,J＝8.9Hz,1H),4.64(s,2H),3.94-3.79(m,4H),3.33-3.12(m,4H)；ESI-MS:m/z＝452[M+1]+。
制备实施例11.4-(4-(N-苄基苯磺酰氨基)-2-氰基苯基)-N,N-二甲基哌嗪-1-甲酰胺(化合物11)的合成：
步骤:在反应瓶中加入5b(0.106g,0.29mol),N,N-二甲基哌嗪-1-甲酰胺(0.05mg,0.32mmol)，碳酸钾(0.12g,0.87mmol)和DMF2mL，升温至100℃反应2h，反应完后将反应液冷却至室温，加水稀释，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱层析纯化(DCM:MeOH＝20:1)，得到11，收率65.2％。1H NMR(500MHz,Chloroform-d):δ7.71-7.64(m,3H),7.55(t,J＝7.8Hz,2H),7.27-7.22(m,3H),7.23-7.18(m,2H),7.13(dd,J＝7.9,2.6Hz,1H),7.09(d,J＝2.6Hz,1H),6.81(d,J＝7.9Hz,1H),4.67(s,2H),3.48-3.40(m,4H),3.23-3.13(m,4H),2.86(s,6H)；ESI-MS:m/z＝504[M+1]+。
制备实施例12.1-(4-(N-苄基苯磺酰氨基)-2-氰基苯基)-N,N-二甲基哌啶-4-磺酰胺(化合物12)的合成：
合成步骤参考实施案例11，只是用5b和N,N-二甲基哌啶-4-磺酰胺为原料制备化合物12,收率78.0％。1H NMR(500MHz,Chloroform-d):δ7.71-7.64(m,3H),7.56(t,J＝7.8Hz,2H),7.27-7.22(m,3H),7.22-7.19(m,2H),7.15(dd,J＝7.8,2.6Hz,1H),7.07(d,J＝2.6Hz,1H),6.81(d,J＝7.8Hz,1H),4.67(s,2H),3.71-3.66(m,2H),3.16-3.05(m,1H),2.97(s,6H),2.87-2.76(m,2H),2.20-2.15(m,2H),2.13-2.03(m,2H)；ESI-MS:m/z＝539[M+1]+。
制备实施例13.4-(2-氰基-4-(N-异丁基苯基磺酰胺基)苯基)哌嗪-1-甲酸乙酯(化合物13)的合成：
步骤1. 4-(2-氰基-4-(异丁基氨基)苯基)哌嗪-1-甲酸乙酯(13a)的合成：
合成步骤参考实施案例8步骤1，只是用1b和异丁醛为原料制备化合物13a,残留物用硅胶柱层析纯化(DCM:EA＝5:1,v/v)，收率40.1％；ESI-MS:m/z＝331[M+1]+。
步骤2. 4-(2-氰基-4-(N-异丁基苯基磺酰胺基)苯基)哌嗪-1-甲酸乙酯(化合物13)的合成：
合成步骤参考实施案例1步骤4，只是用13a和苯磺酰氯为原料制备化合物13,收率63.4％。1H NMR(500MHz,Chloroform-d):δ7.65-7.60(m,1H),7.65-7.62(m,1H),7.60-7.56(m,2H),7.52-7.49(m,2H),7.30-7.28(m,1H),7.13(d,J＝2.6Hz,1H),6.94(d,J＝7.8Hz,1H),4.19(q,J＝7.1Hz,2H),3.73-3.67(m,4H),3.26(d,J＝7.4Hz,2H),3.23-3.17(m,4H),1.59-1.50(m,1H),1.30(t,J＝7.1Hz,3H),0.92(d,J＝6.6Hz,6H)；ESI-MS:m/z＝471[M+1]+。
制备实施例14.1-(4-(N-苄基苯磺酰氨基)-2-氰基苯基)哌啶-4-基氨基甲酸乙酯(化合物14)的合成：
合成步骤参考实施案例5步骤3，只是用5b和哌啶-4-氨基甲酸乙酯为原料制备化合物14,收率65％。1H NMR(500MHz,Chloroform-d):δ7.70-7.63(m,3H),7.55(t,J＝7.8Hz,2H),7.27-7.23(m,3H),7.22-7.18(m,2H),7.12(dd,J＝7.9,2.5Hz,1H),7.05(d,J＝2.5Hz,1H),6.81(d,J＝7.9Hz,1H)，4.67(s,2H),4.60(brs,1H),4.13(q,J＝7.0Hz,2H),3.72-3.62(m,1H),3.53-3.47(m,2H),2.94-2.84(m,2H),2.11-2.05(m,2H),1.65-1.60(m,2H),1.26(t,J＝7.0Hz,3H)；ESI-MS:m/z＝519[M+1]+。
制备实施例15.N-(1-(4-(N-苄基苯磺酰胺基)-2-氰基苯基)吡咯烷-3-基)乙酰胺(化合物15)的合成：
合成步骤参考实施案例5步骤3，只是用5b和N-(吡咯烷-3-基)乙酰胺为原料制备化合物15,收率97.0％。1H NMR(500MHz,Chloroform-d):δ7.69(d,J＝8.0Hz,2H),7.65(t,J＝6.9Hz,1H),7.54(t,J＝7.7Hz,2H),7.25-7.20(m,5H),7.01-6.97(m,1H),6.93(d,J＝2.5Hz,1H),6.44(dd,J＝8.0,2.5Hz,1H),5.82(d,J＝7.0Hz,1H),4.64(s,2H),4.62-4.51(m,1H),3.86-3.66(m,2H),3.67-3.52(m,1H),3.42-3.39(m,1H),2.38-2.16(m,1H),2.01-1.92(m,4H)；ESI-MS:m/z＝475[M+1]+。
制备实施16.N-苄基-N-(3-氰基-4-(2,6-二氧代哌啶-1-基)苯基)苯磺酰胺(化合物16)的合成：
步骤1. 2-(2,6-二氧代哌啶-1-基)-5-硝基苯甲腈(16a)的合成：
将戊二酰亚胺(0.94g,8.31mmol)溶于5mL无水DMF，降温至0～5℃，分批加入60％氢化钠(0.33g,8.31mmol)，加完后保温搅拌0.5h，再加入2-氟-5-硝基苯腈(1.25g,7.55mmol)，升温至50℃反应过夜，反应结束后，将反应液冷却至室温，加水稀释，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，并减压浓缩，残留物用用硅胶柱层析纯化(PE:EA＝1:1,v/v)，得到16a，收率25.1％；ESI-MS:m/z＝260[M+1]+。
步骤2. 5-(苄氨基)-2-(2,6-二氧代哌啶-1-基)苄腈(16c)的合成：
