TW201838977A - 醯胺化合物及其應用 - Google Patents

醯胺化合物及其應用 Download PDF

Info

Publication number
TW201838977A
TW201838977A TW107102333A TW107102333A TW201838977A TW 201838977 A TW201838977 A TW 201838977A TW 107102333 A TW107102333 A TW 107102333A TW 107102333 A TW107102333 A TW 107102333A TW 201838977 A TW201838977 A TW 201838977A
Authority
TW
Taiwan
Prior art keywords
phenyl
compound
amino
oxadiazol
nmr
Prior art date
Application number
TW107102333A
Other languages
English (en)
Other versions
TWI676621B (zh
Inventor
鍾政和
曾喜樑
楊永寧
陳彥甫
Original Assignee
昊運股份有限公司
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 昊運股份有限公司 filed Critical 昊運股份有限公司
Publication of TW201838977A publication Critical patent/TW201838977A/zh
Application granted granted Critical
Publication of TWI676621B publication Critical patent/TWI676621B/zh

Links

Classifications

    • 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
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/107—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with two aryl or substituted aryl radicals attached in positions 2 and 5
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/90—Carboxylic acid amides having nitrogen atoms of carboxamide groups further acylated
    • C07C233/92—Carboxylic acid amides having nitrogen atoms of carboxamide groups further acylated with at least one carbon atom of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • 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
    • C07D213/90—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 more than three double bonds between ring members or between ring members and non-ring members
    • 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
    • C07D231/14—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 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
    • C07D231/18—One oxygen or sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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
    • C07D237/14—Oxygen 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
    • 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
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本發明係提供如下所示之式(I)化合物及其藥學上可接受之鹽類：
Figure TW201838977A_A0001
其中，R1、R2、L、和Z各自於說明書中定義。本發明另提供使用式(I)化合物或其鹽類以及含其之醫藥組合物用於降低血糖濃度和治療升糖素相關疾病之方法。

Description

醯胺化合物及其應用
本發明係關於一種作為升糖素受體之拮抗劑或反激動劑之化合物、包含其之醫藥組合物、及該化合物或該組合物之用途。
糖尿病為公共衛生的重要議題，並且影響世界上數百萬人。二種可調節血糖恆定之重要賀爾蒙：胰島素和升糖素，於糖尿病中具有重要角色。升糖素由胰島細胞α所分泌，並且可促進肝醣分解以及糖質新生。此外，升糖素訊息亦可影響脂質代謝、食物攝取、心血管系統、以及脂肪組織重量。升糖素訊息傳導之拮抗作用長久以來被用於糖尿病的潛在治療方法，許多治療係利用干擾受體-配體之結合而完成。升糖素受體為B類G蛋白偶聯受體，並且主要於肝臟表現，其他組織則較少。小分子對於升糖素受體之拮抗作用可降低下游第二傳訊者(secondary messenger)，包括cAMP和鈣離子，致使糖質新生基因表現以及後續血糖提升。升糖素受體-/-之小鼠對於飲食引發之肥胖以及鏈佐黴素引發之糖尿病具有抗性。多種小分子升糖素受體拮抗劑近期已開始進行臨床試驗，並且，相對於安慰劑而言，對於降低血糖具有顯著功效。升糖素受體拮抗作用可藉由保護心肌細胞，對於心血管疾病亦有所助益。在升糖素受體不活化之模式小鼠中可具有較高存活率以及較低心肌梗塞後的衰竭。
因此，有必要研發新穎升糖素受體調節劑，並且具有較少、較低之不良副作用，以用於治療。
本發明係關於一種醯胺化合物，可作為治療升糖素相關疾病之升糖素受體調節劑。該些化合物可作為升糖素受體之拮抗劑或反激動劑，相較於已知的治療藥劑，更可提高調節升糖素受體之效率以降低血糖濃度，具有無法預期之功效。
本發明之一實施方式係提供如式(I)所示之化合物及其藥學上可接受之鹽類：
於式(I)中，R1係；；；； 或；R2係-CH2CH2CO2R5或-CH2CH2SO3H；L係-X-CH(R6)-或- CH(R6)-X-；X係NH或O；以及Z係C或N；其中R3係C1-6烷基、芳基、或雜芳基，該C1-6烷基選擇性地經一至三鹵素取代，以及該芳基和雜芳基各自選擇性地經選自C1-6烷基、C3-10環烷基、芳基、經鹵素取代之C1-6烷基、C1-6烷氧基、和鹵素所構成之群組之一至三取代基取代；R4係選自氫、鹵素、羥基、氰基、胺基、C1-6烷基、C1-6烷氧基、經鹵素取代之C1-6烷基、和C3-10環烷基所構成之群組之一至三 取代基；R5係氫、C1-6烷基、C3-10環烷基、和經鹵素取代之C1-6烷基；以及R6係C1-6烷基、C3-10環烷基、或C1-10雜環烷基，該C1-6烷基係選擇性地經鹵素、羥基、C1-6烷氧基、和芳基所構成之群組之一至三取代基取代，以及該C3-10環烷基和C1-10雜環烷基選擇性地經C1-6烷基、C1-6烷氧基、和鹵素所構成之群組之一至二取代基取代。
本說明書用語「烷基」指涉直鏈或具有支鏈碳氫取代基，包括1-20(例如，1-10和1-6)個碳原子。烷基之例示包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、三級丁基。
本說明書用語「環烷基」指涉飽和或部分不飽和之單環、雙環、三環、四環碳氫取代基，具有3-12(例如，3-10和3-8)個碳原子。環烷基之例示包括環丙基、環丁基、環戊基、環戊烯基(cyclopentenyl)、環己基；環己烯基(cyclohexenyl)、環庚基、和環辛基。
本說明書用語「雜環烷基」指涉非芳香5-8元單環、8-12元雙環、或11-14元三環系統，具有一或多雜原子(例如O、N、P、和S)。雜環烷基之例示包括哌嗪基(piperazinyl)；咪唑烷基(imidazolidinyl)；氮雜環庚烷基(azepanyl)；吡咯烷基(pyrrolidinyl)；二氫噻二唑基(dihydrothiadiazolyl)；二噁基(dioxanyl)；嗎啉基(morpholinyl)；四氫吡喃基(tetrahydropuranyl)；和四氫呋喃基(tetrahydrofuranyl)。
本說明書用語「烷氧基」指涉-O-烷基基團。烷氧基之例示包括甲氧基、乙氧基、丙氧基、以及異丙氧基。
本說明書用語「鹵素」指涉氟、氯、溴、或碘之自由基。本說明書用語「胺基」指涉衍生自胺之自由基，可為未經取代或具有一或二烷基、芳基、環烷基、雜環烷基、或雜芳基之取代基。
本說明書用語「芳基」指涉6碳單環、10碳雙環、14碳三環之芳香環系統。芳基之例示包括苯基、萘基、和蒽基。
本說明書用語「雜芳基」指涉5-8員單環、8-12員雙環、或11-14員三環之環系統，具有一或多雜原子(例如，O、N、P、和S)。雜芳基之例示包括三唑基(triazolyl)、噁唑基(oxazolyl)、噻二唑基(thiadiazolyl)、四唑基(tetrazolyl)、吡唑基(pyrazolyl)、吡啶基(pyridyl)、呋喃基(furyl)、咪唑基(imidazolyl)、苯並咪唑基(benzimidazolyl)、嘧啶基(pyrimidinyl)、噻吩基(thienyl)、喹啉基(quinolinyl)、吲哚基(indolyl)、噻唑基(thiazolyl)、和苯並噻唑基(benzothiazolyl)。
於本發明中敘及之烷基、環烷基、雜環烷基、烷氧基、芳基、雜芳基皆包括經取代及未經取代之基團。環烷基、雜環烷基、烷氧基、芳基、雜芳基可能所具有之取代基包括但不限於C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C20環烷基、C3-C20環烯基、C1-C20雜環烷基、C1-C20雜環烯基、C1-C10烷氧基、芳基、芳氧基、雜芳基、雜芳氧基、胺基、C1-C10烷胺基、C1-C20二烷胺基(dialkylamino)、芳胺基(arylamino)、二芳胺基(diarylamino)、C1-C10烷磺醯胺基(alkylsulfonamino)、芳磺醯胺基(arylsulfonamino)、C1-C10烷亞胺基(alkylimino)、芳亞胺基(arylimino)、C1-C10烷磺醯亞胺基(alkylsulfonimino)、芳磺醯亞胺基(arylsulfonimino)、羥基、鹵素、硫基、C1-C10烷硫基、芳硫基、C1-C10烷磺醯基、芳磺醯基、醯胺基(acylamino)、胺醯基(aminoacyl)、胺硫醯基(aminothioacyl)、醯胺基(amido)、甲脒基(amidino)、胍(guanidine)、脲基(ureido)、硫脲基(thioureido)、 氰基、硝基、亞硝基、三氮基(azido)、醯基、硫醯基(thioacyl)、醯氧基(acyloxy)、羧基、和羧酸酯。另一方面，烷基可能所具有之取代基包括但不限於全部前述取代基，除了C1-C10烷基。環烷基、雜環烷基、芳基、和雜芳基亦可彼此稠合。
前述式(I)化合物之外，本發明亦應用於其藥學上可接受之鹽類和溶劑合物。一鹽類可形成於化合物之陰離子和正電基團之間。適當之陰離子之例示包括氯離子、溴離子、碘離子、硫酸、硝酸、磷酸、檸檬酸、甲磺酸、三氟乙酸、乙酸、蘋果酸、甲苯磺酸(tosylate)、酒石酸(tartrate)、反丁烯二酸(fumurate)、谷氨酸(glutamate)、葡糖醛酸(glucuronate)、乳酸鹽、戊二酸、和馬來酸(maleate)。一鹽類亦可形成於化合物之陽離子和負電基團之間。適當之陽離子之例示包括鈉離子、鉀離子、鎂離子、鈣離子、和銨離子如四甲基銨離子。鹽類進一步包括具有四級氮原子之化合物。溶劑合物指涉形成於活性化合物和藥學上可接受之溶劑間之複合物。藥學上可接受之溶劑之例示包括水、乙醇、異丙醇、乙酸乙酯、醋酸、和乙醇胺。
本發明另一實施方式係提供一種醫藥組合物，用於治療升糖素相關疾病，例如升糖素相關代謝異常(例如第一型糖尿病或第二型糖尿病)。
該醫藥組合物包括前述式(I)化合物之一或其藥學上可接受之鹽類以及一藥學上可接受之載劑。
本發明亦包括該組合物用於製備治療升糖素相關疾病(例如代謝異常)之藥物之用途。
口服之組成物可為任何口服可接受之劑型，包括膠囊、錠劑、乳劑、及液態懸浮液、分散液、及溶液。若為錠劑，通常使用之載劑包括乳糖和玉米澱粉。一般也會添加潤滑劑，如硬脂酸鎂。若以膠囊的形式用於口服，可 使用之稀釋劑包括乳糖和乾燥玉米澱粉。若為液態懸浮液或乳劑用於口服，活性成分可懸浮或溶解於油相與乳化劑或懸浮劑之混合中。若有需要，可添加特定甜味劑、調味劑或著色劑。口服的固體劑量形式可由噴灑乾燥技術、熱熔擠出成形方法、微粒化及奈米研磨技術製備而成。
鼻式氣霧或吸入組成物可根據醫藥劑型之技術領域中已知的技術製成。例如：該組合物可使用食鹽水而製備為溶液，利用本技術領域中已知的苯甲醇或其他防腐劑、吸收促進劑、氟碳化物、和/或其他溶解劑或分散劑。含活性化合物之組合物之給藥方式亦可為經由直腸給藥的栓劑形式。
醫藥組合物中之載劑必須是「可接受的」，代表載劑和組合物之活性成分相容(較佳可穩定活性成分)且不會對治療對象有害。可使用一種或多種的溶解劑作為藥物賦形劑，用於輸送活性化合物。其他載體之例示包括膠體氧化矽、硬脂酸鎂、纖維素、十二烷基硫酸鈉、及D&C Yellow #10黃色試劑。
本發明另包括一種治療升糖素相關疾病(例如代謝異常)之方法。
前述方法包括給予患者一有效量之式(I)化合物或其藥學上可接受之鹽類。
前述化合物或包括其一或多者之醫藥組合物之給藥途徑包括口服、腸胃道外、噴劑吸入、局部、直腸、鼻腔、口頰、或經由植入型容器向受試者給藥。本說明書用語「腸胃道外」包括皮下、皮內、靜脈內、肌肉內、關節內、動脈內、滑膜內(intrasynovial)、胸骨內(intrasternal)、鞘內(intrathecal)、病灶內(intralesional)、和顱內(intracranial)等注射或輸液技術。
用於「治療」指涉將化合物給予或應用於個體，以達成痊癒、改善、減緩、改變、醫治、改進、或影響疾病、病徵、或體質。「有效量」指涉 可於患者身體產生預期效果之化合物量。如習知技術者所知，有效量依據給藥途徑、賦形劑使用、和合併其他治療方法(例如使用其他活性成分)之可能性而改變。
本發明其中一或多實施例詳述於下文。本發明其他特徵、目的、和優勢明確揭示於說明書和請求項。
下文詳述式(I)化合物及其藥學上可接受之鹽類： 其中取代基R1、R2、L、和Z之定義與摘要相同。
於一實施例，式(I)化合物之R1各自可為；； 或。一般而言，R2係-CH2CH2CO2R5；L係-X-CH(R6)-或-CH(R6)-X-，X 係NH；以及，Z係C。例如，R1係；；或；L係- CH(R6)-X-，X係NH或O；以及，Z係C。L亦可為-X-CH(R6)-，X係NH或O。本實施例中，R3可為C1-6烷基，選擇性地被苯基或吡啶基取代；以及，一般而言R6係C1-6烷基。
式(I)化合物之例示之R1係；；或； R2係-CH2CH2CO2R5；L係-X-CH(R6)-或-CH(R6)-X-；以及，Z係C，其中R3係C1-6 烷基，選擇性地被苯基或吡啶基取代；R5係H或C1-6烷基；R6係C1-6烷基；以及X係NH。
於另一實施例，式(I)化合物中R1係或。一 般而言，R4係H。同樣地，R2可為-CH2CH2CO2R5；L可為-X-CH(R6)-或-CH(R6)-X-，X係NH，以及R6係C1-6烷基；以及，Z可為C或N。本實施例中，式 (I)化合物之例示之R1係或；R2係-CH2CH2CO2R5；L係- X-CH(R6)-或-CH(R6)-X-；以及Z係C，其中R4係H，R5係H或C1-6烷基，R6係C1-6 烷基，以及X係NH。本實施例中，式(I)化合物之另一例示之R1係或 ；R2係-CH2CH2CO2R5；L係-X-CH(R6)-或-CH(R6)-X-；以及Z係N， 其中R4係H，R5係H或C1-6烷基，R6係C1-6烷基，以及X係NH。
前述實施例中，R3可為C1-6烷基、芳基、或6員雜芳基，該C1-6烷基選擇性地經一至三鹵素取代，以及該芳基和6員雜芳基選擇性地經選自甲基、三氟甲基、乙基、丙基、異丙基、丁基、三級丁基、F、和Cl所構成之群組之一至三取代基取代。
前述實施例中，R6可為C1-6烷基或C3-10環烷基，該C1-6烷基選擇性地經選自氟、羥基、甲氧基、和苯基所構成之群組之一至三取代基所取代。
針對式(I)之取代基L，X和R6所具有之碳可具有R或S之立體異構物，以及可具有90%以上之鏡像異構物超越量(例如，95%和99%)。
本發明另提供治療升糖素相關疾病之醫藥組合物，例如升糖素相關代謝異常(例如，第一型和第二型糖尿病)，該組合物包括前述式(I)化合物其中之一或其藥學上可接受之鹽類以及一藥學上可接受之載劑。
本發明另提供治療升糖素相關疾病之方法，包括給予患者一有效量之式(I)化合物或其藥學上可接受之鹽類。
本發明中，患者可為哺乳類動物，例如，人類。
本發明中，升糖素相關之疾病、狀況、或異常可為，例如，高血糖症、第二型糖尿病、代謝症群、葡萄糖耐受不良、糖尿(glucosuria)、糖尿病腎病變(diabetic nephropathy)、糖尿病神經病變(diabetic neuropathy)、糖尿病性視網膜病(diabetic retinopathy)、高胰島素血症(hyperinsulinemia)、胰島素抗性症群、白內障、肥胖、血脂異常(dyslipidemia)、高血壓、和心肌梗塞。但，本發明不限於此，本發明之該化合物或其藥學上可接受之鹽類可應用於與升糖素訊息傳導路徑相關之其他疾病、狀況、或異常。本發明之一實施方式中，升糖素相關之疾病、狀況、或異常為高血糖症、第二型糖尿病、葡萄糖耐受不良、胰島素抗性症群、和肥胖。本發明之另一實施方式中，升糖素相關之疾病、狀況、或異常為第二型糖尿病。
本發明一實施例中，該化合物可選自揭示於表1至7之化合物1-1至1-62、化合物2-1至2-48化合物3-1至3-15、化合物4-1至4-30、化合物5-1至5-8、化合物6-1至6-2、和化合物7-1至7-4所構成之群組其中任一。本發明之一實施方式中，本發明之化合物可選自化合物1-2、化合物1-38、化合物1-39、化合物1-41、化合物1-43、化合物1-45、化合物1-47、化合物1-49、化合物2-18、化合物2-19、化合物2-27、化合物2-28、和化合物4-27至4-30所構成之群組其中任一。
可藉由先前文獻揭示之方法合成式(I)化合物之方法，例如，R.Larock,Comprehensive Organic Transformations(2nd Ed.,VCH Publishers 1999)；P.G.M.Wuts and T.W.Greene,Greene’s Protective Groups in Organic Synthesis(4th Ed.,John Wiley and Sons 2007)；L.Fieser and M.Fieser,Fieser and Fieser’s Reagents for Organic Synthesis(John Wiley and Sons 1994)；L.Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis(2nd ed.,John Wiley and Sons 2009)；P.Roszkowski,J.K.Maurin,Z.Czarnocki“Enantioselective synthesis of(R)-(-)-praziquantel(PZQ)”Tetrahedron：Asymmetry 17(2006)1415-1419；和L.Hu,S.Magesh,L.Chen,T.Lewis,B.Munoz,L.Wang“Direct inhibitors of keap1-nrf2 interaction as antioxidant inflammation modulators,”WO2013/067036等文獻。
藉由上述方法合成後，式(I)化合物可先以體外(in vitro)試驗篩選，例如升糖素cAMP抑制試驗和I125-升糖素結合試驗，均揭露於實施例6，以測試其與升糖素受體結合和抑制下游cAMP之能力。而後，藉由已知的體內(in vivo)試驗測試化合物。選擇化合物後，可進一步測試其治療疾病之功效以及副作用。最後依據試驗結果決定適當劑量範圍和給藥途徑。
習知技術者可依據上述說明並充分利用本發明，而無須於說明書贅述。以下實施例1-7僅為例示，而非本發明範圍之限制。本說明書引用之文獻均可包含於本發明。
於實施例中，實施例1-5揭示製備特定中間物之步驟以及式(I)之172個例示化合物，另有依此方法製備之化合物分析；實施例6-7揭示測試該些化合物之方法。
下文揭示合成前述172個例示化合物之步驟。