将16a(0.25g,0.97mmol)溶于醋酸6mL中，加入10％钯碳0.05g，于30℃加氢还原1h。反应结束后，减压过滤，在上述滤液中加入苯甲醛(0.13g,1.24mmol)，室温反应1h，冷却至10～15℃，加入硼氢化钠(0.055g,1.45mmol)，加完后保温反应0.5h。反应结束后将反应液倒入水中，碳酸氢钠碱化，乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，并减压浓缩，残留物用硅胶柱层析纯化(DCM:EA＝15:1,v/v)，得到16c，两步收率47.5％；ESI-MS:m/z＝320[M+1]+。
步骤3.N-苄基-N-(3-氰基-4-(2,6-二氧代哌啶-1-基)苯基)苯磺酰胺(化合物16)的合成：
将23c(0.14g,0.46mmol)溶于二氯甲烷10mL中，再加入吡啶(0.2g,2.53mmol)和苯磺酰氯(0.1g,0.59mmol)，室温反应1h。反应结束后，用稀盐酸溶液洗涤有机相，二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝1:1,v/v)，得到16，收率30.6％。1H NMR(500MHz,Chloroform-d):δ7.71-7.63(m,3H),7.55(t,J＝7.5,2H),7.37(dd,J＝8.0,2.5Hz,1H),7.34(d,J＝2.5Hz,1H),7.32-7.28(m,1H),7.25-7.21(m,4H),7.13(d,J＝8.0Hz,1H),4.76(s,2H),2.95-2.84(m,2H),2.84-2.71(m,2H),2.29-2.07(m,2H)；ESI-MS:m/z＝460[M+1]+。
制备实施例17.N-苄基-N-(3-氰基-4-(3-甲基-2-氧代四氢嘧啶-1(2H)-基)苯基)苯磺酰胺(化合物17)的合成：
步骤1. 5-(苄基氨基)-2-溴苄腈(17a)的合成：
合成步骤参考实施案例5步骤3，只是用5-氨基-2-溴苯腈和苯甲醛制备化合物17a,收率85.8％；ESI-MS:m/z＝288[M+1]+。
步骤2.N-苄基-N-(4-溴-3-氰基苯基)苯磺酰胺(17b)的合成：
合成步骤参考实施案例5步骤4，只是用17a和苯磺酰氯制备化合物17b,收率85.0％；ESI-MS:m/z＝288[M+1]+。
步骤3.N-苄基-N-(3-氰基-4-(3-甲基-2-氧代四氢嘧啶-1(2H)-基)苯基)苯磺酰胺(化合物17)的合成：
在反应瓶中加入17b(0.427g,1.0mmol)，0.137g(1.2mmol)1-甲基四氢-2(1H)-嘧啶酮(0.137g,1.2mmol)，碳酸钾(0.276g,2.0mmol)，碘化亚铜(0.019g,0.1mmol)和反-N,N'-二甲基-1,2-环己烷二胺(0.015g,0.1mmol)和甲苯1mL，氮气保护下于110℃反应24h，反应完后将反应液冷却至室温，过滤，滤液减压浓缩，残留物用硅胶柱层析纯化(DCM:MeOH＝20:1)得到17，收率11.1％。1H NMR(500MHz,Chloroform-d):δ7.70-7.68(s,2H),7.66(t,J＝7.5Hz,1H),7.55(t,J＝7.7Hz,2H),7.26–7.21(m,7H),7.19(d,J＝2.4Hz,1H),4.71(s,2H),3.67(t,J＝6.4Hz,2H),3.42(t,J＝6.1Hz,2H),3.01(s,3H),2.27–2.10(m,2H)；ESI-MS:m/z＝460[M+1]+。
制备实施例18.N-苄基-N-(3-氰基-4-(4-(2-(二甲基氨基)乙氧基)哌啶-1-基)苯基)苯磺酰胺(化合物18)的合成：
合成步骤参考实施案例5步骤3，只是用5b和N,N-二甲基-2-(4-哌啶基氧基)乙胺为原料制备化合物18,残留物用硅胶柱层析纯化(DCM:MeOH:TEA＝40:1:1)，得到18，收率68％。1H NMR(500MHz,Chloroform-d):δ7.70-7.63(m,3H),7.55(t,J＝7.8Hz,2H),7.26-7.22(m,3H),7.22-7.19(m,2H),7.10(dd,J＝8.9,2.6Hz,1H),7.02(d,J＝2.6Hz,1H),6.80(d,J＝8.9Hz,1H),4.66(s,2H),3.60(t,J＝5.9Hz,2H),3.54–3.48(m,1H),3.45-3.37(m,2H),3.06-2.95(m,2H),2.55(t,J＝5.9Hz,2H),2.31(s,6H),2.04-1.94(m,2H),1.87-1.75(m,2H)；ESI-MS:m/z＝519[M+1]+。
制备实施例19.N-(3-氰基-4-(4-羟基哌啶-1-基)苯基)-N-(4-氟苄基)丙烷-1-磺酰胺(化合物19)的合成：
步骤1. 2-(4-羟基哌啶-1-基)-5-硝基苯甲腈(19a)的合成：
将2-氯-5-硝基苯甲腈(1.5g,8.21mmol)，4-羟基哌啶(0.87g,8.63mmol)和三乙胺(1.25g,12.3mmol)溶于乙腈20mL中，升温至80℃反应2h。减压浓缩，残留物用硅胶柱层析纯化(DCM:MeOH＝20:1,v/v)得到19a，收率74.4％；ESI-MS:m/z＝248[M+1]+。
步骤2. 1-(2-氰基-4-硝基苯基)哌啶-4-基乙酸酯(19b)的合成：
将19a(1.2g,4.85mmol)溶于DCM20mL中，加入三乙胺(0.74g,7.28mmol)，冷却至0～5℃滴加乙酰氯(0.46g,5.82mmol)，滴完后升至室温反应1h，减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝1:1,v/v)得到19b，收率54.1％；ESI-MS:m/z＝290[M+1]+。
步骤3. 1-(4-氨基-2-氰基苯基)哌啶-4-基乙酸酯(19c)的合成：
将19b(0.75g,2.59mmol)和氯化亚锡二水合物(2.93g,12.96mmol)溶于乙醇20mL中，回流反应2h，反应完后将反应液冷却至室温，碳酸钠溶液碱化，过滤，滤液用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，并减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝2:1,v/v)，得到19c，收率81.8％；ESI-MS:m/z＝260[M+1]+。
步骤4. 1-(2-氰基-4–((4-氟苄基)氨基)苯基)哌啶-4-基乙酸酯(19d)的合成：
合成步骤参考实施案例1步骤3，只是用中间体19c和对氟苯甲醛为原料制备化合物19d，所得粗品用硅胶柱层析纯化(PE:EA＝2:1,v/v)得到19d，收率81.1％；ESI-MS:m/z＝368[M+1]+。