若無特別說明，起始材料均為市售可得並直接使用。需要無水條件之反應可使用火焰乾燥之玻璃容器，並於氬氣或氮氣中冷卻後進行反應。若無特別說明，反應則於氬氣或氮氣中進行，並且以分析式薄膜層析法監測，前述薄膜層析法可於預塗佈矽膠60 F254(Merck)之玻璃底盤(5公分(cm)_10cm)中進行。層析圖之顯像可於紫外光燈(λ=254奈米(nm))下觀看，再浸潤於含有醋酸(3% v/v)之茚三酮(Ninhydrin)(0.3% w/v)正丁醇溶液、或磷鉬酸(phosphomolybdic acid)(2.5% w/v)乙醇溶液，並以熱風器炭化(charring)。反應用之溶劑在使用前於氬氣或氮氣中乾燥，方法如下：使用乾燥分子篩(Dried molecular Sieve)5Å(LC technology solution Inc)乾燥四氫呋喃(THF)、甲苯、和二氯甲烷(DCM)，並且可使用市售之氫化鈣或無水獲得二甲基甲醯胺(DMF)。使用RediSep Rf拋棄式矽膠急速層析管柱、Gold® 20-40/40-60微米矽膠(RediSep)、和可重複性之Reusable RediSep Rf Gold® C18逆相管柱，並且配合急速層析法(Flash chromatography)純化和分離產物。沖提系統以體積/體積濃度表示。13C和1H NMR質譜紀錄於Bruker AVIII(400MHz)。氘代氯仿(Chloroform-d)或氘代二甲亞碸(dimethyl sulfoxide-d6)以及氘代甲醇(CD3OD)作為溶劑，以及四甲基矽烷(TMS)(δ 0.00ppm)作為內部標準值。化學位移以ppm表示，相對於TMS的δ單位。多重波峰(Multiplicities)以s(singlet)、br s(broad singlet)、d(doublet)、t(triplet)、q(quartet)、dd(doublet of doublet)、dt(doublet of triplet)、m(multiplet)表示。耦合常數(J)以Hz表示。使用Thermo LTQ XL質譜儀紀錄電灑質譜(ESMS)。質譜數據以m/z表示。
實施例1：表1所示化合物之合成
以下揭示合成化合物1-1至1-62之反應式。
反應式I
步驟I：格林納(Grignard)反應
將4-甲醯基苯甲酸甲酯(methyl 4-formylbenzoate)(9.84克(g)，60.0毫莫耳(mmol))溶於四氫呋喃(30毫升(mL))之溶液冷卻至-78℃。再將2M氯化丁鎂(butylmagnesium chloride)(30ml)滴入該溶液，滴入時間應超過20分鐘。反應於-78℃持續攪拌2小時，再加入飽和氯化銨溶液終止反應，並使用乙酸乙酯萃取。使用硫酸鎂乾燥有機層，過濾後濃縮。再使用矽膠層析純化，獲得無色油狀之化合物I-1：4-(1-羥戊基)苯甲酸甲酯(methyl 4-(1-hydroxypentyl)benzoate)(產率：4.80g,36%)。
步驟II：形成聯胺(hydrazine)
將4-(1-羥戊基)苯甲酸甲酯(4.80g,21.59mmol)溶於絕對酒精(30mL)中，再於室溫加入水合聯胺(hydrazine monohydrate)(2.50g,50mmol)。反應混合物加熱並回流隔夜，再冷卻至室溫並以減壓濃縮。濃縮物懸浮於60mL水，過濾後以水(2×50mL)和乙醇(2×40mL)清洗，獲得米色固態之化合物I-2(3.83g,80%)。
步驟III：醯胺化
於化合物I-2之溶液加入苯甲酸(0.67g,5.5mmol)、1-乙基-3-(3-二甲基氨基丙基)碳醯二亞胺(EDCI)(1.44g,7.5mmol)和丁醇(1.15g,7.5mmole)溶於20ml DMF之溶液。於室溫攪拌反應隔夜，再減壓濃縮。濃縮物加入水，並以乙酸乙酯萃取水層。進一步減壓濃縮，獲得白色固態之化合物I-3(1.04g，64%)。
步驟IV：成環反應
將化合物I-3(1.04g,3.2mmol)、對甲基苯基磺醯氯(TsCl)(0.91g,4.8mmol)、和三乙胺(TEA)(1.5mL,9.6mmol)溶於乙腈(ACN)(20mL)中，於室溫混合攪拌1小時。濃縮反應溶液去除甲醇，再以乙酸乙酯萃取。有機層以水清洗，再以無水硫酸鎂乾燥。過濾後減壓氣化溶劑。粗萃之油狀物使用管柱層析(乙酸乙酯(EA)：己烷(Hex)=30：100)純化，獲得白色固態之化合物I-4(0.80g,81%)。
步驟V：氧化
粗產物溶解於DCM(20mL)，並加入氯鉻酸吡啶(pyridinium chlorochromate)(0.30g,1.4mmol)。反應於室溫攪拌2小時，再以矽藻土過濾並減壓濃縮。濃縮物以具有矽膠之急速管柱層析(EA：Heaxane=10：100)純化，獲得白色固態之化合物I-5(0.30g,100%)。
步驟VI：還原胺化
於化合物I-5(0.17g,0.58mmol)之甲醇(5mL)溶液中加入4-胺苯甲酸乙酯(0.09g,0.53mmol)和十硼烷(decaborane)(0.04g,0.32mmol)隔夜攪拌。反應以薄膜層析法(TLC)監測。起始材料耗盡後，以水以及乙酸乙酯萃取，以硫酸鈉(Na2SO4)乾燥，並減壓濃縮。產物使用矽膠層析純化，並以溶液(EA：Heaxane=20：100)洗滌，獲得白色固態之化合物I-6(0.36g)。
步驟VII：水解
將化合物I-6(0.45g,1.0mmol)溶解於二噁烷(20mL)，再加入2M氫氧化鋰(LiOH)溶液(20mL)。反應物加熱至60℃放置1小時，並以TLC監測反應。反應完成後使用旋轉蒸發去除溶劑，再加入鹽酸調整pH值至4~5。而後以乙酸乙酯萃取，合併有機層以無水硫酸鎂乾燥，減壓濃縮後獲得白色固態之化合物I-7(0.42g,100%)。
步驟VIII：醯胺化
於化合物I-7(426mg,1mmole)溶於乾燥THF(20ml)之溶液中，加入β-丙胺酸乙酯鹽酸鹽(β-alanine ethyl ester hydrochloride)(230毫克(mg),1.5mmol)、EDCI(288mg,1.5mmol)、三乙胺(304mg,3mmol)、和HOBt(229mg,1.5mmol)。反應於室溫攪拌隔夜，再減縮濃縮。於濃縮物中加入水，再以乙酸乙酯萃取水層。而後進一步減壓濃縮，粗萃油狀濃縮物使用管柱層析(EA：Hex=60：100)純化，獲得無色油狀產物I-8。
步驟IX：水解
將化合物I-8(0.52g,1mmol)溶解於THF(20mL)，再加入2M LiOH溶液(20mL)。反應物於室溫攪拌2小時，再以TLC監測反應。待反應完成後，使用旋轉蒸發，再加入鹽酸調整pH值至4~5。而後以乙酸乙酯萃取，合併有機層以無水硫酸鎂乾燥，減壓濃縮後獲得褐色油狀之化合物I-9(二步驟產率：0.21g,43%)。
化合物1-1
3-(4-((2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丙基)胺基)苯甲醯胺基)丙酸(3-(4-((2-Methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 12.11(br.s.,1H),8.04-8.13(m,4H),7.98(t,J=5.6Hz,1H),7.58-7.67(m,5H),7.50(d,J=8.4Hz,2H),6.68(d,J=8.0Hz,1H),6.58(d,J=8.8Hz,2H),4.28(t,J=7.6Hz,1H),3.35-3.46(m,2H),2.43(t,J=7.2Hz,2H),2.05(m,1H),1.04(d,J=6.0Hz,3H),0.83(d,J=6.0Hz,3H).MS(M+1)：485.
化合物1-2
3-(4-((2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丙基)胺基)丙酸甲酯(Methyl 3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propyl)amino)benzamido)propanoate)
1H NMR(400MHz,CDCl3)：δ 8.09-8.16(m,4H),7.52-7.57(m,5H),7.47(d,J=8.4Hz,2H),6.61(t,J=6.0Hz,1H),6.50(d,J=8.0Hz,2H),4.48-4.65(m,1H),4.28(br.s.,1H),3.64-3.71(m,5H),2.61(t,J=6.0Hz,2H),2.08-2.21(m,1H),1.05(d,J=6.8Hz,3H),0.98(d,J=6.8Hz,3H).；MS(M+1)：499.
化合物1-3
3-(4-((2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丙基)胺基)丙酸乙酯(Ethyl 3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.09-8.15(m,2H),8.06(d,J=8.3Hz,2H),7.99(t,J=5.6Hz,1H),7.56-7.68(m,5H),7.49(d,J=8.8Hz,2H),6.69(d,J=7.8Hz,1H),6.57(d,J=8.8Hz,2H),4.29(t,J=7.6Hz,1H),4.02(q,J=7.3Hz,2H), 3.34-3.42(m,2H),2.45-2.49(m,2H),2.05(d,J=6.8Hz,1H),1.09-1.19(m,3H),1.04(d,J=6.4Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：513.HPLC：99.6%
化合物1-4
3-(4-((2-甲基-1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)丙基)胺基)苯甲醯胺基)丙酸(3-(4-((2-Methyl-1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)propyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 7.95-8.04(m,3H),7.62(d,J=8.0Hz,2H),7.49(d,J=8.0Hz,2H),6.63-6.77(m,1H),6.56(d,J=8.0Hz,2H),4.30(br.s.,1H),3.30(br.s.,2H),2.42(t,J=7.2Hz,2H),2.04(m,1H),1.03(d,J=6.4Hz,3H),0.81(d,J=6.4Hz,3H).MS(M+1)：477.
化合物1-5
3-(4-((3-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丙基)胺基)苯甲醯胺基)丙酸(3-(4-((3-Methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 7.95-8.16(m,5H),7.56-7.70(m,5H),7.50(d,J=8.4Hz,2H),6.75(d,J=8.0Hz,1H),6.56(d,J=8.8Hz,2H),4.47-4.64(m,1H),3.50(t,J=6.6Hz,2H),2.39(t,J=6.6Hz,2H),1.63-1.88(m,2H),1.36-1.59(m,1H),0.97(d,J=6.4Hz,3H),0.91(d,J=6.4Hz,3H).MS(M+1)：499.
化合物1-6
3-(4-((1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丙基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl 3-(4-((1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.11(d,J=7.8Hz,2H),8.06(d,J=8.3Hz,2H),7.95-8.03(m,1H),7.62(m,5H),7.49(d,J=8.8Hz,2H),6.77(d,J=8.8Hz,1H),6.54(d,J=8.8Hz,2H),4.47-4.59(m,1H),4.02(q,J=7.3Hz,2H),3.35-3.41(m,2H),1.64-1.87(m,2H),1.28-1.50(m,2H),1.14(t,J=7.1Hz,3H),0.91(t,J=7.3Hz,3H).MS(M+1)：513.
化合物1-7
3-(4-((1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丙基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-Phenyl-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.11(dd,J=7.6,2.2Hz,2H),8.06(d,J=8.3Hz,2H),7.99(t,J=5.4Hz,1H),7.58-7.69(m,5H),7.50(d,J=8.8Hz,2H),6.77(d,J=7.3Hz,1H),6.54(d,J=8.8Hz,2H),4.53(d,J=6.4Hz,1H),2.41(t,J=7.1Hz,2H),1.63-1.88(m,2H),1.28-1.50(m,2H),0.91(t,J=7.3Hz,3H).
化合物1-8
3-(4-((1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)丙基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-(Trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 7.96-8.04(m,3H),7.63(d,J=8.4Hz,2H),7.50(d,J=8.8Hz,2H),6.77(d,J=8.0Hz,1H),6.52(d,J=8.4Hz,2H),4.50-4.58(m,1H),3.21-3.46(m,2H),2.43(t,J=6.0Hz,2H),1.75-1.88(m,1H),1.61-1.74(m,1H),1.22-1.54(m,2H),0.83-1.01(m,3H).MS(M+1)：477.
化合物1-9
3-(4-((3-甲基-1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)丙基)胺基)苯甲醯胺基)丙酸 (3-(4-((3-Methyl-1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 7.96-8.05(m,3H),7.65(d,J=8.8Hz,2H),7.51(d,J=8.8Hz,2H),6.76(d,J=7.2Hz,1H),6.55(d,J=8.8Hz,2H),4.54-4.63(m,1H),3.22-3.47(m,2H),2.43(t,J=6.0Hz,2H),1.65-1.82(m,2H),1.34-1.56(m,1H),0.96(d,J=6.8Hz,3H),0.91(d,J=6.4Hz,3H).MS(M+1)：491.
化合物1-10
3-(4-((2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丙基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl 3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoate)
1H NMR(400MHz,CDCl3)：δ 8.08-8.13(m,2H),8.06(d,J=8.0Hz,2H),7.47-7.56(m,5H),7.43(dd,J=8.4,1.6Hz,2H),6.52-6.60(m,1H),6.46(dd,J=8.4,1.2Hz,2H),4.39-4.46(m,1H),4.10(d,J=7.2Hz,2H),3.58-3.67(m,2H),2.52-2.58(m,2H),1.75-1.92(m,1H),1.45-1.71(m,2H),1.18-1.32(m,3H),0.83-0.97(m,6H).；MS(M+1)：527.
化合物1-11
3-(4-((2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丙基)胺基)苯甲醯胺基)丙酸(3-(4-((2-Methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d 6)：δ 8.08-8.15(m,2H),8.06(d,J=8.4Hz,2H),7.97(s,1H),7.58-7.67(m,5H),7.48-7.51(m,2H),6.51-6.74(m,3H),4.33-4.45(m,1H),3.33(t,J=6.8Hz,2H),2.42(t,J=6.8Hz,2H),1.79-1.91(m,1H),1.22-1.44(m,1H),1.07-1.19(m,1H),0.71-1.00(m,6H).MS(M+1)：499.
化合物1-12
3-(4-((1-(4-(5-(三級丁基)-1,3,4-噁二唑-2-基)苯基)-3-甲基丁基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)phenyl)-3-methylbutyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 7.98(s,1H),7.92(d,J=8.4Hz,2H),7.58(d,J=8.4Hz,2H),7.49(d,J=8.8Hz,2H),6.73(d,J=7.6Hz,1H),6.54(d,J=8.8Hz,2H),4.51-4.57(m,1H),3.32(t,J=7.2Hz,2H),2.42(t,J=7.2Hz,2H),1.62-1.81(m,2H),1.44-1.57(m,1H),1.40(s,9H),0.88-1.00(m,6H).MS(M+1)：479.
化合物1-13
2-(4-((1-(4-(5-苯基-1,3,4-二唑-2-基)苯基)戊基)胺基)苯甲醯胺基)乙-1-磺酸(2-(4-((1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)pentyl)amino)benzamido)ethane-1-sulfonic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.02-8.13(m,5H),7.59-7.66(m,5H),7.44(d,J=8.8Hz,2H),6.77(d,J=7.6Hz,1H),6.55(d,J=8.8Hz,2H),4.43-4.59(m,1H),3.43(m,2H),2.60(t,J=7.2Hz,2H),1.78-1.92(m,1H),1.59-1.76(m,1H),1.22-1.46(m,4H),0.86(t,J=7.2Hz,3H).MS(M+1)：535.
化合物1-14
3-(4-((1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 12.13(br.s.,1H),7.87-8.11(m,3H),7.63(d,J=8.8Hz,2H),7.49(d,J=8.8Hz,2H),6.40-6.87(m,3H),4.42-4.63(m,1H),3.35-3.49(m,2H),2.42(t,J=7.2Hz,2H),1.61-1.94(m,2H),1.16-1.54(m,4H),0.74-0.98(m,3H).MS(M+1)：491.
化合物1-15
3-(4-((1-(4-(5-(吡啶-2-基)-1,3,4-噁二唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl 3-(4-((1-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)amino)benzamido)propanoate)
1H NMR(400MHz,Acetone-d6)：δ 8.77-8.83(m,1H),8.27-8.31(m,1H),8.03-8.13(m,3H),7.69(d,J=8.4Hz,2H),7.55-7.63(m,3H),7.34(t,J=5.6Hz,1H),6.63(d,J=8.4Hz,2H),6.08(d,J=7.2Hz,1H),4.61(m,1H),4.06(d,J=6.0Hz,2H),3.51-3.63(m,2H),2.55(t,J=6.8Hz,2H),1.80-1.99(m,2H),1.30-1.62(m,4H),1.14-1.24(m,3H),0.89(t,J=7.2Hz,3H).MS(M+1)：528.Purity：98.3%
化合物1-16
3-(4-((1-(4-(5-(吡啶-2-基)-1,3,4-噁二唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-(Pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.79-8.82(m,1H),8.25(d,J=8.0Hz,1H),7.96-8.09(m,4H),7.60-7.68(m,3H),7.50(d,J=8.8Hz,2H),6.77(d,J= 7.2Hz,1H),6.54(d,J=8.8Hz,2H),4.51(m,1H),3.23-3.43(m,2H),2.42(t,J=7.2Hz,2H),1.79-1.91(m,1H),1.61-1.78(m,1H),1.22-1.47(m,4H),0.82-0.91(m,3H).；MS(M+1)：500.