步骤5. 1-(2-氰基-4-(N-(4-氟苄基)丙基磺酰氨基)苯基)哌啶-4-基乙酸酯(19e)的合成：
合成步骤参考实施案例2步骤2,只是用19d和丙磺酰氯为原料制备化合物19e,所得粗品用硅胶柱层析纯化(PE:EA＝2:1,v/v)得到19e，收率69.8％；ESI-MS:m/z＝474[M+1]+。
步骤6.N-(3-氰基-4-(4-羟基哌啶-1-基)苯基)-N-(4-氟苄基)丙烷-1-磺酰胺(化合物19)的合成：
将19e(0.16g,0.34mmol)和氢氧化锂(0.033g,1.35mmol)溶于THF 4mL和水1mL配成的溶液中，室温搅拌过夜，加水稀释，乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(DCM:EA＝10:1,v/v)得到19，收率96.0％。1H NMR(500MHz,Chloroform-d):δ7.39(d,J＝2.6Hz,1H),7.24(dd,J＝7.9,2.6,1H),7.24-7.19(m,2H),7.00-6.96(m,2H),6.90(d,J＝7.9Hz,1H),4.76(s,2H),4.13-3.73(m,1H),3.59-3.46(m,2H),3.13-2.85(m,4H),2.22-1.97(m,2H),2.02-1.83(m,2H),1.84-1.71(m,2H),1.09(t,J＝7.4Hz,3H)；ESI-MS:m/z＝432[M+1]+。
制备实施例20.N-(3-氰基-4-(4-羟基哌啶-1-基)苯基)-N-(4-氟苄基)苯磺酰胺(化合物20)的合成：
步骤1. 2-氟-5-((4-氟苄基)氨基)苄腈(20a)的合成：
合成步骤参考实施案例5步骤1,只是用5b和对氟苯甲醛为原料制备化合物20a,收率91.1％。ESI-MS:m/z＝245[M+1]+。
步骤2.N-(3-氰基-4-氟苯基)-N-(4-氟苄基)苯磺酰胺(20b)的合成：
合成步骤参考实施案例5步骤2,只是用5c和苯磺酰氯为原料制备化合物20b,收率89.0％；ESI-MS:m/z＝385[M+1]+。
步骤3.N-(3-氰基-4-(4-羟基哌啶-1-基)苯基)-N-(4-氟苄基)苯磺酰胺(化合物20)的合成：
合成步骤参考实施案例11的合成步骤,只是用20b和4-羟基哌啶醇为原料制备化合物20,得到的粗品用硅胶柱层析纯化(DCM:EA＝10:1,v/v)，收率96％。
1H NMR(500MHz,Chloroform-d):δ7.71-7.62(m,3H),7.59-7.51(m,2H),7.21-7.15(m,2H),7.11-7.04(m,1H),7.04-6.99(m,1H),6.98-6.90(m,2H),6.83(dd,J＝7.9,2.6Hz,1H),4.63(s,2H),3.95-3.81(m,1H),3.63-3.41(m,2H),3.11-2.93(m,2H),2.14-1.98(m,2H),1.84-1.67(m,2H)；ESI-MS:m/z＝466[M+1]+。
制备实施例21.4-(2-氰基-4-(N-(4-氟苄基)丙基)苯基)-N,N-二甲基哌嗪-1-甲酰胺(化合物21)的合成：
步骤1. 5-硝基-2-(哌嗪-1-基)苄腈(21a)的合成：
合成步骤参考实施案例1步骤1,只是用2-氟-5-硝基苯甲腈和哌嗪为原料制备化合物21a,收率为98.2％。ESI-MS:m/z＝233[M+1]+。
步骤2. 4-(2-氰基-4-硝基苯基)-N,N-二甲基哌嗪-1-甲酰胺(21b)的合成：
将21a(0.5g,2.15mmol)溶于DCM10mL中，加入三乙胺(0.65g,6.46mmol)，冷却至0～5℃，滴加二甲基氨基甲酰氯(0.35g,3.23mmol)，滴加毕,升至室温反应2h，反应完后将反应液减压浓缩，残留物用硅胶柱层析纯化(DCM:MeOH＝20:1,v/v)，得到21b，收率91％；ESI-MS:m/z＝304[M+1]+。
步骤3. 4-(4-氨基-2-氰基苯基)-N,N-二甲基哌嗪-1-甲酰胺(21c)的合成：
合成步骤参考实施案例1步骤2,只是用21b为原料制备化合物21c,所得粗品用硅胶柱层析纯化(DCM:MeOH＝20:1,v/v)，收87.6％；ESI-MS:m/z＝248[M+1]+。
步骤4. 4-(2-氰基-4-((4-氟苄基)氨基)苯基)-N,N-二甲基哌嗪-1-甲酰胺(21d)的合成
合成步骤参考实施案例1步骤3,只是用21c和对氟苯甲醛为原料制备化合物21d,所得粗品用硅胶柱层析纯化(DCM:MeOH＝20:1,v/v)，收率86.0％；ESI-MS:m/z＝382[M+1]+。
步骤5. 4-(2-氰基-4-(N-(4-氟苄基)丙基)苯基)-N,N-二甲基哌嗪-1-甲酰胺(化合物21)的合成：
合成步骤参考实施案例1步骤4,只是用21d和丙磺酰氯为原料制备化合物21,所得粗品用硅胶柱层析纯化(PE:EA＝2:1,v/v)，收率46.9％。1H NMR(500MHz,Chloroform-d):δ7.42(d,J＝2.5Hz,1H),7.30(dd,J＝7.9,2.5Hz,1H),7.24-7.16(m,2H),6.98(t,J＝8.6Hz,2H),6.89(d,J＝7.9Hz,1H),4.77(s,2H),3.56–3.37(m,4H),3.27-3.14(m,4H),3.09-2.94(m,2H),2.86(s,6H),1.99-1.84(m,2H),1.09(t,J＝7.4Hz,3H)；ESI-MS:m/z＝488[M+1]+。
制备实施例22.化合物22-36的合成：
步骤1.中间体22a-36a的合成：
合成步骤参考实施案例1步骤3，只是用1b和相应的芳醛为原料制备化合物22a-36a。
步骤2.化合物22-36的合成：
合成步骤参考实施案例3步骤3，只是用22a-36a和丙磺酰氯为原料制备化合物22-36。
表1.1化合物22-36的核磁及质谱数据
制备实施例23.化合物37-48的合成：
37a,37b,37:R1＝N,N-二甲基甲酰胺基,R2＝4-氟苯基,R3＝2-甲基丙基
38a,38b,38:R1＝N,N-二甲基甲酰胺基,R2＝4-氟苯基,R3＝n-丁基
39a,39b,39:R1＝N,N-二甲基甲酰胺基,R2＝4-氟苯基,R3＝3-甲基丁基
40a,40b,40:R1＝N,N-二甲基甲酰胺基,R2＝4-氟苯基,R3＝2,2-二甲基丙基
41a,41b,41:R1＝N,N-二甲基甲酰胺基,R2＝吡啶-4-基,R3＝n-丙基
42a,42b,42:R1＝N,N-二甲基甲酰胺基,R2＝嘧啶-4-基,R3＝n-丙基
43a,43b,43:R1＝N,N-二甲基磺酰胺基,R2＝4-氟苯基,R3＝n-丙基
44a,44b,44:R1＝N,N-二甲基磺酰胺基,R2＝4-氯苯基,R3＝n-丙基
45a,45b,45:R1＝N,N-二甲基磺酰胺基,R2＝4-甲氧基苯基,R3＝n-丙基
46a,46b,46:R1＝N,N-二甲基磺酰胺基,R2＝1-甲基吡唑-5-基,R3＝4-氟苯基
47a,47b,47:R1＝N,N-二甲基磺酰胺基,R2＝2,4-二氟苯基,R3＝环丙基甲基
48a,48b,48:R1＝N,N-二甲基磺酰胺基,R2＝4-氟苯基,R3＝吡啶-3-基
步骤1.中间体37a-48a的合成：
合成步骤参考实施案例1步骤1-2，只是用2-氯-5-硝基苯甲腈和相应的单取代哌嗪为原料,经取代、硝基还原制备化合物37a-48a。
步骤2.化合物37b-48b的合成：
合成步骤参考实施案例1步骤3，只是用37a-48a和相应的芳醛为原料制备化合物37b-48b。
步骤3.化合物37-48的合成：
合成步骤参考实施案例1步骤4，只是用37b-48b和相应的磺酰氯为原料制备化合物37-48。
表1.2化合物37-48的核磁及质谱数据
制备实施例24.4-(4-(N-(4-氟苯基)丙磺酰胺基)-2-(三氟甲基)苯基)哌嗪-1-甲酸乙酯(化合物49)的合成：
合成步骤参考实施案例1步骤1-4，只是用1-氯-4-硝基-2-(三氟甲基)苯和相应单取代哌嗪为原料,经取代、硝基还原、还原氨化、磺酰胺化制备化合物49。
1H NMR(500MHz,Chloroform-d)：δ7.64-7.61(m,2H),7.25(dd,J＝8.8,2.6Hz,2H),6.87(s,1H),6.56(d,J＝7.5Hz,1H),6.49(d,J＝7.4Hz,1H),4.63(s,2H),4.15(q,J＝7.1Hz,2H),3.32-3.29(m,8H),3.15(t,J＝7.1Hz,2H),1.70(m,2H),1.30(t,J＝7.1Hz,3H),0.91(t,J＝7.4Hz,3H)；ESI-MS:m/z＝532[M+1]+。
制备实施例25.化合物50-58的合成：
化合物50-58采用专业技术人员熟知的平行合成法制备。起始原料N-(3-腈基-4-氟苯基)-N-(4-氟苄基)丙磺酰胺参照制备实施例5.步骤1、2中5b的合成方法制备。
步骤1.中间体50b-52b的合成：
将50a-52a(2.5mmol)分别置于三个平行反应瓶中，用无水DMF溶解，降温至0℃，加入60％氢化钠(0.12g,3.0mmol)，保温搅拌0.5h，再向其中加入N-(3-腈基-4-氟苯基)-N-(4-氟苄基)丙磺酰胺(1.0g,2.7mmol)，升至室温反应1h，反应完后将反应液倒入水中，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝2:1,v/v)，得到50b-52b。
步骤2.化合物50-52的合成：
将中间体50b-52b(1.5mmol)分别溶于DCM30mL中，向其中加入三氟乙酸(5.0g,43.1mmol),室温搅拌1h，用碳酸钠溶液碱化，二氯甲烷萃取，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(DCM:MeOH＝20:1,v/v)，得到化合物50-52。
步骤3.化合物53-55的合成：
将50-52(0.45mmol)分别溶于DCM5mL中，加入三乙胺(0.05g,0.49mmol)，再加入乙酰氯(0.053g,0.67mmol)，室温搅拌1h，减压浓缩，残留物用硅胶柱层析纯化(DCM:MeOH＝20:1,v/v)，得到化合物53-55。
步骤4.化合物56-58的合成：
将N-甲酰基糖精(0.047g,0.22mmol)加入到THF1mL中，然后分别加入50-52(0.22mmol)，室温搅拌15min，碳酸钠溶液碱化，乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(DCM:MeOH＝20:1,v/v)，得到化合物56-58。
制备实施例26.化合物59、60的合成：
合成步骤参考实施案例25步骤1-4，只是用5b为原料,经取代、脱Boc保护基、N-乙酰化/甲酰化制备化合物59、60。
表1.3化合物50-60的核磁及质谱数据
制备实施例27.4-(4-(N-苄基丙磺酰胺基)2-腈基苯基)-3-氧哌嗪-1-甲酸乙酯
(化合物61)的合成：
步骤1.中间体N-苄基-N-(4-溴-3-氰基苯基)丙磺酰胺(61a)的合成：
合成步骤参考实施案例17步骤2,只是用17a和丙磺酰氯为原料制备化合物61a,ESI-MS：m/z＝394[M+1]+。
步骤2. 4-(4-(N-苄基丙磺酰胺基)2-腈基苯基)-3-氧哌嗪-1-甲酸乙酯(化合物61)的合成：
合成步骤参考实施案例17步骤3,只是用61a和3-氧代哌嗪-1-甲酸乙酯为原料制备化合物61。1H NMR(500MHz,Chloroform-d):δ7.43(d,J＝7.5Hz,2H),7.31-7.29(m,3H)，7.25(d,J＝7.5Hz，2H),7.21(d,J＝7.5Hz,1H),6.97(s,1H),4.65(s,2H),4.14(q,J＝7.1Hz,2H),3.79(s,2H),3.64(t,J＝7.1Hz,2H),3.24(t,J＝7.1Hz，2H),3.10(t,J＝7.1Hz,2H),1.70(m,2H),1.22(t,J＝7.2Hz,3H),0.99(t,J＝7.2Hz,3H)；ESI-MS：m/z＝485[M+1]+。
实施例28生物学评估一、对Kv1.3的抑制活性的IonWorks全自动膜片钳测定
对于Kv1.3IonWorks测定的原理和方法参见施罗德等人的文献报道[Schroederet al.J Biomol Screen 2003,8(1):50-64]
1、细胞培养
化合物对Kv1.3抑制活性的评估使用稳定表达人体Kv1.3的CHO-K1重组细胞株(Charles River,California)。细胞在含有5％小牛血清F-12K培养液(Invitrogen,Carlsbad.CA)在37℃和含6％CO2的空气湿度条件的培养箱中培养。在IonWorks***中使用之前，用凡尔赛(Versene)在37℃下处理粘附细胞6-7分钟，轻轻敲打培养瓶后，重新将细胞悬浮在PBS磷酸盐缓冲液，然后经50x g离心4分钟。在短暂的研磨后，最终将细胞以大约1x106/ml的密度重新悬浮在外部记录溶液中。
2、化合物测定板的准备
化合物经DMSO溶解后，在母板上制成300x倍的最终测定梯度浓度。最终测定的梯度浓度为0.00384,0.00192,0.096,0.048,0.24,1.2,6和30μM。将所有300x倍浓度的化合物DMSO原液转移到384-孔的化合物测定板，每孔放置2μl。将化合物测定板密封后在-80℃保存至测定当天。