化合物1-17
3-(4-((1-(4-(5-(4-氟苯基)-1,3,4-噁二唑-2-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl 3-(4-((1-(4-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.13-8.23(m,2H),8.05(m,2H),7.96-8.02(m,1H),7.56-7.64(m,2H),7.48(d,J=4.4Hz,4H),6.64-6.73(m,1H),6.51-6.62(m,2H),4.23-4.35(m,1H),4.02(d,J=6.8Hz,2H),3.35-3.42(m,2H),2.48(m,2H),1.99-2.11(m,1H),1.14(t,J=7.1Hz,3H),1.04(d,J=6.8Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：531.
化合物1-18
3-(4-((1-(4-(5-(4-氟苯基)-1,3,4-噁二唑-2-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-(4-Fluorophenyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.13-8.23(m,2H),8.06(m,3H),7.60(d,J=8.3Hz,2H),7.48(t,J=4.4Hz,4H),6.62-6.73(m,1H),6.57(d,J=8.8Hz,2H),4.22-4.34(m,1H),2.34-2.43(m,2H),1.99-2.11(m,1H),1.04(d,J=6.4Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：503.HPLC：100.0%
化合物1-19
3-(4-((1-(4-(5-(三級丁基)-1,3,4-噁二唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl 3-(4-((1-(4-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.00(s,1H),7.92(d,J=8.4Hz,2H),7.56(d,J=8.4Hz,2H),7.48(d,J=8.8Hz,2H),6.75(d,J=7.2Hz,1H),6.51(d,J=8.8Hz,2H),4.39-4.56(m,1H),4.03(q,J=6.8Hz,2H),3.39(m,2H),2.44-2.49(m,2H),1.62-1.89(m,2H),1.22-1.45(s,10H),1.14(t,J=7.2Hz,3H),0.85(t,J=7.2Hz,3H).MS(M+1)：507.
化合物1-20
3-(4-((1-(4-(5-(三級丁基)-1,3,4-噁二唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸 (3-(4-((1-(4-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 7.98(s,1H),7.92(d,J=8.4Hz,2H),7.57(d,J=8.4Hz,2H),7.49(d,J=8.8Hz,2H),6.74(d,J=7.8Hz,1H),6.51(d,J=8.4Hz,2H),4.40-4.55(m,1H),3.36-3.24(m,2H),2.42(t,J=7.2Hz,2H),1.75-1.89(m,1H),1.60-1.75(m,1H),1.40(m,10H),1.21-1.35(m,4H),0.85(t,J=7.2Hz,3H).MS(M+1)：479.
化合物1-21
3-(4-((1-(4-(5-(三級丁基)-1,3,4-噁二唑-2-基)苯基)-2-甲基丁基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl 3-(4-((1-(4-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methylbutyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 7.95-8.03(m,1H),7.92(dd,J=8.4,1.6Hz,2H),7.55(dd,J=8.4,6.0Hz,2H),7.47(dd,J=8.8,3.2Hz,2H),6.45-6.69(m,3H),4.26-4.46(m,1H),4.03(q,J=7.2Hz,2H),3.38(m,2H),2.45-2.52(m,2H),1.73-1.91(m,1H),1.40(s,9H),1.14(t,J=7.1Hz,5H),0.67-1.02(m,6H).MS(M+1)：507.
化合物1-22
3-(4-((1-(4-(5-(三級丁基)-1,3,4-噁二唑-2-基)苯基)-2-甲基丁基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methylbutyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 7.97(br.s.,1H),7.88-7.94(m,2H),7.55(dd,J=8.0,5.6Hz,2H),7.48(dd,J=8.8,3.2Hz,2H),6.50-6.70(m,3H),4.25-4.45(m,1H),3.22-3.42(m,2H),2.42(t,J=7.2Hz,2H),1.71-1.92(m,1H),1.40(s,9H),1.17(m,2H),0.65-1.01(m,6H).MS(M+1)：479.
化合物1-23
3-(4-((1-(4-(5-(三級丁基)-1,3,4-噁二唑-2-基)苯基)-2-甲基丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-((1-(4-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 7..99(t,1H),7.92(d,J=8.3Hz,2H),7.55(d,J=8.3Hz,2H),7.47(d,J=8.8Hz,2H),6.66(d,1H),6.55(d,J=8.8Hz, 2H),4.25(t,1H),4.03(d,J=6.8Hz,2H),3.38(d,J=5.9Hz,2H),1.96-2.09(m,1H),1.40(s,9H),1.14(t,J=7.1Hz,3H),1.03(d,J=6.4Hz,3H),0.80(d,J=6.8Hz,3H).MS(M+1)：493.
化合物1-24
3-(4-((1-(4-(5-(三級丁基)-1,3,4-噁二唑-2-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 7.96(s,1H),7.92(d,J=8.3Hz,2H),7.55(d,J=8.3Hz,2H),7.48(d,J=8.8Hz,2H),6.66(d,J=7.8Hz,1H),6.55(d,J=8.8Hz,2H),4.25(s,1H),2.42(t,J=7.1Hz,2H),1.40(s,8H),1.03(d,J=6.4Hz,3H),0.80(d,J=6.4Hz,3H).MS(M+1)：465.
化合物1-25
3-(4-((1-(4-(5-(4-甲氧苯基)-1,3,4-噁二唑-2-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-((1-(4-(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.04(dd,J=8.6,4.2Hz,7H),7.59(d,J=8.3Hz,3H),7.48(d,J=8.8Hz,3H),7.17(d,J=8.8Hz,3H),6.64-6.74(m,1H),6.57(d,J=8.8Hz,3H),4.21-4.35(m,1H),4.02(d,J=7.3Hz,3H),3.86(s,4H),3.34-3.42(m,3H),2.48(s,3H),1.98-2.12(m,1H),1.14(t,J=7.3Hz,4H),1.04(d,J=6.8Hz,5H),0.82(d,J=6.4Hz,4H).MS(M+1)：543.
化合物1-26
3-(4-((1-(4-(5-(4-甲氧苯基)-1,3,4-噁二唑-2-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.01-8.08(m,7H),7.97(t,J=5.6Hz,2H),7.59(d,J=8.3Hz,3H),7.49(d,J=8.8Hz,3H),7.12-7.22(m,3H),6.68(d,J=7.8Hz,1H),6.57(d,J=8.8Hz,3H),4.28(t,J=7.6Hz,1H),3.86(s,3H),2.42(t,J=7.1Hz,2H),2.05(d,J=6.8Hz,1H),1.04(d,J=6.8Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：515.
化合物1-27
3-(4-((1-(4-(5-(4-氟苯基)-1,3,4-噁二唑-2-基)苯基)-3-甲基丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-((1-(4-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)phenyl)-3-methylbutyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.11-8.24(m,2H),7.95-8.06(m,3H),7.58-7.68(m,2H),7.49(d,J=9.2Hz,4H),6.70-6.83(m,1H),6.48-6.61(m,2H),4.48-4.66(m,1H),4.02(q,J=7.2Hz,2H),3.35-3.38(m,2H),2.46-2.51(m,2H),1.59-1.86(m,2H),1.39-1.59(m,1H),1.11-1.29(m,3H),0.83-0.99(m,6H).MS(M+1)：545.
化合物1-28
3-(4-((1-(4-(5-(4-氟苯基)-1,3,4-噁二唑-2-基)苯基)-3-甲基丁基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)phenyl)-3-methylbutyl)amino)benzamido)propanoic acid.)
1H NMR(400MHz,DMSO-d6)：δ12.14(br.s.,1H),8.17(br.s.,2H),8.05(d,J=7.2Hz,2H),7.99(br.s.,1H),7.63(d,J=7.2Hz,2H),7.39-7.56(m,4H),6.76(d,J=6.8Hz,1H),6.56(d,J=7.8Hz,2H),4.48-4.68(m,1H),3.33(br.s.,2H), 2.42(br.s.,2H),1.62-1.84(m,2H),1.42-1.61(m,1H),0.84-1.06(m,6H).MS(M+1)：517.
化合物1-29
3-(4-((1-(4-(5-(4-氟苯基)-1,3,4-噁二唑-2-基)苯基)-2-甲基丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-((1-(4-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methylbutyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.14-8.20(m,2H),7.97-8.07(m,3H),7.60(dd,J=8.4,6.0Hz,2H),7.44-7.51(m,4H),6.55-6.71(m,3H),4.29-4.49(m,1H),3.99-4.05(m,2H),3.38(m,2H),2.46-2.51(m,2H),1.59-1.95(m,2H),1.20-1.32(m,1H),1.08-1.19(m,3H),0.75-1.00(m,6H).MS(M+1)：545.
化合物1-30
3-(4-((1-(4-(5-(4-氟苯基)-1,3,4-噁二唑-2-基)苯基)-2-甲基丁基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methylbutyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 12.13(br.s.,1H),8.14-8.20(m,2H),7.95-8.07(m,3H),7.60(dd,J=8.4,6.0Hz,2H),7.44-7.52(m,4H),6.47-6.81 (m,3H),4.24-4.50(m,1H),3.24-3.43(m,2H),2.37-2.47(m,2H),1.79-1.89(m,1H),1.24-1.43(m,1H),1.03-1.20(m,1H),0.72-1.01(m,6H).MS(M+1)：517.
化合物1-31
3-(4-((2-甲基-1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-((2-methyl-1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoate)
1H NMR(400MHz,CDCl3)：δ 8.03(d,J=8.3Hz,2 H),7.56-7.42(m,4H),6.60(br.s.,1H),6.49-6.37(m,2H),4.62-4.45(m,1H),4.45-4.28(m,1H),4.10(q,J=7.3Hz,2H),3.62(q,J=5.5Hz,2H),2.54(t,J=5.4Hz,2H),1.92-1.77(m,1H),1.49(td,J=7.0,13.8Hz,1H),1.32-1.16(m,4H),0.98-0.83(m,6H).MS(M+1)：519.
化合物1-32
3-(4-((2-甲基-1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)丁基)胺基)苯甲醯胺基)丙酸(3-(4-((2-methyl-1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,CDCl3)：δ 8.04-7.97(m,2H),7.51-7.40(m,4H),6.82-6.75(m,1 H),6.45-6.36(m,2H),4.42-4.24(m,1H),3.65-3.50(m,2H),2.62-2.50(m,2H),1.90-1.77(m,1H),1.62-1.40(m,1H),1.29-1.12(m,1H),0.96-0.80(m,6H).MS(M+1)：591.
化合物1-33
3-(4-((1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-((1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 7.96-8.07(m,3H),7.63(d,J=8.3Hz,2H),7.49(d,J=9.3Hz,2H),6.78(d,J=7.8Hz,1H),6.52(d,J=8.8Hz,2H),4.52(q,1H),4.03(q,J=6.8Hz,2H),3.39(d,J=5.9Hz,2H),1.64-1.91(m,2H),1.21-1.50(m,4H),1.14(t,J=7.1Hz,3H),0.86(t,3H).MS(M+1)：519.
化合物1-34
3-(4-(((1S)-2-甲基-1-(4-(5-(三氟甲基)-1,3,4-二唑-2-基)苯基)丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-(((1S)-2-methyl-1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 7.97-8.04(m,3H),7.62(dd,J=8.4,6.0Hz,2H),7.48(dd,J=8.8,3.6Hz,2H),6.53-6.72(m,3H),4.29-4.52(m,1H),4.00-4.06(m,1H),4.00-4.05(m,2H),3.38(m,2H),2.45-2.49(m,2H),1.21-1.92(m,3H),1.08-1.19(m,3H),0.64-1.01(m,6H).MS(M+1)：518.
化合物1-35
3-(4-(((1R)-2-甲基-1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-(((1R)-2-methyl-1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 7.93-8.08(m,3H),7.62(dd,J=8.4,6.0Hz,2H),7.48(dd,J=8.8,3.2Hz,2H),6.47-6.76(m,3H),4.31-4.49(m,1H),4.03(q,J=7.2Hz,2H),3.38-3.50(m,2H),2.46-2.48(m,2H),1.21-1.90(m,3H),1.14(t,J=6.0Hz,3H),0.79-1.02(m,6H).MS(M+1)：518.
化合物1-36
3-(4-(((1S)-2-甲基-1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)丁基)胺基)苯甲醯胺基)丙酸 (3-(4-(((1S)-2-methyl-1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 7.90-8.08(m,3H),7.62(dd,J=8.4,6.4Hz,2H),7.49(dd,J=8.8,3.2Hz,2H),6.64-6.71(m,3H),4.45(t,J=7.2Hz,1H),3.34-3.43(m,2H),2.37-2.47(m,2H),1.04-1.91(m,3H),0.80-0.99(m,6H).MS(M+1)：491.
化合物1-37
3-(4-(((1R)-2-甲基-1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)丁基)胺基)苯甲醯胺基)丙酸(3-(4-(((1R)-2-methyl-1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 7.90-8.08(m,3H),7.62(dd,J=8.0,6.0Hz,2H),7.49(dd,J=8.8,3.2Hz,2H),6.48-6.64(m,3H),4.45(t,J=7.2Hz,1H),3.36-3.41(m,2H),2.36-2.47(m,2H),1.11-1.93(m,3H),0.62-1.04(m,6H).MS(M+1)：491.
化合物1-38
3-(4-((1-(4-(5-(吡啶-2-基)-1,3,4-噁二唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸甲酯(methyl 3-(4-((1-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.78-8.86(dt,1H),8.23-8.28(d,1H),8.06(m,J=8.3Hz,4H),7.64(m,3H),7.49(d,J=8.8Hz,2H),6.77(d,1H),6.54(d,2H),4.53(q,1H),3.38(q,2H),1.66-1.90(m,2H),1.37-1.50(m,1H),1.32(s,3H),0.87(t,3H).MS(M+1)：514.
化合物1-39
(S)-3-(4-(2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丙基胺基)苯甲醯胺基)丙酸乙酯((S)-ethyl 3-(4-(2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propylamino)benzamido)propanoate)
1H NMR(DMSO-d6)：δ 8.08-8.15(m,2H),8.06(d,J=8.8Hz,2H),7.99(t,J=5.6Hz,1H),7.56-7.67(m,5H),7.49(d,J=8.8Hz,2H),6.53-6.73(m,3H),4.28(t,J=7.6Hz,1H),4.02(q,J=7.2Hz,2H),3.38(q,J=6.8Hz,2H),2.43-2.50(m, 2H),2.00-2.13(m,1H),1.10-1.17(m,3H),1.04(d,J=6.4Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：513.
化合物1-40
(R)-3-(4-(2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丙基胺基)苯甲醯胺基)丙酸乙酯
((R)-ethyl 3-(4-(2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propylamino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.09-8.14(m,2H),8.06(d,J=8.4Hz,2H),7.96-8.03(m,1H),7.56-7.66(m,5H),7.49(d,J=8.8Hz,2H),6.57(m,3H),4.20-4.35(m,1H),4.02(d,J=7.2Hz,2H),3.34-3.47(m,2H),2.40-2.53(m,2H),1.97-2.12(m,1H),1.14(t,J=7.2Hz,3H),1.04(d,J=6.8Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：513.
化合物1-41
(S)-3-(4-(2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丙基胺基)苯甲醯胺基)丙酸((S)-3-(4-(2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propylamino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.09-8.14(m,2H),8.06(d,J=8.4Hz,2H),7.97(t,J=5.6Hz,1H),7.57-7.67(m,5H),7.50(d,J=8.8Hz,2H),6.48-6.75(m,3H),4.29(t,J=7.6Hz,1H),3.27-3.42(m,2H),2.42(t,J=7.2Hz,2H),2.00-2.14(m,1H),1.04(d,J=6.4Hz,3H),0.75-0.90(d,J=6.4Hz,3H).MS(M+1)：485.
化合物1-42
(R)-3-(4-(2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丙基胺基)苯甲醯胺基)丙酸((R)-3-(4-(2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propylamino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.08-8.14(m,2H),8.06(d,J=8.4Hz,2H),797(t,J=5.6Hz,1H),7.57-7.67(m,5H),7.49(d,J=8.8Hz,2H),6.46-6.76(m,3H),4.28(t,J=7.6Hz,1H),3.33-3.42(m,2H),2.42(t,J=7.2Hz,2H),2.00-2.13(m,1H),1.04(d,J=6.4Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：485.
化合物1-43
(S)-3-(4-((1-(4-(5-(吡啶-2-基)-1,3,4-噁二唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl (S)-3-(4-((1-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.79-8.82(m,1H),8.24-8.27(m,1H),7.99-8.09(m,4H),7.60-7.67(m,3H),7.49(d,J=8.8Hz,2H),6.78(d,J=7.2Hz,1H),6.54(d,J=8.8Hz,2H),4.44-4.59(m,1H),4.02(q,J=6.8Hz,2H),3.38(d,J=6.4Hz,2H),2.45-2.49(m,2H),1.62-1.92(m,2H),1.23-1.46(m,4H),1.14(t,J=7.1Hz,3H),0.81-0.89(m,3H).MS(M+1)：528.
化合物1-44
(R)-3-(4-((1-(4-(5-(吡啶-2-基)-1,3,4-噁二唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(R)-3-(4-((1-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.70-8.91(m,1H),8.17-8.34(m,1H),7.92-8.13(m,4H),7.58-7.75(m,3H),7.49(d,J=8.8Hz,2H),6.42-6.84(m,3H),4.42-4.64(m,1H),4.02(q,J=6.8Hz,2H),3.38(d,J=6.4Hz,2H),2.37-2.60(m,2H),124-1.93(m,6H),1.14(t,J=7.2Hz,3H),0.79-0.94(m,3H).MS(M+1)：528.