测定当天，将化合物测定板在室温下解冻，经离心后，加入198μl的外部记录溶液(其成分为：130mM Na-Gluconate,20mM NaCl,4mM KCl,1mM MgCl2,1.8mM CaCl2,5mMGlucose和10mM HEPES,pH7.3)并充分混合。这步骤提供了化合物1:100的稀释。在IonWorks中加入细胞后进一步稀释1:3，故总稀释度为1:300。每个测定板上至少保留8个孔用于空白对照，即仅含0.3％DMSO，另外至少保留8个孔用于阳性对照，以检测细胞信号的特异性。用于阳性对照的化合物为氟西汀(Fluoxetine)，在其最大阻断浓度(100μM)和次级最大阻断浓度(10μM)下进行测试。另外，在测试用的内部记录溶液(其成分为：100mM K-Gluconate,40mM KCl,1mM MgCl2,1mM EGTA和10mM HEPES,pH7.3)中含有最终浓度为200μg/ml的两性霉素B(Amphotericin B)，以获得细胞内的电流通道。溶液的渗透压用蔗糖调节。
3、实验步骤和数据分析
实验步骤按照IonWorks Quattro***(Molecular Devices,San Jose,CA)设定的程序进行。人体Kv1.3的电流经持续1秒钟的脉冲诱导至0毫伏(mV)，共诱导四次。多脉冲之间维持-80毫伏的电位势，持续5秒钟。首先IonWorks Quattro***起动前期电压施加程序，然后加入化合物并进行600秒钟的孵育。接下来起动后期电压施加程序，直至完成全部测试过程。
在化合物加入前后均测量最大外向峰值电流以及测量在第四脉冲升至0毫伏时诱发的平均末端电流。将化合物加入后所测得的电流幅度除以化合物加入前的电流幅度，即可计算化合物对Kv1.3的抑制活性。
所有数据经IonWorks Quattro***设置的数据过滤程序校正。其过滤标准为：封接质量>30MΩ，封接电阻下降<50％及电流幅度>200pA。
表2.1化合物对Kv1.3的抑制活性(全自动膜片钳法)
二、对Kv1.3的抑制活性的传统膜片钳测定
为了比较不同测定方法对化合物抑制活性的影响，同时采用传统膜片钳法测定了化合物21、37、44、61对于Kv1.3的抑制活性。传统膜片钳测定的原理和方法参见格里斯默尔等人的文献报道[Grissmer et al.Molecular Pharmacology 1994,45:1227-1234]
1、细胞培养
化合物对Kv1.3抑制活性的评估使用稳定表达人体Kv1.3的CHO-K1重组细胞株(Charles River,California)。细胞在含有5％小牛血清F-12K培养液(Invitrogen,Carlsbad.CA)在37℃和含6％CO2的空气湿度条件的培养箱中培养。
实验时，贴壁细胞放置在倒置显微镜下的记录室中。所有实验都在室温下进行。每个细胞都以自身为对照
2、化合物的测试
测试化合物的最终浓度均在当天配制，再溶于细胞外液。细胞外液(mM)为:NaCl,137；KCl,4；CaCl2,1.8；MgCl2,1；HEPES,10；glucose 10；pH 7.4(NaOH滴定)。所有测试化合物和对照化合物溶液均含0.3％DMSO。
化合物均采用利用自身重力的灌流***进行灌流。化合物每个浓度至少测试两个细胞。在电流稳定后，再比较化合物使用前后的电流大小变化来计算化合物的阻断作用。阳性对照物使用1000μM 4-AP
3、电生理
将细胞转移到灌流槽中，用细胞外液进行灌流。细胞内液(mM)为：K-aspartate,130；MgCl2,5；EGTA 5；HEPES,10；pH 7.2(KOH滴定)。细胞内液分批少量储存于-80度冰箱，实验当天融化。电极用PC-10(Narishige，Japan)拉制。全细胞膜片钳记录，噪音用采样频率的五分之一进行过滤。
4、测试过程和结果分析
将细胞钳制在–80mV，然后用持续2秒方波去极化到0mV，以得到Kv1.3电流。这一程序每20秒重复一次。检测方波引发的最大电流，待其稳定后，灌流测试化合物，当反应稳定后，计算阻断的强度。
资料采集和分析使用pCLAMP 10(Molecular Devices,Union City,CA)。电流稳定指的是电流随时间变化在有限的范围内。电流稳定后的大小说明用来计算化合物在此溶度的作用。
表2.2部分化合物对Kv1.3的抑制活性(传统膜片钳法)
三、对Kv1.5的抑制活性的传统膜片钳测定
对于Kv1.5传统膜片钳测定的原理和方法参见格里斯默尔等人的文献报道[Grissmer et al.Molecular Pharmacology 1994,45:1227-1234]。
1、细胞培养
化合物对Kv1.5抑制活性的评估使用稳定表达人体Kv1.5的CHO-K1重组细胞。株(Charles River,California)。细胞在含有5％小牛血清F-12K培养液(Invitrogen,Carlsbad.CA)在37℃和含6％CO2的空气湿度条件的培养箱中培养。
实验时，贴壁细胞放置在倒置显微镜下的记录室中。所有实验都在室温下进行。每个细胞都以自身为对照
2、化合物的测试
测试化合物的最终浓度均在当天配制，再溶于细胞外液。细胞外液(mM)为:NaCl,137；KCl,4；CaCl2,1.8；MgCl2,1；HEPES,10；glucose 10；pH 7.4(NaOH滴定)。所有测试化合物和对照化合物溶液均含0.3％DMSO。
化合物均采用利用自身重力的灌流***进行灌流。化合物每个浓度至少测试两个细胞。在电流稳定后，再比较化合物使用前后的电流大小变化来计算化合物的阻断作用。
阳性对照物使用1000μM 4-AP
3、电生理
将细胞转移到灌流槽中，用细胞外液进行灌流。细胞内液(mM)为：K-aspartate,130；MgCl2,5；EGTA 5；HEPES,10；pH 7.2(KOH滴定)。细胞内液分批少量储存于-80度冰箱，实验当天融化。电极用PC-10(Narishige，Japan)拉制。全细胞膜片钳记录，噪音用采样频率的五分之一进行过滤。
4、测试过程和结果分析
将细胞钳制在–80mV，然后用持续2秒方波去极化到20mV，以得到Kv1.5电流。这一程序每20秒重复一次。检测方波引发的最大电流，待其稳定后，灌流测试化合物，当反应稳定后，计算阻断的强度。
资料采集和分析使用pCLAMP 10(Molecular Devices,Union City,CA)。电流稳定指的是电流随时间变化在有限的范围内。电流稳定后的大小说明用来计算化合物在此溶度的作用。
表2.2部分化合物对Kv1.5的抑制活性(传统膜片钳法)