化合物1-45
(S)-3-(4-((1-(4-(5-(吡啶-2-基)-1,3,4-噁二唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2yl)phenyl)pentyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.81(dt,J=4.9,1.2Hz,1H),8.18-8.32(m,1H),8.02-8.14(m,3H),7.98(t,J=5.6Hz,1H),7.56-7.71(m,3H),7.42-7.56(m,J=8.8Hz,2H),6.77(d,J=7.3Hz,1H),6.43-6.62(m,J=8.8Hz,2H),4.43-4.61(m,1H),3.34-3.44(m,3H),2.42(t,J=7.3Hz,2H),1.83(td,J=8.4,4.2Hz,1H),1.62-1.77(m,1H),1.39-1.51(m,1H),1.19-1.39(m,3H),0.78-0.96(m,3H).
化合物1-46
(R)-3-(4-((1-(4-(5-(吡啶-2-基)-1,3,4-噁二唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸
((R)-3-(4-((1-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.70-8.82(m,1H),8.19-8.32(m,1H),8.02-8.13(m,3H),7.98(t,J=5.6Hz,1H),7.58-7.70(m,3H),7.50(d,J=8.8Hz,2H),6.44-6.87(m,3H),4.42-4.60(m,1H),3.32-3.46(m,2H),2.42(t,J=7.2Hz,2H),1.19-1.92(m,6H),0.78-0.94(m,3H).MS(M+1)：500.
化合物1-47
3-(4-(((1S)-2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-(((1S)-2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoate)
1H NMR(400MHz,CDCl3)：δ 8.14-8.08(m,2 H),8.06(d,J=7.8Hz,2 H),7.57-7.48(m,5 H),7.43(dd,J=2.0,8.3Hz,2 H),6.62-6.53(m,1 H),6.51-6.42(m,2 H),4.54-4.27(m,2 H),4.14-4.05(m,2 H),3.67-3.58(m,2 H),2.60-2.50(m,2 H),1.86(dt,J=4.2,6.2Hz,1 H),1.64-1.44(m,3 H),1.30-1.17(m,4 H),0.98-0.86(m,6 H).MS(M+1)：527.
化合物1-48
3-(4-(((1R)-2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-(((1R)-2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoate)
1H NMR(400MHz,CDCl3)：δ 8.12-8.09(m,2 H),8.06(d,J=8.3Hz,2 H),7.53-7.47(m,5 H),7.43(dd,J=1.5,8.3Hz,2 H),6.56(br.s.,1 H),6.49-6.41(m,2 H),4.50-4.29(m,2 H),4.10(q,J=7.3Hz,2 H),3.66-3.59(m,2 H),2.58-2.52(m,2 H),1.85(dd,J=2.9,6.4Hz,1 H),1.60-1.44(m,1 H),1.35-1.18(m,4 H),0.98-0.88(m,6 H).MS(M+1)：527.
化合物1-49
3-(4-(((1S)-2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丁基)胺基)苯甲醯胺基)丙酸(3-(4-(((1S)-2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,CDCl3)：δ 8.09(dd,J=2.2,7.6Hz,2H),8.04(dd,J=1.2,8.6Hz,2H),7.53-7.45(m,5H),7.41(dd,J=2.0,8.3Hz,2H),6.73-6.63(m,1H),6.43(dd,J=2.0,8.8Hz,2H),4.42-4.28(m,1H),3.64-3.56(m,2H),2.61-2.56(m,2H),1.90-1.79(m,1H),1.65-1.43(m,1H),1.29-1.17(m,1H),0.95-0.85(m,6H).MS(M+1)：499.
化合物1-50
3-(4-(((1R)-2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丁基)胺基)苯甲醯胺基)丙酸(3-(4-(((1R)-2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,CDCl3)：δ 8.11-8.06(m,2H),8.05-8.00(m,2H),7.53-7.44(m,5H),7.41(dd,J=1.5,8.3Hz,2H),6.72(br.s.,1H),6.42(dd,J=2.0,8.8Hz,2 H),4.41-4.25(m,1H),3.63-3.54(m,2H),2.57(t,J=4.6Hz,2H),1.89-1.78(m,1 H),1.63-1.42(m,1H),1.28-1.15(m,1H),0.96-0.83(m,6H).MS(M+1)：499.
化合物1-51
(S)-3-(4-((1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)amino)benzamido)propanoate)
1H NMR(400MHz,CDCl3)：δ 8.07-8.00(m,2 H),7.54-7.44(m,4 H),6.59(t,J=6.1Hz,1 H),6.48-6.37(m,2 H),4.52-4.36(m,2 H),4.11(q,J=7.0Hz,2 H),3.66-3.56(m,2 H),2.59-2.51(m,2 H),1.81(dt,J=2.7,6.0Hz,2 H),1.46-1.27(m,4 H),1.22(t,J=7.1Hz,3 H),0.92-0.84(m,3 H).MS(M+1)：519.
化合物1-52
(R)-3-(4-((1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl (R)-3-(4-((1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)amino)benzamido)propanoate)
1H NMR(400MHz,CDCl3)：δ 8.09-7.97(m,2 H),7.54-7.44(m,4 H),6.59(t,J=5.9Hz,1 H),6.47-6.38(m,2 H),4.50-4.36(m,2 H),4.11(q,J=7.0Hz,2 H),3.67-3.55(m,2 H),2.60-2.49(m,2 H),1.87-1.72(m,2 H),1.44-1.27(m,4 H),1.26-1.17(m,3 H),0.91-0.81(m,3 H).MS(M+1)：519.
化合物1-53
(S)-3-(4-((1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,CDCl3)：δ 8.08-7.97(m,2H),7.47(dd,J=1.7,8.6Hz,4H),6.66(t,J=6.1Hz,1H),6.47-6.37(m,2H),4.40(t,J=6.8Hz,1H),3.66-3.50(m,2H),2.59(t,J=5.9Hz,2H),1.92-1.75(m,2H),1.46-1.27(m,4H),0.91-0.80(m,3H),MS(M+1)：491.
化合物1-54
(R)-3-(4-((1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,CDCl3)：δ 8.08-7.93(m,2H),7.51-7.43(m,4H),6.82-6.64(m,1 H),6.44-6.37(m,2H),4.39(t,J=6.6Hz,1H),3.64-3.51(m,2H),2.57(q,J=5.5Hz,2H),1.92-1.68(m,2H),1.42-1.24(m,4H),0.86(dt,J=1.7,7.0Hz,3H).MS(M+1)：491.
化合物1-55
(S)-3-(4-((2-甲基-1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)丙基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((2-methyl-1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)propyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.05-7.99(m,3H),7.62(d,J=6Hz,2H),7.47(d,J=6Hz,2H),6.69(d,J=6Hz,1H),6.56(d,J=6Hz,2H),4.30(t,J=6Hz,1H),4.03(d,J=7.3Hz,2H),3.35-3.43(m,2H),1.96-2.10(m,1H),1.14(t,J=7.1Hz,3H),1.03(d,J=6.4Hz,3H),0.81(d,J=6.4Hz,3H).MS(M+1)：505.
化合物1-56
(R)-3-(4-((2-甲基-1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)丙基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(R)-3-(4-((2-methyl-1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)propyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 7.94-8.07(m,3H),7.60-7.64(m,2H),7.45-7.53(m,2H),6.65-6.73(m,1H),6.52-6.60(m,2H),3.99-4.07(m,2H),1.97-2.11(m,3H),1.14(s,4H),1.00-1.06(m,3H),0.77-0.86(m,3H).MS(M+1)：505.
化合物1-57
(RS)-3-(4-((2-甲基-1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)丙基)胺基)苯甲醯胺基)丙酸乙酯((RS)-3-(4-((2-methyl-1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)propyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.02(d,J=8.3Hz,2H),7.98(t,J=5.4Hz,1H),7.62(d,J=8.3Hz,2H),7.48(d,J=8.8Hz,2H),6.68(d,J=7.8Hz,1H), 6.55(d,J=8.8Hz,2H),4.30(t,J=7.6Hz,1H),2.41(t,J=7.1Hz,2H),1.98-2.11(m,1H),1.03(d,J=6.4Hz,3H),0.81(d,J=6.8Hz,3H).MS(M+1)：477.
化合物1-58
(R)-3-(4-((2-甲基-1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)丙基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((2-methyl-1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenyl)propyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.00-8.07(m,2H),7.95-7.99(m,1H),7.59-7.66(m,2H),7.44-7.53(m,2H),6.64-6.72(m,1H),6.51-6.58(m,2H),4.26-4.36(m,1H),2.39-2.46(m,2H),1.98-2.11(m,1H),1.00-1.08(m,3H),0.76-0.84(m,2H).MS(M+1)：477.
化合物1-59
(S)-3-(4-((3-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((3-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoate)
1H NMR(400MHz,CDCl3)：δ 8.14-8.03(m,4H),7.56-7.40(m,7H),6.60(s,1H),6.49-6.42(m,2H),4.46(d,J=5.4Hz,2H),4.10(q,J=7.0Hz,2H),3.67-3.57(m,2H),2.60-2.51(m,2H),1.79-1.56(m,3H),1.27-1.16(m,3H),0.97(dd,J=6.1,18.3Hz,6H).MS(M+1)：527.
化合物1-60
(R)-3-(4-((3-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(R)-3-(4-((3-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoate)
1H NMR(400MHz,CDCl3)：δ 8.15-8.00(m,4H),7.55-7.42(m,7H),6.60(d,J=5.4Hz,1H),6.51-6.42(m,2H),4.54-4.39(m,2H),4.10(q,J=7.3Hz,2H),3.62(q,J=6.2Hz,2H),2.59-2.49(m,2H),1.80-1.57(m,3H),1.25-1.17(m,3H),0.96(dd,J=5.9,18.1Hz,6H).MS(M+1)：527.
化合物1-61
(S)-3-(4-((3-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丁基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((3-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,CDCl3)：δ 8.13-7.97(m,4H),7.55-7.38(m,7H),6.83(dd,J=5.4,14.2Hz,1H),6.43(d,J=8.8Hz,2H),4.47-4.42(m,2H),3.62-3.55(m,2H),2.59-2.54(m,2H),1.76-1.51(m,3H),0.98-0.88(m,6H).MS(M+1)：499.
化合物1-62
(R)-3-(4-((3-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丁基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((3-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,CDCl3)：δ 8.05(dddd,J=1.7,3.9,6.0,19.7Hz,4H),7.55-7.40(m,7H),6.77(dt,J=5.6,11.4Hz,1H),6.50-6.38(m,2H),4.48-4.42(m,2H),3.63-3.55(m,2H),2.61-2.54(m,2H),1.80-1.53(m,3H),0.99-0.89(m,6H).MS(M+1)：499.
化合物1-63
(S)-3-(4-((2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丙基)胺基)苯甲醯胺基)丙酸甲酯(methyl (S)-3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.09-8.14(m,2H),8.06(d,J=8.8Hz,2H),8.00(t,J=5.6Hz,1H),7.57-7.67(m,5H),7.49(d,J=8.8Hz,2H),6.69(d,J=7.8Hz,1H),6.57(d,J=8.8Hz,2H),4.28(t,J=7.3Hz,1H),3.56(s,3H),3.29-3.45(m,2H),1.99-2.12(m,1H),1.04(d,J=6.8Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：499.
化合物1-64
(S)-2-(4-((2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基)丙基)胺基)苯甲醯胺基)乙-1-磺酸((S)-2-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propyl)amino)benzamido)ethane-1-sulfonic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.09-8.14(m,2H),8.00-8.08(m,3H),7.58-7.66(m,5H),7.44(d,J=8.8Hz,2H),6.74(d,J=7.8Hz,1H),6.58(d,J=8.8Hz,2H),4.28(t,J=7.6Hz,1H),3.39-3.47(m,2H),2.60(t,J=6.8Hz,2H),2.00-2.11(m,1H),1.04(d,J=6.4Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：521.
實施例2：表2所示化合物之合成
以下揭示合成化合物2-1至2-48之反應式。
將4-甲醯苯甲腈(formylbenzonitrile)(7.27g,55.5mmol)、(S)-(+)-三級-丁基亞磺醯胺(butanesulfinamide)(8.06g,66.5mmol)、和碳酸銫(Cs2CO3)(21.68g,66.5mmol)於DCM(200mL)中混合，並加熱回流1小時。再將反應溶液濃縮去除甲醇，並以乙酸乙酯萃取。有機層以水清洗，再以無水硫酸鎂乾燥。過濾後減壓蒸發溶劑，獲得白色固態之產物II-1(13.6g,100%)。
將化合物II-1(6.80g,29.0mmol)溶於四氫呋喃(100mL)，並冷卻至-78℃。再於溶液中滴入1.2M二級氯化丁鎂(25mL)，滴入時間應超過20分鐘。 反應溶液於-78℃攪拌2小時，再加入飽和氯化銨溶液終止反應。而後以乙酸乙酯萃取，有機層以硫酸鎂乾燥，再過濾濃縮。使用矽膠層析法純化，獲得無色固態化合物II-2(7.2g,85%)。
將化合物II-2(2.00g,6.84mmol)懸浮於2M氯化氫(HCl)之甲醇(30mL)溶液，於室溫放置1小時。蒸發後，滴入碳酸氫鈉(NaHCO3(aq))中和過量的HCl，調整pH值至10。再以乙酸乙酯和水萃取。合併有機層以無水硫酸鎂乾燥濃縮，並以矽膠層析法獲得粗產物II-3。
將無水三氟乙酸酐滴入(1.0mL,6.84mmol)苯胺(1.30g,6.84mmol)、和三乙胺(1.0mL,6.84mmol)之二氯甲烷(CH2Cl2)溶液，並加熱至室溫放置至少30分鐘。減壓蒸發溶劑後，產物以水和乙酸乙酯清洗，並以硫酸鎂乾燥有機層，獲得粗產物II-4。
將羥胺鹽酸鹽(1.66g,23.94mmol)和碳酸鈉碳酸鈉(1.50g,13.68mmol)加入化合物II-4(1.94g,6.84mmol)之乙醇溶液(20ml)，並回流1小時。反應 冷卻至室溫後減壓濃縮，再以水和乙酸乙酯萃取。有機層以硫酸鎂乾燥，獲得無色油狀之粗產物II-5，用於下一步驟而無須再純化。
於溶液中加入苯甲酸(0.84g,6.84mmol)、HOBt(1.26g,8.21mmol)、和EDCI(1.44g,7.53mmol)之DMF溶液，於室溫放置30分鐘，再加入苯甲脒(benzamidine)(300mg,2.20mmol,1.00當量)之DMF溶液(無水，2mL)，於室溫放置10分鐘再回流3小時。待初始材料耗盡，將水加入反應物並以乙酸乙酯萃取水層，進一步減壓濃縮獲得產物。將油狀粗產物以管柱層析(EA：Hex=10：90)純化，獲得白色固態之化合物II-6(1.8g,65%)(產率=1.80/2.7593=65%)。
將化合物II-6(1.80g,4.46mmol)溶解於二噁烷(30mL)，再加入6M鹽酸(30mL)。反應物於100℃攪拌隔夜，並以TLC監測反應。待反應完全後，以旋轉蒸發去除溶劑。而後以乙酸乙酯萃取反應物，合併有機層以無水硫酸鎂乾燥，減壓濃縮後獲得黃色油狀粗產物II-7(1.4g,100%)。
醋酸鈀(Pd(OAc)2)(0.11g,0.5mmol)、2,2'-雙二苯膦基-1,1'-聯萘(BINAP)(0.62g,1mmol)、碳酸銫(2.91g,8.92mmole)、4-(三氟甲基磺醯氧基(trifluoromethylsulfonyloxy))苯甲酸乙酯(1.60g,5.35mmol)、和R-ANU-NH2(1.40g,4.46mmol)之苯甲酸(30ml)溶液以氮氣除氣30分鐘，再於80℃油浴中攪拌隔夜。降溫至室溫後，以乙酸乙酯稀釋，再以矽藻土過濾並以乙酸乙酯清洗。反應物以水和鹽水清洗，有機層以硫酸鎂乾燥，濃縮後獲得粗產物。油狀粗產物使用管柱層析(EA：Hex=8：92)純化，獲得白色固態之化合物II-8(1.1g,54%)。
將化合物II-8(0.5g,1.09mmol)溶解於二噁烷(20mL)，再加入2M LiOH(aq)20mL，並於60℃攪拌3小時，以及使用TLC監測反應。待反應完全後，以旋轉蒸發去除溶劑，再加入鹽酸調整pH值至4~5。混合化合物以乙酸乙酯萃取，合併有機層以無水硫酸鎂乾燥，再減壓濃縮，獲得粗產物II-9(0.43g,89%)。
將化合物II-9(1.0g,2.34mmole)、β-丙胺酸乙酯鹽酸鹽(0.54g,3.51mmole)、EDCI(0.67g,3.51mmol)、三乙胺(0.71g,7.02mmol)、和HOBt(0.54g, 3.51mmol)溶於乾燥THF(30ml)，並於室溫攪拌隔夜，再減壓濃縮。將水加入反應物，並以乙酸乙酯萃取水層。進一步地減壓濃縮，獲得油狀粗產物，再以管柱層析純化產物(EA：Hex=30：70)，獲得白色固態之化合物II-10(0.9g,73%)。
將化合物II-10(0.6g,1.14mmol)溶解於THF(20mL)，再加入2M LiOH(aq)20mL，並於室溫攪拌3小時，並以TLC監測反應。待反應完全後，以旋轉蒸發去除溶劑，再加入鹽酸調整pH值至4~5。反應物以乙酸乙酯萃取，合併有機層以無水硫酸鎂乾燥，再減壓濃縮。油狀粗產物以管柱層析(EA：Hex=45：50)純化，獲得白色固態之化合物II-11(0.3g,53%)。
將化合物II-11(1.9g,10mmol)、BINAP(3.1g,5mmol)、4-(((三氟甲基)磺醯基)氧)苯甲酸苯甲酯(4.36g,12mmol)、和Cs2CO3(6.57g,20mmol)溶於70ml甲苯，並且以氮氣除氣30分鐘，而後加入Pd(OAc)2(0.57g,2.5mmol)，並於80℃油浴中攪拌隔夜。冷卻至室溫後，以乙酸乙酯稀釋，並以矽藻土過濾，再以乙酸乙酯清洗。產物以水和鹽水清洗，有機層以硫酸鎂乾燥，再濃縮獲得 粗產物。油狀粗產物以40g管柱層析(EA：hex=1：9)，獲得化合物II-12(2.6g,65%)。
化合物II-12(2.6g,6.5mmol)溶解於50mL甲醇，再加入Pd/C，並於室溫攪拌1小時，以及使用TLC監控反應。而後以矽藻土去除催化劑，並減壓濃縮，獲得粗產物II-13(2g,99%)。
將化合物II-13(2.0g,6.5mmole)溶解於包括3-胺丙酸三級丁酯鹽酸鹽(1.76g,10mmol)、EDCI(2.5g,13mmole)、N,N-二異丙基乙基胺(DIPEA)(2.5g,13mmol)、和HOBt(2.0g,13mmol)之乾燥THF溶液(30ml)，並將反映溶液於室溫隔夜攪拌，再減壓濃縮。而後將水加入反應物，並以乙酸乙酯萃取水層，再減壓濃縮，獲得粗產物II-14(1.97g,70%)。
將羥胺鹽酸鹽(1.1g,15.8mmol)和碳酸鈉(0.96g,9mmol)加入化合物II-14(1.97g,4.5mmol)之乙醇溶液(20ml)並回流1小時，再冷卻至室溫並減壓濃縮。反應物以乙酸乙酯和水萃取，並將有機層以硫酸鎂乾燥，獲得無色油狀粗產物II-15(colorless oil)，用於下一步驟且無須純化。
將化合物II-15(1.94g,4.5mmol)溶解於乾燥THF(20ml)，並滴入無水三氟乙酸(TFAA)(1.03g,4.9mmol)。淡黃色反應溶液在惰性氣氛下於室溫攪拌2小時，再減壓濃縮，粗產物以乙酸乙酯(100ml)清洗，獲得化合物II-16(1.68g,2 steps 68%)。
將TFA(1.5mL)加入化合物II-16(1.1g,2mmol)溶於DCM之溶液(10mL)，再於室溫攪拌2小時。反應溶液以水和DCM分層，再使用硫酸鎂乾燥並濃縮，獲得化合物II-17(0.6g,61%)。
化合物II-17(0.5g,1mmol)溶解於10ml乙醇，並加入SOCl2(1mL)，再將反應溶液於室溫攪拌15分鐘。而後反應溶液以乙酸乙酯和水分層，再使用硫酸鎂乾燥並濃縮，獲得化合物II-18(0.45g,87%)。
化合物2-1
3-(4-((1-(4-(5-(三級丁基)-1,2,4-噁二唑-3-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-((1-(4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoate)
白色固態物質。1H NMR(400MHz,CDCl3)：δ 7.99(d,J=7.8Hz,2H),7.48(d,J=7.8Hz,2H),7.35(d,J=7.8Hz,2H),6.54(t,J=7.8Hz,1H),6.45(d,J=7.8Hz,2H),4.2(d,J=5.9Hz,1H),4.11(q,J=6.8Hz,1H),3.61(q,J=6.3Hz,2H),2.55(t,J=6.3Hz,2H),2.09-202(m,1H),1.45(s,9H),1.22(t,J=6.8Hz,3H),0.99(d,J=6.3Hz,3H),0.92(d,J=6.3Hz,3H).MS(M+1)：493.
化合物2-2
3-(4-((1-(4-(5-(三級丁基)-1,2,4-噁二唑-3-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoic acid)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 7.97(t,J=5.6Hz,1H),7.91(d,J=8.8Hz,2H),7.53-7.47(m,4H),6.65(d,J=8.3Hz,1H),6.55(d,J=8.8Hz,2H),4.23(t,J=5.6Hz,1H),3.38(q,J=6.8Hz,2H),2.42(t,J=6.8Hz,2H),2.03-2.01(m,1H),1.45(s,9H),1.02(d,J=6.3Hz,3H),0.80(d,J=6.3Hz,3H).MS(M+1)：465.
化合物2-3
3-(4-((1-(4-(5-(三級丁基)-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-((1-(4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoate)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 8.02(d,J=8.3Hz,2H),7.51(d,J=8.3Hz,2H),7.41(d,J=8.3Hz,2H),6.58(t,J=5.8Hz,1H),6.47(d, J=8.3Hz,2H),4.46-4.38(m,2H),4.13(q,J=6.8Hz,2H),3.65(q,J=6.3Hz,2H),2.58(t,J=6.3Hz,2H),1.84-1.81(m,2H),1.38-1.31(m,4H),1.48(s,9H),1.24(t,J=6.8Hz,3H),0.88(t,J=6.5Hz,3H).MS(M+1)：507.
化合物2-4
3-(4-((1-(4-(5-(三級丁基)-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 7.98(t,J=5.6Hz,1H),7.92(d,J=8.8Hz,2H),7.54-7.48(m,4H),6.73(d,J=8.8Hz,1H),6.51(d,J=8.8Hz,2H),4.47-4.44(m,1H),3.35(q,J=6.8Hz,2H),2.40(t,J=6.8Hz,2H),1.85-1.75(m,1H),1.75-1.68(m,1H),1.42(s,9H),1.33-1.28(m,4H),0.85(t,J=6.5Hz,3H).MS(M+1)：479.
化合物2-5
3-(4-((1-(4-(5-(三級丁基)-1,2,4-噁二唑-3-基)苯基)-3-甲基丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-((1-(4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-methylbutyl)amino)benzamido)propanoate)
白色固態物質。1H NMR(400MHz,CDCl3)：δ 7.80(d,J=7.8Hz,2H),7.49(d,J=7.8Hz,2H),7.39(d,J=7.8Hz,2H),6.55(t,J=7.8Hz,1H),6.46(d,J=7.8Hz,2H),4.45-4.37(m,2H),4.11(q,J=6.3Hz,2H),3.63(q,J=6.3Hz,2H),2.56(t,J=6.3Hz,2H),1.74-1.59(m,3H),1.46(s,9H),1.22(t,J=6.8Hz,3H),0.98(d,J=6.3Hz,3H),0.93(d,J=6.3Hz,3H).MS(M+1)：507.
化合物2-6
3-(4-((1-(4-(5-(三級丁基)-1,2,4-噁二唑-3-基)苯基)-3-甲基丁基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-methylbutyl)amino)benzamido)propanoic acid)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 7.98(t,J=5.6Hz,1H),7.91(d,J=8.8Hz,2H),7.55(d,J=8.8Hz,2H),7.49(d,J=8.8Hz,2H),6.73(d,J=8.8Hz,1H),6.53(d,J=8.8Hz,2H),4.54-4.49(m,1H),3.35(q,J=6.8Hz,2H),2.42(t,J=6.8Hz,2H),1.75-1.67(m,2H),1.50-1.47(m,1H),1.42(s,9H),0.95(d,J=6.3Hz,3H),0.90(d,J=6.3Hz,3H).MS(M+1)：479.
化合物2-7
3-(4-((1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-((1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoate)
白色固態物質。1H NMR(400MHz,CDCl3)：δ 8.19(d,J=8.3Hz,2H),8.10(d,J=8.3Hz,2H),7.61-7.48(m,5H),7.41(d,J=8.3Hz,2H),6.59(t,J=5.8Hz,1H),6.46(d,J=8.3Hz,2H),4.40(t,J=6.8Hz,1H),4.11(q,J=6.8Hz,2H),3.63(q,J=6.3Hz,2H),2.55(t,J=6.3Hz,2H),1.84-1.81(m,2H),1.38-1.33(m,4H),1.22(t,J=6.8Hz,3H),0.88(t,J=6.5Hz,3H).MS(M+1)：527
化合物2-8
3-(4-((1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 8.17(d,J=8.8Hz,2H),8.03-7.98(m,3H),7.75-7.72(m,1H),7.68-7.64(m,2H),7.58(d,J=8.8Hz,2H), 7.50(d,J=8.8Hz,2H),6.76(d,J=8.8Hz,1H),6.53(d,J=8.8Hz,2H),4.48(q,J=6.8Hz,1H),3.35(q,J=6.8Hz,2H),2.42(t,J=6.8Hz,2H),1.84-1.82(m,1H),1.74-1.70(m,1H),1.42-1.27(m,4H),0.86(t,J=6.5Hz,3H).MS(M+1)：499.
化合物2-9
3-(4-((3-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-((3-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)butyl)amino)benzamido)propanoate)
白色固態物質。1H NMR(400MHz,CDCl3)：δ 8.19(d,J=8.3Hz,2H),8.10(d,J=8.3Hz,2H),7.61-7.49(m,5H),7.44(d,J=8.3Hz,2H),6.56(t,J=5.8Hz,1H),6.48(d,J=8.3Hz,2H),4.47-4.40(m,2H),4.11(q,J=6.8Hz,2H),3.63(q,J=6.3Hz,2H),2.55(t,J=6.3Hz,2H),1.76-1.62(m,3H),1.22(t,J=6.8Hz,3H),1.00(t,J=6.5Hz,3H),0.94(t,J=6.5Hz,3H).MS(M+1)：527.
化合物2-10
3-(4-((3-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丁基)胺基)苯甲醯胺基)丙酸(3-(4-((3-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)butyl)amino)benzamido)propanoic acid)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 8.17(d,J=8.8Hz,2H),8.03-8.01(m,3H),7.75-7.58(m,5H),7.50(d,J=8.8Hz,2H),6.76(d,J=8.8Hz,1H),6.55(d,J=8.8Hz,2H),4.54(q,J=6.8Hz,1H),3.35(q,J=6.8Hz,2H),2.39(t,J=6.8Hz,2H),1.78-1.68(m,2H),1.53-1.48(m,1H),0.96(t,J=6.5Hz,3H),0.90(t,J=6.5Hz,3H).MS(M+1)：499
化合物2-11
3-(4-((2-甲基-1-(4-(5-(噻吩-2-基)-1,2,4-噁二唑-3-基)苯基)丙基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-((2-methyl-1-(4-(5-(thiophen-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propyl)amino)benzamido)propanoate)
白色固態物質。1H NMR(400MHz,CDCl3)：δ 8.06(d,J=8.3Hz,2H),7.93-7.92(m,1H),7.64-7.62(m,1H),7.49(d,J=8.3Hz,2H),7.39(d,J=8.3Hz,2H),7.21-7.18(m,1H),6.54(t,J=5.8Hz,1H),6.46(d,J=6.4Hz,1H),4.22(t,J=6.8Hz,1H),4.11(q,J=6.8Hz,2H),3.63(q,J=6.3Hz,2H),2.55(t,J=6.3Hz,2H),2.15-2.05(m,1H),1.22(t,J=6.8Hz,3H),1.00(d,J=6.5Hz,3H),0.93(d,J=6.5Hz,3H).MS(M+1)：519.
化合物2-12
3-(4-((2-甲基-1-(4-(5-(噻吩-2-基)-1,2,4-噁二唑-3-基)苯基)丙基)胺基)苯甲醯胺基)丙酸(3-(4-((2-methyl-1-(4-(5-(thiophen-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propyl)amino)benzamido)propanoic acid)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 8.11-8.06(m,2H),7.99-7.96(m,3H),7.55(d,J=8.6Hz,2H),7.49(d,J=8.6Hz,2H),7.37-7.35(m,1H),6.67(d,J=8.8Hz,1H),6.56(d,J=8.6Hz,2H),4.26(t,J=7.6Hz,1H),3.41-3.37(m,2H),2.42(t,J=6.8Hz,2H),2.06-2.01(m,1H),1.03(d,J=6.3Hz,3H),0.82(d,J=6.3Hz,3H).MS(M+1)：491
化合物2-13
3-(4-((1-(4-(5-(噻吩-2-基)-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-(thiophen-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 8.11-8.06(m,2H),7.99-7.97(m,3H),7.57(d,J=8.6Hz,2H),7.50(d,J=8.6Hz,2H),7.6(t,J=4.4Hz, 1H),6.75(d,J=8.8Hz,1H),6.53(d,J=8.6Hz,2H),4.48(q,J=6.8Hz,1H),3.38-3.33(m,2H),2.41(t,J=6.8Hz,2H),1.85-1.79(m,1H),1.73-1.70(m,1H),1.43-1.39(m,1H),1.36-1.23(m,3H),0.86(t,J=6.5Hz,3H).MS(M+1)：505.
化合物2-14
3-(4-((3-甲基-1-(4-(5-(噻吩-2-基)-1,2,4-噁二唑-3-基)苯基)丁基)胺基)苯甲醯胺基)丙酸(3-(4-((3-methyl-1-(4-(5-(thiophen-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)butyl)amino)benzamido)propanoic acid)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 8.10-8.08(m,1H),8.07-7.97(m,3H),7.58(d,J=8.6Hz,2H),7.50(d,J=8.6Hz,2H),7.35(dd,J=4.9,3.4Hz,1H),6.75(d,J=8.8Hz,1H),6.55(d,J=8.6Hz,2H),4.54(q,J=6.8Hz,1H),3.38-3.33(m,2H),2.41(t,J=6.8Hz,2H),1.78-1.68(m,2H),1.53-1.48(m,1H),0.95(d,J=6.3Hz,3H),0.90(d,J=6.3Hz,3H).MS(M+1)：505
化合物2-15
3-(4-((環戊基(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)甲基)胺基)苯甲醯胺基)丙酸(3-(4-((cyclopentyl(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)methyl)amino)benzamido)propanoic acid)
白色固態物質。1H NMR(400MHz,CDCl3)：δ 8.16(d,J=8.7Hz,2H),8.01-7.98(m,3H),7.73-7.59(m,5H),7.50(d,J=8.2Hz,2H),6.78(d,J=8.2Hz,1H),6.56(d,J=8.7Hz,2H),4.26(t,J=6.8Hz,1H),3.36(q,J=6.3Hz,2H),2.42(t,J=6.3Hz,2H),2.25-2.19(m,1H),1.97-1.93(m,1H),1.64-1.41(m,5H),1.26-1.21(m,2H).MS(M+1)：511.
化合物2-16
3-(4-((環己基(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)甲基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-((cyclohexyl(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)methyl)amino)benzamido)propanoate)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 8.21(d,J=8.6Hz,2H),8.11(d,J=8.6Hz,2H),7.63-7.49(m,5H),7.41(d,J=8.6Hz,2H),6.56(t,J=6.8Hz,1H),6.48(d,J=8.6Hz,2H),4.53(d,J=5.4Hz,1H),4.24(t,J=5.4Hz,1H),4.13(q,J=5.4Hz,2H),3.64(q,J=6.3Hz,2H),1.92-1.88(m,1H),1.80-1.69(m,4H),1.27-1.06(m,8H).MS(M+1)：553
化合物2-17
3-(4-((環己基(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)甲基)胺基)苯甲醯胺基)丙酸(3-(4-((cyclohexyl(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)methyl)amino)benzamido)propanoic acid)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 8.17(d,J=8.6Hz,2H),8.02-7.95(m,3H),7.75-7.71(m,1H),7.66(t,J=8.6Hz,2H),7.55(d,J=8.6Hz,2H),7.48(d,J=8.6Hz,2H),6.71(d,J=8.8Hz,1H),6.56(d,J=8.6Hz,2H),4.28(t,J=6.8Hz,1H),3.38-3.33(m,2H),2.42(t,J=6.8Hz,2H),2.01-2.00(brs,1H),1.74-1.61(m,4H),1.37-1.34(m,1H),1.22-0.97(m,5H).MS(M+1)：525.
化合物2-18
3-(4-(((1S)-2-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-(((1S)-2-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)butyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)δ：8.13-8.23(m,2H),7.94-8.09(m,3H),7.62-7.79(m,3H),7.57(dd,J=8.0,5.6Hz,2H),7.49(dd,J=8.8,3.2Hz,2H), 6.58-6.72(m,3H),4.27-4.45(m,1H),3.95-4.10(m,2H),3.39(d,J=6.8Hz,2H),2.40-2.55(m,2H),1.76-1.93(m,1H),1.04-1.73(m,5H),0.76-0.97(m,6H).MS(M+1)：527.
化合物2-19
3-(4-(((1S)-2-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丁基)胺基)苯甲醯胺基)丙酸(3-(4-(((1S)-2-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)δ：8.18(d,J=6.8Hz,2H),7.89-8.10(m,3H),7.61-7.80(m,3H),7.40-7.61(m,4H),6.58-6.68(m,3H),4.41(m,1H),3.33-3.43(m,2H),2.42(t,J=7.2Hz,2H),1.76-1.95(m,1H),1.12-1.66(m,2H),0.75-1.03(m,6H).MS(M+1)：499.
化合物2-20
3-(4-(((1R)-2-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-(((1R)-2-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)butyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)δ：8.12-8.22(m,2H),7.92-8.08(m,3H),7.69-7.79(m,1H),7.62-7.69(m,2H),7.56(dd,J=8.0,5.6Hz,2H),7.49(dd,J=8.8,3.2Hz,2H),6.56-6.70(m,3H),4.26-4.49(m,1H),3.94-4.13(m,2H),3.39(d,J=6.8Hz,2H),2.42-2.53(m,2H),1.57-1.89(m,1H),1.06-1.49(m,2H),0.75-0.97(m,6H).MS(M+1)：527.
化合物2-21
3-(4-(((1R)-2-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丁基)胺基)苯甲醯胺基)丙酸(3-(4-(((1R)-2-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)δ：8.09-8.24(m,2H),7.92-8.07(m,3H),7.70-7.80(m,1H),7.62-7.70(m,2H),7.57(dd,J=8.4,5.6Hz,2H),7.49(dd,J=8.8,3.2Hz,2H),6.51-6.68(m,3H),4.32(m,1H),3.31-3.42(m,2H),2.35-2.47(m,2H),1.75-1.92(m,1H),1.05-1.47(m,2H),0.76-1.01(m,6H).MS(M+1)：499.
化合物2-22
(R)-3-(4-((2-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丙基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(R)-3-(4-((2-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)δ：8.12-8.24(m,2H),7.93-8.07(m,3H),7.60-7.79(m,3H),7.57(d,J=8.4Hz,2H),7.43-7.53(m,2H),6.51-6.68(m,3H),4.26(t,J=7.6Hz,1H),4.02(q,J=7.2Hz,2H),3.34-3.45(m,2H),2.39-2.55(m,2H),2.05(m,1H),1.14(t,J=7.2Hz,3H),1.04(d,J=6.4Hz,3H),0.82(d,J=6.4Hz,3H).MS(M+1)：513.