Claims (10)

1.一种N-苄基-N-芳基磺酰胺类衍生物，其特征在于，具有通式(Ⅰ)的化合物或其药学上可接受的盐或溶剂合物，
其中：
环A选自取代的苯基，所述取代的取代基选自和R3基团；
环B选自取代或无取代的包含1～3个选自O、N和S的五元或六元脂杂环基，所述取代的取代基选自Z和R4；
R选自无取代或取代的苯基或包含1-2个氮原子的无取代或取代的五元或六元芳杂环或C1-6直链、支链烷基或卤代的C1-6直链、支链烷基，苯基或芳杂环取代为单取代、双取代或三取代，所述的取代基选自Ra基团；
Ra选自H、卤素、硝基、氰基、C1-3烷基、C1-3烷氧基、卤代的C1-3烷基、-C-O-C-；
R1选自无取代或取代的苯基或包含1～3个选自O、N和S的无取代或取代的五元或六元杂环芳基,取代为单取代、双取代或三取代，所述的取代基选自Rb基团；
Rb任选自H、卤素、硝基、氰基、C1-3烷基、C1-3烷氧基、卤代的C1-3烷基、-C-O-C-；
R2选自C1-3直链、支链烷基、环丙基、＝O；
R3选自卤素、硝基、氰基、三氟甲基、酰胺基、取代烷基酰胺基；
R4选自H、卤素、＝O、OH、NH2、甲酸酯基、氨基甲酸酯基、烷酰基、乙酸酯基、磺酰胺基、吡咯烷酮基、环丙基、氨基甲酰胺基、二甲基氨基乙氧基、烷酰氧基、烷酰胺基；
Z选自O、S、NH或缺失。
2.根据权利要求1所述的一种N-苄基-N-芳基磺酰胺类衍生物，其特征在于，其中环A选自下列取代苯环：
3.根据权利要求1所述的一种N-苄基-N-芳基磺酰胺类衍生物，其特征在于，其中环B选自下列含氧、氮的五元或六元脂杂环：
4.通式(Ⅰ)优选自下列化合物：
4-(4-(N-苄基苯基磺酰氨基)-2-氰基苯基)哌嗪-1-甲酸乙酯
4-(2-氰基-4-((4-氟-N-(4-氟苄基)苯基)磺酰氨基)苯基)哌嗪-1-甲酸乙酯
4-(2-氰基-4-((4-氟-N-(4-氟-3-甲氧基苄基)苯基)磺酰氨基)苯基)哌嗪-1-甲酸乙酯
4-(2-氰基-4-(N-(苯磺酰基)苯甲酰氨基)苯基)哌嗪-1-甲酸乙酯
N-苄基-N-(3-氰基-4-(4-氧代哌啶-1-基)苯基)苯磺酰胺
N-苄基-N-(3-氰基-4-(4-羟基哌啶-1-基)苯基)苯磺酰胺
N-苄基-N-(3-氰基-4-(4-乙酰氧基哌啶-1-基)苯基)苯磺酰胺
4-(2-氰基-4-((4-氟-N-丙基苯基)磺酰氨基)苯基)哌嗪-1-甲酸乙酯
4-(2-氰基-4-(N-(4-氟代苄基)丙磺酰氨基)苯基)哌嗪-1-甲酸乙酯
N-(3-氰基-4-吗啉基苯基)-N-(4-氟苄基)苯磺酰胺
4-(4-(N-苄基苯磺酰氨基)-2-氰基苯基)-N,N-二甲基哌嗪-1-甲酰胺
1-(4-(N-苄基苯磺酰氨基)-2-氰基苯基)-N,N-二甲基哌啶-4-磺酰胺
4-(2-氰基-4-(N-异丁基苯基磺酰胺基)苯基)哌嗪-1-甲酸乙酯
1-(4-(N-苄基苯磺酰氨基)-2-氰基苯基)哌啶-4-基氨基甲酸乙酯
N-(1-(4-(N-苄基苯磺酰胺基)-2-氰基苯基)吡咯烷-3-基)乙酰胺
N-苄基-N-(3-氰基-4-(2,6-二氧代哌啶-1-基)苯基)苯磺酰胺
N-苄基-N-(3-氰基-4-(3-甲基-2-氧代四氢嘧啶-1(2H)-基)苯基)苯磺酰胺
N-苄基-N-(3-氰基-4-(4-(2-(二甲基氨基)乙氧基)哌啶-1-基)苯基)苯磺酰胺
N-(3-氰基-4-(4-羟基哌啶-1-基)苯基)-N-(4-氟苄基)丙烷-1-磺酰胺
N-(3-氰基-4-(4-羟基哌啶-1-基)苯基)-N-(4-氟苄基)苯磺酰胺
4-(2-氰基-4-(N-(4-氟苄基)丙基)苯基)-N,N-二甲基哌嗪-1-甲酰胺
4-(4-(N-苄基丙磺酰胺基)2-腈基苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(3-氟苄基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(4-(4-(N-(4-氯苄基)丙磺酰胺基)2-腈基苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(2-氟苄基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(3-甲氧基苄基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(4-甲氧基苄基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(3,4-二甲氧基苄基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(2-氟-4-甲氧基苄基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(4-氟-2-甲氧基苄基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(嘧啶-4-基甲基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(吡啶-2-基甲基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(呋喃-2-基甲基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-(噻唑-4-基甲基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-((1-甲基-1H-咪唑-5-基)甲基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-(N-((1-甲基-1H-吡唑-5-基)甲基)丙磺酰胺基)苯基)哌嗪-1-甲酸乙酯
4-(2-腈基-4-((N-(4-氟苄基)-2-甲基丙基)磺酰胺基)苯基)-N,N-二甲基哌嗪-1-甲酰胺
4-(2-腈基-4-(N-(4-氟苄基)丁磺酰胺基)苯基)-N,N-二甲基哌嗪-1-甲酰胺
4-(2-腈基-4-((N-(4-氟苄基)-3-甲基丁基)磺酰胺基)苯基)-N,N-二甲基哌嗪-1-甲酰胺
4-(2-腈基-4-((N-(4-氟苄基)-2,2-二甲基丙基)磺酰胺基)苯基)-N,N-二甲基哌嗪-1-甲酰胺