化合物2-23
(R)-3-(4-((2-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丙基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((2-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.11-8.26(m,2H),7.90-8.07(m,3H),7.70-7.80(m,1H),7.62-7.70(m,2H),7.57(d,J=8.4Hz,2H),7.45-7.53(m,J=8.8Hz,2H),6.47-6.67(m,3H),4.26(t,J=7.6Hz,1H),3.35(t,J=7.2Hz,2H),2.42(t,J=7.2Hz,2H),1.96-2.12(m,1H),1.04(d,J=6.4Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：485.
化合物2-24
3-(4-((1-(4-(5-(4-氟苯基)-1,2,4-噁二唑-3-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-((1-(4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoate)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 8.22-8.19(m,2H),8.08(d,J=8.8Hz,2H),7.5(d,J=8.8Hz,2H),7.40(d,J=8.8Hz,2H),7.23-7.20(m,3H),6.69(d,J=8.8Hz,1H),6.55(t,J=8.6Hz,1H),6.47(d,J=8.6Hz,2H),4.47(d,J=5.4Hz,1H),4.23(t,J=5.4Hz,1H),4.11(q,J=6.8Hz,2H),3.65-3.61(m,2H),2.55(t,J=6.8Hz,2H),2.12-2.07(m,1H),1.01(t,J=6.8Hz,3H),0.94(d,J=6.8Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：531
化合物2-25
3-(4-((1-(4-(5-(4-氟苯基)-1,2,4-噁二唑-3-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoic acid)
白色固態物質。1H NMR(400MHz,DMSO-d6)δ：7.46-7.43(m,2H),7.25(d,J=8.8Hz,2H),6.70(d,J=8.8Hz,4H),6.54(t,J=8.8Hz,2H),5.77(d,J=8.8Hz,2H),3.241(d,J=5.4Hz,1H),2.75-2.71(m,2H),1.75(t,J=6.8Hz,2H),1.31-1.26(m,1H),1.23(t,J=6.8Hz,3H),0.29(t,J=6.8Hz,3H),0.10(t,J=6.8Hz,3H).MS(M+1)：503
化合物2-26
3-(4-((2-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丙基)胺基)苯甲醯胺基)丙酸(3-(4-((2-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propyl)amino)benzamido)propanoic acid)
白色固態物質。1H NMR(400MHz,DMSO-d6)δ：8.17(d,J=8.6Hz,2H),8.02-7.96(m,3H),7.75-7.71(m,1H),7.68-7.64(m,2H),7.57(d,J=8.6Hz,2H),7.49(d,J=8.6Hz,2H),6.66(d,J=8.8Hz,1H),6.57(d,J=8.6Hz,2H),4.25(t,J=7.6Hz,1H),2.42(t,J=6.8Hz,2H),2.05-2.02(m,1H),1.03(d,J=6.3Hz,3H),0.82(d,J=6.3Hz,3H).MS(M+1)：485.
化合物2-27
(S)-3-(4-((2-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丙基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((2-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)δ：8.13-8.22(m,2H),7.93-8.07(m,3H),7.62-7.78(m,3H),7.57(d,J=8.4Hz,2H),7.49(d,J=8.8Hz,2H),6.56-6.69(m,3H),4.26(s,1H),4.02(q,J=6.8Hz,2H),3.38(d,J=6.0Hz,2H),2.45-2.49(m,2H),2.00-2.10(m,1H),1.10-1.19(m,3H),1.04(d,J=6.4Hz,3H),0.82(d,J=6.4Hz,3H).MS(M+1)：513.
化合物2-28
(S)-3-(4-((2-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((2-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)δ：8.15-8.21(m,2H),7.93-8.05(m,3H),7.61-7.76(m,3H),7.57(d,J=8.4Hz,2H),7.49(d,J=8.8Hz,2H),6.56-6.68(m,3H),4.26(t,J=7.6Hz,1H),3.24-3.42(m,2H),2.42(t,J=7.2Hz,2H),1.98-2.09(m,1H),1.04(d,J=6.8Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：485.
化合物2-29
3-(4-(((1S)-2-甲基-1-(4-(5-(三氟甲基)-1,2,4-噁二唑-3-基)苯基)丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-(((1S)-2-methyl-1-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)butyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.05(dd,J=8.4,1.6Hz,2H),7.43-7.60(m,4H),6.49-6.64(m,2H),4.24-4.47(m,1H),4.03-4.16(m,2H),3.55(td,J=6.8,2.0Hz,2H),2.58(td,J=6.8,1.6Hz,2H),1.14-1.99(m,6H),0.75-1.09(m,6H).MS(M+1)：519.
化合物2-30
3-(4-(((1S)-2-甲基-1-(4-(5-(三氟甲基)-1,2,4-噁二唑-3-基)苯基)丁基)胺基)苯甲醯胺基)丙酸(3-(4-(((1S)-2-methyl-1-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)δ：7.94-8.11(m,2H),7.36-7.60(m,4H),6.46-6.66(m,2H),4.23-4.49(m,1H),3.54(td,J=6.8,1.2Hz,2H),2.57(td,J=6.8,1.2Hz,2H),1.10-2.01(m,3H),0.71-1.06(m,6H).MS(M+1)：491.
化合物2-31
3-(4-((2-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丙基)胺基)苯甲醯胺基)丙酸甲酯(methyl 3-(4-((2-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propyl)amino)benzamido)propanoate)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 8.19(d,J=8.8Hz,2H),8.09(d,J=8.8Hz,2H),7.61-7.48(m,5H),7.40(d,J=8.8Hz,2H),6.53(t,J=8.6Hz,1H),6.47(d,J=8.8Hz,2H),4.23(d,J=5.8Hz,1H),3.62-3.60(m,2H),2.57(t,J=6.8Hz,2H),2.15-2.06(m,1H),1.01(t,J=6.8Hz,3H),0.94(t,J=6.8Hz,3H).MS(M+1)：499.
化合物2-32
3-(4-((1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸甲酯(methyl 3-(4-((1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoate)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 8.21(d,J=8.8Hz,2H),8.12(d,J=8.8Hz,2H),7.63-7.50(m,5H),7.45(d,J=8.8Hz,2H),6.55(t,J=8.6Hz,1H),6.49(d,J=8.8Hz,2H),4.46-4.40(m,2H),3.66-3.63(m,2H),2.59(t,J=6.8Hz,2H),1.87-1.81(m,2H),1.43-1.31(m,4H),0.90(t,J=6.8Hz,3H).MS(M+1)：513.
化合物2-33
(S)-3-(4-((1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.17(d,J=7.3Hz,2H),8.04-7.98(m,3H),7.76-7.70(m,1H),7.69-7.62(m,2H),7.58(d,J=8.3Hz,2H),7.50(d,J=8.8Hz,2H),6.75(d,J=7.3Hz,1H),6.54(d,J=7.3Hz,2H),4.52-4.45(m,1H),4.03(q,J=6.8Hz,2 H),3.45-3.35(m,2 H),2.49-2.46(m,2 H),1.89-1.78(m,1 H),1.76-1.66(m,1 H),1.49-1.22(m,4 H),1.14(t,J=7.1Hz,3 H),0.86(t,J=6.6Hz,3 H).MS(M+1)：527.
化合物2-34
(S)-3-(4-((1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.17(d,J=7.8Hz,2H),8.02(d,J=8.3Hz,2H),7.98(t,J=5.4Hz,1H),7.76-7.70(m,1H),7.69-7.63(m,2H),7.58(d, J=8.3Hz,2H),7.50(d,J=8.8Hz,2H),6.75(d,J=7.3Hz,1H),6.54(d,J=8.8Hz,2H),4.49(d,J=6.4Hz,1H),3.39-3.33(m,2H),2.42(t,J=7.1Hz,2H),1.88-1.78(m,1H),1.76-1.66(m,1H),1.46-1.27(m,4H),0.86(t,J=6.8Hz,3H).MS(M+1)：499.
化合物2-35
(R)-3-(4-((1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(R)-3-(4-((1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.18(d,J=7.3Hz,2H),8.04-7.97(m,3H),7.76-7.71(m,1H),7.69-7.63(m,2H),7.58(d,J=8.3Hz,2H),7.49(d,J=8.8Hz,2H),6.75(d,J=7.3Hz,1H),6.54(d,J=8.3Hz,2H),4.53-4.44(m,1H),4.03(q,J=6.8Hz,2 H),3.43-3.35(m,2H),2.49-2.44(m,2H),1.89-1.78(m,1H),1.76-1.66(m,1 H),1.47-1.23(m,4 H),1.14(t,J=7.1Hz,3H),0.86(t,J=7.1Hz,3 H).MS(M+1)：527.
化合物2-36
(R)-3-(4-((1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.17(d,J=7.8Hz,2H),8.02(d,J=8.3Hz,2H),7.98(t,J=5.4Hz,1H),7.76-7.70(m,1H),7.69-7.62(m,2H),7.58(d,J=8.3Hz,2 H),7.50(d,J=8.3Hz,2 H),6.75(d,J=7.3Hz,1 H),6.54(d,J=8.8Hz,2H),4.49(d,J=6.8Hz,1H),3.40-3.34(m,2 H),2.43(t,J=7.1Hz,2H),1.88-1.78(m,1 H),1.76-1.65(m,1H),1.47-1.26(m,4H),0.86(t,J=6.8Hz,3H).MS(M+1)：499.
化合物2-37
(S)-3-(4-((1-(4-(5-(吡啶-2-基)-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((1-(4-(5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)enzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.82(d,J=4.4Hz,1H),8.29(d,J=7.8Hz,1H),8.08(dt,J=1.5,7.8Hz,1H),8.05-7.99(m,3H),7.69(ddd,J=1.0,4.9,7.8Hz,1 H),7.58(d,J=8.3Hz,2H),7.52(d,J=8.8Hz,2H),6.75(d,J=7.3Hz,1H),6.55(d,J=8.8Hz,2H),4.48(d,J=6.4Hz,1H),4.06-3.97(m,2H),3.44-3.37(m,2H),2.52-2.46(m,2H),1.88-1.78(m,1H),1.75-1.65(m,1H),1.46-1.24(m,4H),1.13(t,J=7.1Hz,3H),0.84(t,J=7.1Hz,3H).MS(M+1)：528.
化合物2-38
(S)-3-(4-((1-(4-(5-(吡啶-2-基)-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.84(d,J=4.9Hz,1H),8.31(d,J=7.8Hz,1H),8.11(t,J=7.8Hz,1H),8.04(d,J=8.3Hz,2H),7.98(t,J=5.6Hz,1H),7.72(dd,J=4.6,7.6Hz,1H),7.59(d,J=8.3Hz,2H),7.51(d,J=8.3Hz,2H),6.75(d,J=7.3Hz,1H),6.54(d,J=8.8Hz,2H),4.49(q,J=7.3Hz,1H),3.40-3.33(m,2H),2.43(t,J=7.1Hz,2H),1.90-1.77(m,1H),1.77-1.65(m,1H),1.46-1.25(m,4H),0.86(t,J=7.1Hz,3H).MS(M+1)：500.
化合物2-39
(R)-3-(4-((1-(4-(5-(吡啶-2-基)-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(R)-3-(4-((1-(4-(5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.82(dd,J=1.5,4.4Hz,1H),8.30(d,J=7.8Hz,1H),8.09(dt,J=1.7,7.7Hz,1H),8.05-7.99(m,3H),7.70(ddd,J=1.0,4.9,7.8Hz,1H),7.58(d,J=8.3Hz,2H),7.52(d,J=8.8Hz,2H),6.75(d,J=7.3Hz, 1H),6.55(d,J=8.8Hz,2H),4.48(d,J=6.8Hz,1H),4.06-3.99(m,2H),3.44-3.37(m,2H),2.52-2.46(m,2H),1.88-1.78(m,1H),1.75-1.66(m,1H),1.46-1.25(m,4H),1.13(t,J=7.1Hz,3H),0.85(t,J=7.1Hz,3H).MS(M+1)：528.
化合物2-40
(R)-3-(4-((1-(4-(5-(吡啶-2-基)-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.84(d,J=4.9Hz,1H),8.31(d,J=7.8Hz,1H),8.11(t,J=7.8Hz,1H),8.04(d,J=8.3Hz,2H),7.98(t,J=5.4Hz,1H),7.72(dd,J=4.6,7.6Hz,1H),7.59(d,J=8.3Hz,2H),7.51(d,J=8.3Hz,2H),6.75(d,J=7.3Hz,1H),6.54(d,J=8.8Hz,2H),4.49(q,J=7.3Hz,1H),3.40-3.34(m,2H),2.43(t,J=7.1Hz,2H),1.90-1.77(m,1H),1.77-1.65(m,1H),1.48-1.24(m,4H),0.86(t,J=7.1Hz,3H).MS(M+1)：500.
化合物2-41
(S)-3-(4-((3-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((3-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)butyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.12-8.23(m,2H),7.96-8.07(m,3H),7.72(d,J=6.8Hz,1H),7.62-7.68(m,2H),7.59(d,J=8.3Hz,2H),7.51(d,J=8.3Hz,2H),6.75(d,J=7.8Hz,1H),6.56(d,J=8.3Hz,2H),4.50-4.60(m,1H),4.02(q,J=7.2Hz,2H),3.36-3.45(m,2H),2.44-2.49(m,2H),1.66-1.82(m,2H),1.46-1.56(m,1H),1.14(t,J=7.1Hz,3H),0.96(d,J=6.4Hz,3H),0.90(d,J=6.4Hz,3H).MS(M+1)：527.
化合物2-42
(R)-3-(4-((3-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(R)-3-(4-((3-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)butyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.12-8.21(m,2H),7.96-8.07(m,3H),7.72(d,J=6.8Hz,1H),7.62-7.69(m,2H),7.59(d,J=8.3Hz,2H),7.50(d,J=8.3Hz,2H),6.74(d,J=7.8Hz,1H),6.56(d,J=8.3Hz,2H),4.50-4.60(m,1H),4.02(q,J=7.3Hz,2H),3.36-3.44(m,2H),2.44-2.49(m,2H),1.62-1.83(m,2H),1.43-1.57(m,1H),1.14(t,J=7.1Hz,3H),0.96(d,J=6.4Hz,3H),0.91(d,J=6.4Hz,3H).MS(M+1)：527.
化合物2-43
(S)-3-(4-((3-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丁基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((3-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.11-8.22(m,2H),7.95-8.08(m,3H),7.68-7.74(m,1H),7.61-7.67(m,2H),7.59(d,J=8.3Hz,2H),7.52(d,J=8.8Hz,2H),6.74(d,J=7.8Hz,1H),6.57(d,J=8.8Hz,2H),4.50-4.58(m,1H),3.34-3.41(m,2H),2.43(t,J=7.1Hz,2H),1.67-1.81(m,2H),1.47-1.55(m,1H),0.96(d,J=6.4Hz,3H),0.90(d,J=6.4Hz,3H).MS(M+1)：499.
化合物2-44
(R)-3-(4-((3-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丁基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((3-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.12-8.21(m,2H),7.94-8.07(m,3H),7.69-7.75(m,1H),7.62-7.68(m,2H),7.60(d,J=8.3Hz,2H),7.51(d,J=8.8Hz,2H),6.74(d,J=7.3Hz,1H),6.56(d,J=8.8Hz,2H),4.51-4.60(m,1H),3.34-3.41(m,2H),2.43(t,J=7.1Hz,2H),1.65-1.82(m,2H),1.45-1.55(m,1H),0.94-0.99(m,3H),0.91(d,J=6.4Hz,3H).MS(M+1)：499.
化合物2-45
(S)-3-(4-((1-(4-(5-(三氟甲基)-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((1-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 7.93-8.05(m,3H),7.60(d,J=8.3Hz,2H),7.49(d,J=8.3Hz,2H),6.77(d,J=7.8Hz,1H),6.53(d,J=8.8Hz,2H),4.44-4.55(m,1H),4.03(q,J=7.3Hz,2H),3.39(q,J=6.5Hz,2H),2.42-2.50(m,2H),1.76-1.88(m,1H),1.63-1.75(m,1H),1.22-1.46(m,4H),1.14(t,J=7.1Hz,3H),0.85(t,J=7.1Hz,3H).MS(M+1)：519.
化合物2-46
(R)-3-(4-((1-(4-(5-(三氟甲基)-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(R)-3-(4-((1-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 7.93-8.05(m,3H),7.60(d,J=8.3Hz,2H),7.49(d,J=8.8Hz,2H),6.77(d,J=7.8Hz,1H),6.53(d,J=8.8Hz,2H),4.44-4.55(m,1H),4.03(q,J=7.3Hz,2H),3.39(q,J=6.5Hz,2H),2.46-2.50(m,2H),1.77-1.88(m,1H),1.64-1.75(m,1H),1.22-1.45(m,4H),1.14(t,J=7.1Hz,3H),0.85(t,J=7.1Hz,3H).MS(M+1)：519.
化合物2-47
(S)-3-(4-((1-(4-(5-(三氟甲基)-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 7.99(d,J=7.8Hz,3H),7.60(d,J=8.3Hz,2H),7.49(d,J=8.8Hz,2H),6.76(d,J=7.3Hz,1H),6.52(d,J=8.8Hz,2H),4.43-4.56(m,1H),3.35-3.40(m,2H),2.40-2.47(m,2H),1.76-1.89(m,1H),1.64-1.75(m,1H),1.23-1.46(m,4H),0.85(t,J=7.1Hz,3H).MS(M+1)：491.
化合物2-48
(R)-3-(4-((1-(4-(5-(三氟甲基)-1,2,4-噁二唑-3-基)苯基)戊基)胺基)苯甲醯胺基)丙酸 ((R)-3-(4-((1-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 7.99(d,J=8.3Hz,3H),7.60(d,J=8.3Hz,2H),7.50(d,J=8.8,2H),6.76(d,J=7.3Hz,1H),6.53(d,J=8.6Hz,2H),4.43-4.56(m,1H),3.35-3.40(m,2H),2.40-2.47(m,2H),1.77-1.90(m,1H),1.60-1.74(m,1H),1.22-1.45(m,4H),0.85(t,J=7.1Hz,3H).MS(M+1)：491.