4-(2-腈基-4-(N-(吡啶-4-基甲基)丙磺酰胺基)苯基)-N,N-二甲基哌嗪-1-甲酰胺
4-(2-腈基-4-(N-(嘧啶-4-基甲基)丙磺酰胺基)苯基)-N,N-二甲基哌嗪-1-甲酰胺
4-(2-腈基-4-(N-(4-氟苄基)乙磺酰胺基)苯基)-N,N-二甲基哌嗪-1-磺酰胺
4-(4-(N-(4-氯苄基)丙磺酰胺基)-2-腈基苯基)-N,N-二甲基哌嗪-1-磺酰胺
4-(2-腈基-4-(N-(4-甲氧基苄基)丙磺酰胺基)苯基)-N,N-二甲基哌嗪-1-磺酰胺
4-(2-腈基-4-((4-氟-N-((1-甲基-1H-吡唑-5-基)甲基)苯基)磺酰胺基)苯基)-N,N-二甲基哌嗪-1-磺酰胺
4-(2-腈基-4-((1-环丙基-N-(2,4-二氟苄基)甲基)磺酰胺基)苯基)-N,N-二甲基哌嗪-1-磺酰胺
4-(2-腈基-4-(-N-(4-氟苯基)吡啶-3-磺酰胺基)苯基)-N,N-二甲基哌嗪-1-磺酰胺4-(4-(N-(4-氟苯基)丙磺酰胺基)-2-(三氟甲基)苯基)哌嗪-1-甲酸乙酯
4-(2-氰基-4-((4-氟-N-(4-氟苄基)苯基)磺酰氨基)苯基)哌嗪-1-甲酸乙酯
N-(3-氰基-4-(哌啶-4-基硫)苯基)-N-(4-氟苄基)丙磺酰胺
N-(3-氰基-4-(哌啶-4-基氨)苯基)-N-(4-氟苄基)丙磺酰胺
N-(4-((1-乙酰基哌啶-4-基)氧)-3-腈基苯基)-N-(4-氟苄基)丙磺酰胺
N-(4-((1-乙酰基哌啶-4-基)硫)-3-腈基苯基)-N-(4-氟苄基)丙磺酰胺
N-(4-((1-乙酰基哌啶-4-基)氨)-3-腈基苯基)-N-(4-氟苄基)丙磺酰胺
N-(4-((1-甲酰基哌啶-4-基)氧)-3-腈基苯基)-N-(4-氟苄基)丙磺酰胺
N-(4-((1-甲酰基哌啶-4-基)硫)-3-腈基苯基)-N-(4-氟苄基)丙磺酰胺
N-(4-((1-乙酰基哌啶-4-基)氧)-3-腈基苯基)-N-苄基苯磺酰胺
N-(4-((1-甲酰基哌啶-4-基)氧)-3-腈基苯基)-N-苄基苯磺酰胺
N-(4-((1-甲酰基哌啶-4-基)氨)-3-腈基苯基)-N-(4-氟苄基)丙磺酰胺
及其上述化合物的药学上可接受的盐或溶剂合物。
5.一种通式(Ⅰ)化合物的制备方法，其特征在于，通过以下步骤实现：
方法一：当通式(I)的化合物中，环A为取代苯环，同时Z缺失时：
1-卤代-2-R3-4-硝基苯在碱性条件下与含氮五元或六元脂杂环(B环)缩合，再将硝基还原成氨基,进而经还原胺化，磺酰胺化，必要时经脱保护基得到目标化合物；或采用1-卤代-2-R3-4-硝基苯先经硝基还原，进而经还原胺化，磺酰胺化，所得中间体再在碱性条件下与含氮五元或六元脂杂环(B环)缩合，最后必要时经脱保护基得到目标化合物。
化合物1-49,61按照下列合成路线制备：
方法二：当通式(I)的化合物中，环A为苯环，环B为哌啶，Z选自O、S、NH时：
1-卤代-2-R3-4-硝基苯在碱性条件下与4-羟基或4-巯基或4-氨基哌啶反应，再将硝基还原成氨基,进而经还原胺化，磺酰胺化得目标分子；或采用N-苄基/烷基-N-(3-R3-4-氟苯基)磺酰胺与N-Boc保护的4-羟基或4-巯基或4-氨基哌啶反应，进而脱Boc保护基,再经哌啶N取代得目标分子；
化合物50-60按照下列合成路线制备：
6.权利要求1所述的N-苄基-N-芳基磺酰胺类衍生物在制备治疗由Kv1.3介导的自身免疫性疾病抑制剂中的应用，其特征在于，所述的自身免疫性疾病包括银屑病、银屑病性关节炎、变应性以及刺激性接触性皮炎、特应性皮炎、白癜风、类风湿性关节炎、Ⅰ型糖尿病、多发性硬化、哮喘、肾小球肾炎、牙周疾病、睫状体扁平部炎、移植排斥、神经退行性变、肥胖症、高血压。
7.权利要求1所述的应用，其特征在于，所述抑制剂包含至少一种活性组分以及一种或多种药学上可接受的载体或赋形剂，所述的活性组分是本发明的N-苄基-N-芳基磺酰胺类化合物及其在药学上可接受的盐、所述化合物的溶剂合物中的任意一种或任意多种。
8.权利要求7所述的应用，其特征在于，所述载体或赋形剂包括药学领域的常规稀释剂，填充剂，粘合剂，湿润剂，崩解剂，吸收促进剂，表面活性剂，吸附载体，润滑剂，必要时加入香味剂，甜味剂。
9.权利要求7所述的应用，其特征在于，所述抑制的剂型为片剂、胶囊、贴剂、乳剂、混悬剂、凝胶剂,粉剂、颗粒剂、口服液及注射剂。
10.权利要求7所述的应用，其特征在于，所述的N-苄基-N-芳基磺酰胺类化合物的盐，选用无机酸盐、有机酸盐，所述的无机酸盐包括与氢卤酸，硝酸，碳酸，硫酸，磷酸形成的盐；所述的有机酸盐包括与苹果酸、L-苹果酸、D-苹果酸、枸橼酸、富马酸、草酸、乳酸、樟脑磺酸、L-樟脑磺酸、D-樟脑磺酸、对甲苯磺酸、甲磺酸、苯甲酸形成的盐。
CN201910058021.1A 2019-01-22 2019-01-22 一种n-苄基-n-芳基磺酰胺类衍生物及制备和应用 Active CN109651297B (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CN201910058021.1A CN109651297B (zh) 2019-01-22 2019-01-22 一种n-苄基-n-芳基磺酰胺类衍生物及制备和应用
EP20744951.3A EP3915978A4 (en) 2019-01-22 2020-01-21 N-BENZYL-N-ARYLSULFONAMIDE DERIVATIVES, THEIR PREPARATION AND USE
US17/424,292 US11993576B2 (en) 2019-01-22 2020-01-21 N-benzyl-N-arylsulfonamide derivative and preparation and use thereof
PCT/CN2020/073367 WO2020151687A1 (zh) 2019-01-22 2020-01-21 一种n-苄基-n-芳基磺酰胺类衍生物及制备和应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910058021.1A CN109651297B (zh) 2019-01-22 2019-01-22 一种n-苄基-n-芳基磺酰胺类衍生物及制备和应用