化合物2-49
(S)-3-(4-((2-甲基-1-(4-(5-苯基-1,2,4-噁二唑-3-基)苯基)丙基)胺基)苯甲醯胺基)丙酸甲酯(methyl(S)-3-(4-((2-methyl-1-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propyl)amino)benzamido)propanoat)
1H NMR(400MHz,DMSO-d6)：δ 8.14-8.19(m,2H),7.97-8.03(m,3H),7.70-7.76(m,1H),7.62-7.69(m,2H),7.53-7.59(m,2H),7.45-7.50(m,2H),6.64-6.68(m,1H),6.54-6.59(m,2H),4.22-4.28(m,1H),3.55-3.56(m,3H),2.68(s,8H),1.99-2.09(m,1H),1.01-1.06(m,3H),0.79-0.84(m,3H)MS(M+1)：499.實施例3：表2所示化合物之合成
以下揭示合成化合物3-1至3-15之反應式。
步驟I：格林納反應
將4-甲醯基苯甲酸甲酯(9.84g，60.0mmol)溶於四氫呋喃(30mL)之溶液冷卻至-78℃。再將2M氯化丁鎂(30ml)滴入該溶液，滴入時間應超過20分鐘。反應於-78℃持續攪拌2小時，再加入飽和氯化銨溶液終止反應，並使用乙酸乙酯萃取。使用硫酸鎂乾燥有機層，過濾後濃縮。再使用矽膠層析純化，獲得無色油狀之化合物III-1：4-(1-羥戊基)苯甲酸甲酯(產率：4.80g,36%)。
步驟II：氧化反應
將化合物III-1：4-(1-羥戊基)苯甲酸甲酯溶於(4.45g,20.0mmol)絕對DCM(100mL)中，並加入氯鉻酸吡啶鹽(PCC)(6.04g,28.0mmol)再於室溫放置隔夜。反應溶液以矽藻土過濾去除PCC，再以乙酸乙酯萃取，並以硫酸鎂乾燥有機層。而後以矽膠層析(EA：Hex=10：90)純化，獲得白色固態之化合物III-2(4.10g,93%)。
步驟III：還原胺化反應
將化合物III-2(1.10g,5mmol)加入4-胺苯甲酸苯甲酯(1.05g4.6mmol)和十硼烷(0.34g,2.75mmol)溶於20mL甲醇之溶液，於室溫攪拌隔夜後減壓濃縮。而後將水加入反應溶液，再以乙酸乙酯萃取水層，油狀粗萃物以管柱層析(EA：Hex=35：65)純化後，獲得無色油狀產物III-3(1.90g,88%)。
步驟IV：去保護反應
將化合物III-3(1.90g,4.40mmol)溶於甲醇(100mL)，再加入Pd/C和氫氣球並放置隔夜，以及以TLC監控反應。待反應完全後，以旋轉蒸發去除溶劑，再以乙酸乙酯萃取。合併有機層以無水硫酸鎂乾燥，並減壓濃縮，獲得白色固態產物III-4(0.8g,53%)。
步驟V：醯胺化
將化合物III-4(2.34g,6.85mmol)加入苯甲醯肼(benzohydrazide)(7.7g,7.53mmol)、EDCI(2.0g,10.28mmol)、和HOBt(1.58g,10.28mmol)溶解於30mL DMF溶液中，並於室溫隔夜攪拌，再減壓濃縮。而後加入水，並以乙酸乙酯萃取水層，再減壓濃縮，獲得白色固態產物III-5(1.0g,93%)。
步驟VI：成環反應
將化合物III-5(1.0g,2.2mmol)、TsCl(0.62g,3.3mmol)、和TEA(1.0mL,6.51mmol)混合於ACN(30mL)，並於室溫攪拌1小時。而後濃縮去除甲醇，並以乙酸乙酯萃取。有機層以水清洗，再以無水硫酸鎂清洗，過濾後減壓濃縮。油狀粗產物以管柱層析(EA：Hex=40：60)純化，獲得無色油狀產物III-6(0.70g,73%)。
步驟VII：水解反應
將化合物III-6(0.70g,1.58mmol)溶解於二噁烷(20mL)，並加入2M LiOH溶液(20mL)。反應溶液加熱至60℃放置隔夜，並以TLC監測。待反應完全後，以旋轉蒸發去除溶劑，再加入HCl(aq)調整pH值至4~5。再將反應物以乙酸乙酯萃取，合併有機層以無水硫酸鎂乾燥，減壓濃縮後獲得白色固態之粗產物III-7(0.74g,108%)。
步驟VIII：醯胺化反應
將化合物III-7(0.36g,0.84mmol)加入β-丙胺酸乙酯鹽酸鹽(0.19g,1.27mmol)、EDCI(0.24g,1.27mmol)、Et3N(0.26g,2.54mmol)、和HOBt(0.19g,1.27mmol)溶解於乾燥THF(30mL)之溶液，並於室溫攪拌隔夜，再減壓濃縮。將水加入反應溶液，並以乙酸乙酯萃取水層，再減壓濃縮獲得反應物。油狀粗產物以管柱層析(EA：Hex=60：40)純化，獲得白色固態產物III-8(0.30g,68%)。
步驟IX：水解反應
將化合物III-8(0.20g,0.38mmol)溶解於THF(20mL)，並加入2M LiOH(aq)(20mL)，反應溶液於室溫攪拌2小時，並以TLC監測。待反應完全後，以旋轉蒸發去除溶劑，並加入HCl(aq)調整pH值至4~5。反應物以乙酸乙酯萃取，合併有機層以無水硫酸鎂乾燥，並減壓濃縮。油狀粗產物以管柱層析(EA：Hex=90：10)純化，獲得白色固態產物III-9(0.17g,89%)。
化合物3-1
3-(4-(1-((4-(5-苯基-1,3,4-噁二唑-2-基)苯基)胺基)戊基)苯甲醯胺基)丙酸(3-(4-(1-((4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)amino)pentyl)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.42(t,J=5.2Hz,1H),8.02-8.07(m,2H),7.76(d,J=8.0Hz,2H),7.73(d,J=8.4Hz,2H),7.55-7.63(m,3H),7.45(d,J=8.4Hz,2H),7.04(d,J=7.2Hz,1H),6.69(d,J=8.8Hz,2H),4.46-4.53(m,1H),3.40-3.48(m,2H),2.44-2.49(m,2H),1.65-1.91(m,2H),1.20-1.48(m,4H),0.82-0.90(m,3H).MS(M+1)：499.
化合物3-2
3-(4-(2-甲基-1-((4-(5-苯基-1,3,4-噁二唑-2-基)苯基)胺基)丙基)苯甲醯胺基)丙酸(3-(4-(2-methyl-1-((4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)amino)propyl)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.43(t,J=5.6Hz,1H),8.00-8.10(m,2H),7.74(dd,J=15.4,8.6Hz,4H),7.55-7.63(m,3H),7.44(d,J=8.3Hz,2H),6.96(d,J=7.8Hz,1H),6.72(d,J=8.8Hz,2H),4.27(t,J=7.6Hz,1H),3.40-3.45(m,2H),1.99-2.10(m,1H),1.04(d,J=6.8Hz,3H),0.80(d,J=6.8Hz,3H).MS(M+1)：485.
化合物3-3
3-(4-(1-((4-(5-苯基-1,3,4-噁二唑-2-基)苯基)胺基)戊基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-(1-((4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)amino)pentyl)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.37-8.51(m,1H),8.02-8.06(m,2H),7.72-7.76(m,4H),7.56-7.62(m,3H),7.46(d,J=8.4Hz,2H),6.98-7.12(m,1H),6.69(d,J=8.8Hz,2H),4.41-4.59(m,1H),4.04(d,J=6.8Hz,2H),3.46(m,2H),2.54 (t,J=6.8Hz,2H),1.76-1.93(m,1H),1.59-1.76(m,1H),1.20-1.47(m,4H),1.15(t,J=6.8Hz,3H),0.86(t,J=6.8Hz,3H).MS(M+1)：527.
化合物3-4
3-(4-(2-甲基-1-((4-(5-苯基-1,3,4-噁二唑-2-基)苯基)胺基)丙基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-(2-methyl-1-((4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)amino)propyl)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.36-8.52(m,1H),7.99-8.11(m,2H),7.67-7.83(m,4H),7.53-7.64(m,3H),7.35-7.49(m,2H),6.89-7.02(m,1H),6.64-6.80(m,2H),4.22-4.33(m,1H),3.99-4.13(m,2H),3.43-3.48(m,3H),2.51-2.56(m,2H),1.97-2.10(m,1H),1.15(s,3H),1.01-1.06(m,3H),0.78-0.82(m,3H).MS(M+1)：513.
化合物3-5
3-(4-(2-甲基-1-((4-(5-苯基-1,3,4-噁二唑-2-基)苯基)胺基)丁基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-(2-methyl-1-((4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)amino)butyl)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.45(s,1H),8.02-8.07(m,2H),7.70-7.77(m,4H),7.56-7.63(m,3H),7.44(dd,J=8.4,5.6Hz,2H),6.83-7.04(m,1H),6.73(dd,J=8.8,6.0Hz,2H),4.26-4.52(m,1H),4.04(q,J=7.2Hz,2H),3.46(m,2H),2.54(t,J=7.2Hz,2H),1.73-1.92(m,1H),1.03-1.46(m,5H),0.65-0.99(m,6H).MS(M+1)：527.
化合物3-6
3-(4-(2-甲基-1-((4-(5-苯基-1,3,4-噁二唑-2-基)苯基)胺基)丁基)苯甲醯胺基)丙酸(3-(4-(2-methyl-1-((4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)amino)butyl)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 12.19(br.s.,1H),8.43(t,J=5.6Hz,1H),8.02-8.07(m,2H),7.70-7.78(m,4H),7.55-7.63(m,3H),7.44(dd,J=8.4,5.2Hz,2H),6.84-7.02(m,1H),6.73(dd,J=8.8,6.0Hz,2H),4.28-4.47(m,1H),3.37-3.50(m,2H),2.46-2.52(m,2H),1.02-1.93(m,3H),0.66-1.00(m,6H).MS(M+1)：499.
化合物3-7
3-(4-(1-((4-(5-(4-氟苯基)-1,3,4-噁二唑-2-基)苯基)胺基)-2-甲基丁基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-(1-((4-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)phenyl)amino)-2-methylbutyl)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.45(t,J=5.6Hz,1H),8.07-8.13(m,2H),7.69-7.77(m,4H),7.41-7.47(m,4H),6.82-7.04(m,1H),6.73(dd,J=8.4,6.0Hz,2H),4.26-4.48(m,1H),4.04(q,J=6.8Hz,2H),3.42-3.49(m,2H),2.54(t,J=6.8Hz,2H),1.78-1.88(m,1H),1.02-1.45(m,5H),0.66-1.00(m,6H).MS(M+1)：545.
化合物3-8
3-(4-(1-((4-(5-(4-氟苯基)-1,3,4-噁二唑-2-基)苯基)胺基)-2-甲基丁基)苯甲醯胺基)丙酸(3-(4-(1-((4-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)phenyl)amino)-2-methylbutyl)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 12.19(br.s.,1H),8.43(t,J=5.2Hz,1H),8.10(dd,J=8.8,5.6Hz,2H),7.67-7.81(m,4H),7.37-7.50(m,4H),6.84-7.02(m,1H),6.73(dd,J=8.4,6.4Hz,2H),4.29-4.44(m,1H),3.37-3.48(m,2H),2.43-2.54(m,2H),1.77-1.88(m,1H),1.21-1.41(m,1H),1.03-1.21(m,1H),0.64-1.00(m,6H).MS(M+1)：517.
化合物3-9
3-(4-(1-((4-(5-(4-氟苯基)-1,3,4-噁二唑-2-基)苯基)胺基)-2-甲基丙基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-(1-((4-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)phenyl)amino)-2-methylpropyl)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.38-8.50(m,1H),8.10(dd,J=8.8,5.4Hz,2H),7.73(dd,J=12.0,8.6Hz,4H),7.38-7.50(m,4H),6.90-7.03(m,1H),6.72(d,J=8.8Hz,2H),4.21-4.34(m,1H),4.04(d,J=7.3Hz,2H),3.46(d,J=5.9Hz,2H),2.54(t,J=6.8Hz,2H),1.95-2.12(m,1H),1.15(t,J=7.1Hz,3H),1.04(d,J=6.8Hz,3H),0.80(d,J=6.8Hz,3H).MS(M+1)：531.
化合物3-10
3-(4-(1-((4-(5-(4-氟苯基)-1,3,4-噁二唑-2-基)苯基)胺基)-2-甲基丙基)苯甲醯胺基)丙酸(3-(4-(1-((4-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)phenyl)amino)-2-methylpropyl)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 11.78-12.54(m,1H),8.42(t,J=5.4Hz,1H),8.05-8.16(m,2H),7.74(dd,J=15.9,8.6Hz,4H),7.39-7.50(m,4H),6.97(d,J=7.8Hz,1H),6.72(d,J=8.8Hz,2H),4.27(t,J=7.6Hz,1H),3.39-3.47(m,2H),2.43-2.49(m,2H),2.04(d,J=7.3Hz,1H),1.04(d,J=6.8Hz,3H),0.80(d,J=6.8Hz,3H).MS(M+1)：503.
化合物3-11
3-(4-(2-甲基-1-((4-(5-苯基-1,2,4-噁二唑-3-基)苯基)胺基)丙基)苯甲醯胺基)丙酸(3-(4-(2-methyl-1-((4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)amino)propyl)benzamido)propanoic acid)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 8.43(d,J=8.6Hz,1H),8.12(d,J=8.6Hz,2H),7.76-7.61(m,7H),7.44(d,J=8.6Hz,2H),6.81(d,J=8.6Hz,1H),6.70(d,J=8.8Hz,2H),4.24(t,J=7.6Hz,1H),3.45-3.43(q,J=6.8Hz,2H),2.47(t,J=6.8Hz,2H),2.05-2.02(m,1H),1.03(d,J=6.3Hz,3H),0.80(d,J=6.3Hz,3H).MS(M+1)：485.
化合物3-12
(S)-3-(4-(2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基胺基)丙基)苯甲醯胺基)丙酸乙酯((S)-ethyl 3-(4-(2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenylamino)propyl)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.40-8.50(m,1H),7.97-8.12(m,2H),7.74(dd,J=12.0,8.8Hz,4H),7.53-7.65(m,3H),7.44(d,J=8.4Hz,2H),6.71-6.98(m,3H),4.21-4.34(m,1H),4.04(q,J=7.2Hz,2H),3.46(d,J=6.0Hz,2H),2.54(t,J=7.2Hz,2H),1.99-2.11(m,1H),1.15(t,J=7.2Hz,3H),1.03(d,J=6.8Hz,3H),0.80(d,J=6.8Hz,3H).MS(M+1)：513.
化合物3-13
(R)-3-(4-(2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基胺基)丙基)苯甲醯胺基)丙酸乙酯((R)-ethyl 3-(4-(2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenylamino)propyl)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.45(s,1H),7.99-8.10(m,2H),7.74(dd,J=12.0,8.8Hz,4H),7.54-7.64(m,3H),7.44(d,J=8.4Hz,2H),6.65-7.03(m,3H),4.26(s,1H),4.04(q,J=7.2Hz,2H),3.46(d,J=5.6Hz,2H),2.54(t,J=7.2Hz,2H),1.99-2.12(m,1H),1.15(t,J=7.2Hz,3H),1.04(d,J=6.8Hz,3H),0.80(d,J=6.8Hz,3H).MS(M+1)：513.
化合物3-14
(S)-3-(4-(2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基胺基)丙基)苯甲醯胺基)丙酸((S)-3-(4-(2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenylamino)propyl)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.43(t,J=5.6Hz,1H),7.98-8.11(m,2H),7.74(dd,J=14.8,8.8Hz,4H),7.55-7.65(m,3H),7.44(d,J=8.4Hz,2H),6.65-7.04(m,3H),4.27(t,J=7.6Hz,1H),3.38-3.51(m,2H),2.43-2.49(m,2H),1.97-2.13(m,1H),1.03(d,J=6.4Hz,3H),0.80(d,J=6.8Hz,3H).MS(M+1)：485.
化合物3-15
(R)-3-(4-(2-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯基胺基)丙基)苯甲醯胺基)丙酸((R)-3-(4-(2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenylamino)propyl)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.43(t,J=5.6Hz,1H),7.98-8.11(m,2H),7.74(dd,J=15.6,8.8Hz,4H),7.53-7.66(m,3H),7.44(d,J=8.4Hz,2H),6.65-7.02(m,3H),4.27(t,J=7.6Hz,1H),3.39-3.50(m,2H),2.40-2.49(m,2H),1.98-2.11(m,1H),1.04(d,J=6.8Hz,3H),0.80(d,J=6.4Hz,3H).MS(M+1)：485.