Publications (2)

Publication Number Publication Date
CN109651297A true CN109651297A (zh) 2019-04-19
CN109651297B CN109651297B (zh) 2022-05-27

Family

ID=66120391

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910058021.1A Active CN109651297B (zh) 2019-01-22 2019-01-22 一种n-苄基-n-芳基磺酰胺类衍生物及制备和应用

Country Status (4)

Country Link
US (1) US11993576B2 (zh)
EP (1) EP3915978A4 (zh)
CN (1) CN109651297B (zh)
WO (1) WO2020151687A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110776494A (zh) * 2019-11-12 2020-02-11 中国药科大学 苄基哌啶-苯并咪唑衍生物或其可药用的盐、制备方法及用途
WO2020151687A1 (zh) * 2019-01-22 2020-07-30 杭州壹瑞医药科技有限公司 一种n-苄基-n-芳基磺酰胺类衍生物及制备和应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004026823A1 (en) * 2002-09-20 2004-04-01 Pfizer Products Inc. Amide and sulfonamide ligands for the estrogen receptor
CN101389622A (zh) * 2006-01-20 2009-03-18 诺瓦提斯公司 用作pi-3激酶抑制剂的嘧啶衍生物
WO2010023445A1 (en) * 2008-08-29 2010-03-04 Xention Limited Novel potassium channel blocker
US20100113449A1 (en) * 2008-10-30 2010-05-06 Gilead Palo Alto, Inc. Fused heterocyclic compounds as ion channel modulators
WO2010130638A1 (en) * 2009-05-14 2010-11-18 Evotec Ag Sulfonamide compounds, pharmaceutical compositions and uses thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0815782D0 (en) 2008-08-29 2008-10-08 Xention Ltd Novel potassium channel blockers
CN109651297B (zh) * 2019-01-22 2022-05-27 杭州壹瑞医药科技有限公司 一种n-苄基-n-芳基磺酰胺类衍生物及制备和应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004026823A1 (en) * 2002-09-20 2004-04-01 Pfizer Products Inc. Amide and sulfonamide ligands for the estrogen receptor
CN101389622A (zh) * 2006-01-20 2009-03-18 诺瓦提斯公司 用作pi-3激酶抑制剂的嘧啶衍生物
WO2010023445A1 (en) * 2008-08-29 2010-03-04 Xention Limited Novel potassium channel blocker
US20100113449A1 (en) * 2008-10-30 2010-05-06 Gilead Palo Alto, Inc. Fused heterocyclic compounds as ion channel modulators
WO2010130638A1 (en) * 2009-05-14 2010-11-18 Evotec Ag Sulfonamide compounds, pharmaceutical compositions and uses thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020151687A1 (zh) * 2019-01-22 2020-07-30 杭州壹瑞医药科技有限公司 一种n-苄基-n-芳基磺酰胺类衍生物及制备和应用
US11993576B2 (en) 2019-01-22 2024-05-28 Hangzhou Yirui Pharmaceutical Technology Co., Ltd N-benzyl-N-arylsulfonamide derivative and preparation and use thereof
CN110776494A (zh) * 2019-11-12 2020-02-11 中国药科大学 苄基哌啶-苯并咪唑衍生物或其可药用的盐、制备方法及用途

Also Published As

Publication number Publication date
EP3915978A1 (en) 2021-12-01
EP3915978A4 (en) 2022-10-26
WO2020151687A1 (zh) 2020-07-30
US11993576B2 (en) 2024-05-28
CN109651297B (zh) 2022-05-27
US20220089555A1 (en) 2022-03-24

Similar Documents

Publication Publication Date Title
KR101415426B1 (ko) 디아릴아민-함유 화합물 및 조성물, 및 ｃ-ｋｉｔ 수용체의조절제로서의 그의 용도
US6498168B2 (en) Muscarinic antagonists
KR101019313B1 (ko) Ｎ-[페닐(피페리딘-2-일)메틸]벤즈아미드의 유도체, 그의제조 방법 및 치료법에서의 그의 용도
TW200813073A (en) Thiazolo-pyrimidine/pyridine urea derivatives
BRPI0620081B1 (pt) Composto e composição farmacêutica
ES2201907A1 (es) Nuevos derivados de indolilpiperidina como potentes agentes antihistaminicos y antialergicos.
KR102569031B1 (ko) Nr2b nmda 수용체 길항제로서의 피롤로피리미딘 유도체
CA2483368A1 (en) (s)-4-amino-5-chloro-2-methoxy-n-[1-[1-(2-tetrahydrofurylcarbonyl)-4-piperidinylmethyl]-4-piperidinyl]benzamide, process for the preparation thefeof, pharmaceutical composition containing the same, and intermediate therefor
KR102613179B1 (ko) Nr2b nmda 수용체 길항제로서의 3,3-디플루오로피페리딘 카바메이트 헤테로사이클릭 화합물
KR20070116965A (ko) 5-ｈｔ 수용기에서 활성을 갖는(3,4-다이하이드로-퀴나졸린-2-일)-(2-아릴옥시-에틸)-아민
WO2012101453A1 (en) Protease activated receptor 2 (par2) antagonists
JP4719681B2 (ja) キナゾリンカリウムチャネル阻害剤
JPH11514671A (ja) ムスカリン様アンタゴニストとしての１，４―ジ―置換ピペリジン
CN109651297A (zh) 一种n-苄基-n-芳基磺酰胺类衍生物及制备和应用
TW200808779A (en) Novel compound
EP1667973B1 (en) Quinoline potassium channel inhibitors
EP1735302B1 (en) 4-amino-piperidine derivatives as monoamine uptake inhibitors
JP2004277318A (ja) １−（１−置換カルボニル−４−ピペリジニルメチル）ピペリジン誘導体およびそれを含有する医薬組成物
US8372980B2 (en) Fused ring thrombin receptor antagonists
JP2004277319A (ja) １−（４−ピペリジニルメチル）ピペリジニルアミド誘導体およびそれを含有する医薬組成物
CN109705033A (zh) N-杂芳基磺酰胺类衍生物及制备和应用
JP2005104896A (ja) ２−アルコキシ−６−アミノ−５−ハロゲノピリジン−３−カルボキサミド誘導体およびそれを含有する医薬組成物
Itoh et al. Synthesis and pharmacological evaluation of carboxamide derivatives as selective serotoninergic 5-HT4 receptor agonists
JP2001122784A (ja) １−［（１−置換−４−ピペリジニル）メチル］−４−ピペリジン誘導体からなる医薬
AU2017239419B2 (en) Benzenesulfonyl-asymmetric ureas and medical uses thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
PE01 Entry into force of the registration of the contract for pledge of patent right
PE01 Entry into force of the registration of the contract for pledge of patent right

Denomination of invention: A N-benzyl-N-arylsulfonamide derivative and its preparation and application

Granted publication date: 20220527

Pledgee: Hangzhou High-tech Financing Guarantee Co.,Ltd.

Pledgor: HANGZHOU YIRUI PHARMACEUTICAL TECHNOLOGY Co.,Ltd.

Registration number: Y2024330000055