實施例4：表4和表5所示化合物之合成
以下揭示合成化合物4-1至4-30和化合物5-1至5-8之反應式。
反應式IV
合成胺基醯胺之通常步驟
將4-溴苯甲醛(bromobenzaldehyde)(37.0g,200.0mmol)、(S)-(+)-三級-丁基亞磺醯胺(29.0g,240.0mmol)、和碳酸銫(78.1g,240mmol)於THF(370mL)中混合並於室溫放置隔夜，再濃縮去除甲醇並以乙酸乙酯萃取。而後以水清洗有機層，並以無水硫酸鎂乾燥。過濾後減壓蒸發，獲得白色固態之(S,E)-N-(4-溴苯亞甲基)-2-甲基丙烷-2-磺醯胺((S,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide)(54.72g,95%)。
將(S,E)-N-(4-溴苯亞甲基)-2-甲基丙烷-2-磺醯胺(28.8g,100mmol)溶於THF(300mL)，並冷卻至-78℃。再於溶液中滴入氯化正丁鎂(65mL,2M，溶於THF)和二甲鋅(12.5ml,1.2M，溶於甲苯)，滴入時間應超過30分鐘，再於-78℃攪拌2小時。而後以飽和氯化銨溶液終止反應，並以乙酸乙酯萃取。有機層以硫酸鎂乾燥後，減壓濃縮。再以矽膠層析(20% EA溶於己烷)，獲得(S)-N-((S)-1-(4-溴苯基)戊基)-2-甲基丙烷-2-磺醯胺((S)-N-((S)-1-(4-bromophenyl)pentyl)-2-methylpropane-2-sulfinamide)(23.8g,69%)。
將苯並[d]噁唑(benzo[d]oxazole)(2.0g,16.5mmol)、(S)-N-((S)-1-(4-溴苯基)戊基)-2-甲基丙烷-2-磺醯胺(4.77g,13.7mmol)、Pd(OAc)2(0.31g,1.37mmol)、醋酸銅(Cu(OAc)2)(0.51g,2.75mmol)、和碳酸鉀(K2CO3)(27.5mmol)溶於甲苯(50mL)並隔夜回流，而後過濾並減壓濃縮。反應產物以管柱層析(15% EA，溶於己烷)，獲得(S)-N-((S)-1-(4-(苯並[d]噁唑-2-基)苯基)戊基)-2-甲基丙烷-2-磺醯胺((S)-N-((S)-1-(4-(benzo[d]oxazol-2-yl)phenyl)pentyl)-2-methylpropane-2-sulfinamide)(3.84g,72%)。
將(S)-N-((S)-1-(4-(苯並[d]噁唑-2-基)苯基)戊基)-2-甲基丙烷-2-磺醯胺(3.84g,10mmol)懸浮於2M HCl之甲醇溶液(30mL)，於室溫放置1小時。蒸發溶劑後，滴入碳酸氫鈉(NaHCO3(aq))中和過量HCl，調整pH值至10，再以乙酸乙酯和水萃取。合併有機層以無水硫酸鎂乾燥，濃縮後獲得(S)-1-(4-(苯並[d]噁唑-2-基)苯基)戊-1-胺((S)-1-(4-(benzo[d]oxazol-2-yl)phenyl)pentan-1-amine)(2.74g,98%)。
將(S)-1-(4-(苯並[d]噁唑-2-基)苯基)戊-1-胺(2.74g,9.8mmol)、4-(((三氟甲基)磺醯基)氧)苯甲酸乙酯(3.5g,11.7mmol)、BINAP(3g,4.9mmol)、和Cs2CO3(6.37g,19.5mmol)溶於100ml甲苯，並以氮氣除氧30分鐘。而後加入Pd(OAc)2(0.55g,2.4mmol)，並於90℃加熱隔夜，再以乙酸乙酯萃取。以水清洗有機層，乾燥後減壓蒸發。反應產物以矽膠層析(15% EA溶於己烷)純化，獲得(S)-4-((1-(4-(苯並[d]噁唑-2-基)苯基)戊)胺基)苯甲酸乙酯(ethyl(S)-4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)pentyl)amino)benzoate)(3g,72%)。
通常步驟中，水解反應後獲得酸性化合物，再以β-丙胺酸乙酯進行醯胺化獲得醯胺化合物，再水解獲得SAR類似化合物。
化合物4-1
3-(4-((1-(4-(苯並[d]噁唑-2-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoate)
White solid.1H NMR(400MHz,DMSO-d6)：δ 8.20(d,J=8.8Hz,2H),7.77-7.74(m,1H),7.58-7.56(m,1H),7.51(d,J=8.8Hz,2H),7.44(d,J=8.8Hz,2H),7.36-7.32(m,2H),6.59(t,J=6.8Hz,1H),6.49(d,J=8.8Hz,2H),4.53(d,J=5.4Hz,1H),4.24(t,J=5.4Hz,1H),4.12(q,J=6.8Hz,2H),3.64(q,J=6.8Hz,2H),2.57(t,J=6.8Hz,2H),2.17-2.09(m,1H),1.23(t,J=6.8Hz,3H),1.03(t,J=6.8Hz,3H),0.97(t,J=6.8Hz,3H).MS(M+1)：486.
化合物4-2
3-(4-((1-(4-(苯並[d]噁唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)pentyl)amino)benzamido)propanoate)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 8.21(d,J=8.8Hz,2H),7.77-7.75(m,1H),7.58-7.57(m,1H),7.53(d,J=8.8Hz,2H),7.47(d,J=8.8Hz,2H),7.37-7.32(m,2H),6.59(t,J=6.8Hz,1H),6.49(d,J=8.8Hz,2H),4.47-4.41(m,2H),4.12(q,J=6.8Hz,2H),3.64(q,J=6.8Hz,2H),2.57(t,J=6.8Hz,2H),1.87-1.82(m,2H),1.43-1.34(m,4H),1.23(t,J=6.8Hz,3H),0.9(t,J=6.8Hz,3H).MS(M+1)：500.
化合物4-3
3-(4-((1-(4-(苯並[d]噁唑-2-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoic acid)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 12(brs,1H),8.13(d,J=8.8Hz,2H),7.98(t,J=5.4Hz,1H),7.81-7.74(m,2H),7.58(d,J=8.8Hz,2H),7.50(d,J=8.8Hz,2H),7.43-7.37(m,2H),6.69(d,J=8.8Hz,1H),6.58(d,J=8.8Hz,2H),4.28(t,J=5.4Hz,1H),3.38-3.33(m,2H),2.42(t,J=6.8Hz,2H),2.09-2.01(m,1H),1.23(t,J=6.8Hz,3H),1.04(t,J=6.8Hz,3H),0.82(t,J=6.8Hz,3H).MS(M+1)：458.
化合物4-4
3-(4-((1-(4-(苯並[d]噁唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸(3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
白色固態物質。1H NMR(400MHz,DMSO-d6)：δ 7.37(d,J=8.8Hz,2H),6.92-6.85(m,2H),6.78-6.71(m,4H),6.62-6.56(m,2H),5.77(d,J=8.8Hz,1H),6.58(d,J=8.8Hz,2H),3.70-3.67(m,2H),2.73(t,J=6.8Hz,2H),1.76(t,J=6.8Hz,2H),1.12-0.99(m,2H),0.71-0.54(m,4H),0.12(t,J=6.8Hz,3H).MS(M+1)：503.
化合物4-5
(S)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.13(d,J=8.4Hz,2H),7.95-8.04(m,1H),7.72-7.83(m,2H),7.58(d,J=8.4Hz,2H),7.49(d,J=8.8Hz,2H),7.36-7.44(m,2H),6.52-6.73(m,3H),4.23-4.34(m,1H),4.02(q,J=6.8Hz,2H),3.38(d,J=6.0Hz,2H),2.44-2.50(m,1H),1.98-2.12(m,1H),1.13(t,J=7.2Hz,3H),1.04(d,J=6.4Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：486.
化合物4-6
(R)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸乙酯(ethyl (R)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.13(d,J=8.4Hz,2H),7.99(s,1H),7.72-7.82(m,2H),7.58(d,J=8.4Hz,2H),7.49(d,J=8.8Hz,2H),7.35-7.44(m,2H),6.53-6.73(m,3H),4.28(s,1H),4.02(q,J=6.8Hz,2H),3.38(d,J=6.0Hz,2H),2.44-2.49(m,3H),2.00-2.12(m,1H),1.13(t,J=7.2Hz,3H),1.04(d,J=6.4Hz,3H),0.82(d,J=6.4Hz,3H).MS(M+1)：486.
化合物4-7
(S)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.13(d,J=8.8Hz,2H),7.97(t,J=5.6Hz,1H),7.72-7.83(m,2H),7.58(d,J=8.3Hz,2H),7.50(d,J=8.8Hz,2H),7.35-7.44(m,2H),6.53-6.73(m,3H),4.28(t,J=7.6Hz,1H),2.42(t,J=7.2Hz,2H),2.00-2.12(m,1H),1.04(d,J=6.8Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：458.
化合物4-8
(R)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.13(d,J=8.4Hz,2H),7.97(t,J=5.6Hz,1H),7.71-7.84(m,2H),7.59(d,J=8.4Hz,2H),7.50(d,J=8.8Hz,2H),7.35-7.45(m,2H),6.52-6.73(m,3H),4.28(t,J=7.6Hz,1H),3.32-3.44(m,2H),2.42(t,J=6.8Hz,2H),1.99-2.13(m,1H),1.04(d,J=6.4Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：458.
化合物4-9
(R)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(R)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)pentyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.14(d,J=8.4Hz,2H),7.95-8.03(m,1H),7.77(s,2H),7.60(d,J=8.4Hz,2H),7.50(d,J=8.8Hz,2H),7.35-7.45(m,2H),6.55(d,J=9.2Hz,3H),4.41-4.57(m,1H),4.02(q,J=6.8Hz,2H),3.39(d,J= 6.0Hz,2H),2.43-2.56(m,2H),1.31(s,6H),1.14(t,J=7.2Hz,3H),0.78-0.93(m,3H).MS(M+1)：500.
化合物4-10
(R)-3-(4-((1-(4-(苯[d]噁唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.14(d,J=8.4Hz,2H),7.97(t,J=5.6Hz,1H),7.72-7.82(m,2H),7.60(d,J=8.4Hz,2H),7.51(d,J=9.2Hz,2H),7.34-7.45(m,2H),6.50-6.80(m,3H),4.41-4.58(m,1H),3.34-3.45(m,2H),2.43(t,J=7.2Hz,2H),1.20-1.93(m,6H),0.81-0.91(m,3H).MS(M+1)：472.
化合物4-11
(R)-3-(4-(((4-(苯並[d]噁唑-2-基)苯基)(環戊基)甲基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(R)-3-(4-(((4-(benzo[d]oxazol-2-yl)phenyl)(cyclopentyl)methyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.12(d,J=8.4Hz,2H),7.93-8.02(m,1H),7.71-7.83(m,2H),7.63(d,J=8.4Hz,2H),7.48(d,J=8.8Hz,2H),7.35-7.44(m,2H),6.57(d,J=8.8Hz,3H),4.23-4.37(m,1H),4.02(q,J=6.8Hz,2H),3.38(d,J=6.4Hz,2H),2.44-2.49(m,2H),2.13-2.34(m,1H),1.87-2.04(m,1H),1.35-1.72(m,5H),1.18-1.33(m,2H),1.10-1.16(m,3H).MS(M+1)：512.
化合物4-12
(R)-3-(4-(((4-(苯並[d]噁唑-2-基)苯基)(環戊基)甲基)胺基)苯甲醯胺基)丙酸((R)-3-(4-(((4-(benzo[d]oxazol-2-yl)phenyl)(cyclopentyl)methyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.12(d,J=8.4Hz,2H),7.95(t,J=5.6Hz,1H),7.72-7.83(m,2H),7.63(d,J=8.4Hz,2H),7.49(d,J=8.8Hz,2H),7.34-7.44(m,2H),6.50-6.83(m,3H),4.29(t,J=8.4Hz,1H),3.33-3.45(m,2H),2.42(t,J=7.2Hz,2H),2.23(m,1H),1.87-2.03(m,1H),1.36-1.73(m,5H),1.16-1.35(m,2H).MS(M+1)：484.
化合物4-13
(R)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯基)-3-甲基丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl (R)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)-3-methylbutyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.13(d,J=8.4Hz,2H),7.95-8.03(m,1H),7.77(s,2H),7.61(d,J=8.4Hz,2H),7.50(d,J=8.8Hz,2H),7.35-7.44(m,2H),6.57(d,J=8.8Hz,3H),4.49-4.64(m,1H),4.02(d,J=7.2Hz,2H),3.39(d,J=6.0Hz,2H),2.45-2.49(m,2H),1.39-1.84(m,4H),1.14(t,J=7.2Hz,3H),0.97(d,J=6.4Hz,3H),0.91(d,J=6.4Hz,3H).MS(M+1)：500.
化合物4-14
(R)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯基)-3-甲基丁基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)-3-methylbutyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.14(d,J=8.4Hz,2H),7.97(t,J=5.6Hz,1H),7.72-7.83(m,2H),7.61(d,J=8.4Hz,2H),7.51(d,J=8.8Hz,2H),7.34-7.45(m,2H),6.51-6.80(m,3H),4.48-4.65(m,1H),3.33-3.43(m,2H),2.43(t,J =7.2Hz,2H),1.43-1.86(m,4H),0.97(d,J=6.4Hz,3H),0.91(d,J=6.4Hz,3H).MS(M+1)：472.
化合物4-15
(S)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)pentyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.14(d,J=8.3Hz,2H),8.01(t,J=5.6Hz,1H),7.74-7.80(m,2H),7.60(d,J=8.3Hz,2H),7.51(d,J=8.8Hz,2H),7.35-7.45(m,2H),6.77(d,J=7.8Hz,1H),6.55(d,J=8.8Hz,2H),4.45-4.56(m,1H),4.03(q,J=6.8Hz,2H),3.36-3.43(m,2H),2.46-2.50(m,2H),1.77-1.90(m,1H),1.64-1.75(m,1H),1.32(d,J=6.8Hz,4H),1.14(t,J=7.1Hz,3H),0.86(t,J=7.1Hz,3H).MS(M+1)：500.HPLC 95%.
化合物4-16
(S)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯基)戊基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.13(d,J=8.3Hz,2H),7.97-8.04(m,1H),7.68-7.83(m,2H),7.59(d,J=8.3Hz,2H),7.53(d,J=8.8Hz,2H),7.34-7.45(m,2H),6.76(d,J=7.3Hz,1H),6.55(d,J=8.8Hz,2H),4.44-4.54(m,1H),3.38(q,J=6.7Hz,2H),2.44(t,J=7.1Hz,2H),1.77-1.89(m,1H),1.64-1.75(m,1H),1.22-1.46(m,4H),0.84(t,J=6.8Hz,3H).MS(M+1)：472.HPLC 96%.
化合物4-17
(S)-3-(4-((1-(4-(苯並[d]並唑-2-基)苯基)-3-甲基丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)-3-methylbutyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.13(d,J=8.3Hz,2H),7.99(t,J=5.6Hz,1H),7.77(t,J=8.6Hz,2H),7.61(d,J=7.8Hz,2H),7.50(d,J=8.8Hz,2H),7.36-7.44(m,2H),6.74(d,J=7.8Hz,1H),6.57(d,J=8.8Hz,2H),4.52-4.64(m,1H),4.02(q,J=7.3Hz,2H),3.39(q,J=6.5Hz,2H),2.45-2.49(m,2H),1.65-1.82(m,2H),1.47-1.56(m,1H),1.14(t,J=7.1Hz,3H),0.96(d,J=6.4Hz,3H),0.91(d,J=6.4Hz,3H).MS(M+1)：500.HPLC 95%.
化合物4-18
(S)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯基)-3-甲基丁基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenyl)-3-methylbutyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.14(d,J=7.8Hz,2H),7.98(t,J=5.4Hz,1H),7.71-7.82(m,2H),7.61(d,J=8.3Hz,2H),7.52(d,J=8.3Hz,2H),7.34-7.44(m,2H),6.74(d,J=7.8Hz,1H),6.57(d,J=8.8Hz,2H),4.51-4.62(m,1H),3.36-3.42(m,2H),2.43(t,J=7.1Hz,2H),1.65-1.83(m,2H),1.45-1.57(m,1H),0.96(d,J=5.9Hz,3H),0.91(d,J=5.9Hz,3H).MS(M+1)：472.HPLC 96%.
化合物4-19
3-(4-(((1S)-1-(4-(苯並[d]噁唑-2-基)苯基)-3-甲基丁基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl3-(4-(((1S)-1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylbutyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.13(dd,J=8.6,1.7Hz,2H),7.97-8.05(m,1H),7.72-7.81(m,2H),7.58(dd,J=8.3,5.4Hz,2H),7.50(dd,J=9.0,3.2Hz,2H),7.35-7.44(m,2H),6.49-6.73(m,3H),4.26-4.50(m,1H),4.02(q,J=7.3Hz,2H),3.39(q,J=6.8Hz,2H),2.42-2.50(m,2H),1.77-1.91(m,1H),1.58-1.71(m,1H),1.22-1.44(m,1H),1.13(t,J=7.1Hz,3H),0.70-0.99(m,6H).MS(M+1)：500.HPLC 94%.
化合物4-20
3-(4-(((1S)-1-(4-(苯並[d]噁唑-2-基)苯基)-3-甲基丁基)胺基)苯甲醯胺基)丙酸(3-(4-(((1S)-1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylbutyl)amino)benzamido)propanoic acid)
1H NMR(DMSO-d6)：δ 8.13(dd,J=8.3,2.0Hz,2H),7.93-8.01(m,1H),7.73-7.83(m,2H),7.58(dd,J=8.3,5.4Hz,2H),7.46-7.52(m,2H),7.31-7.45(m,2H),6.53-6.70(m,3H),4.30-4.47(m,1H),2.42(t,J=7.1Hz,2H),1.80-1.89(m,1H),1.66(br.s.,1H),1.24-1.45(m,1H),0.71-0.99(m,6H).MS(M+1)：472.HPLC 94%
化合物4-21
3-(4-(((1R)-1-(4-(苯並[d]噁唑-2-基)苯基)-3-甲基丁基)胺基)苯甲醯胺基)丙酸乙酯 (ethyl3-(4-(((1R)-1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylbutyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.13(dd,J=8.3,2.0Hz,2H),7.97-8.03(m,1H),7.74-7.80(m,2H),7.58(dd,J=8.3,5.4Hz,2H),7.50(dd,J=8.8,3.4Hz,2H),7.35-7.44(m,2H),6.54-6.73(m,3H),4.30-4.46(m,1H),4.02(q,J=7.3Hz,2H),3.39(q,J=6.8Hz,2H),2.44-2.49(m,2H),1.79-1.90(m,1H),1.59-1.72(m,1H),1.24-1.45(m,1H),1.14(t,J=7.1Hz,3H),0.73-0.98(m,6H).MS(M+1)：500.HPLC 95%.
化合物4-22
3-(4-(((1R)-1-(4-(苯並[d]噁唑-2-基)苯基)-3-甲基丁基)胺基)苯甲醯胺基)丙酸(3-(4-(((1R)-1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylbutyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.13(dd,J=8.3,2.0Hz,2H),7.93-8.01(m,1H),7.72-7.82(m,2H),7.58(dd,J=8.3,5.4Hz,2H),7.46-7.52(m, 2H),7.33-7.46(m,2H),6.50-6.72(m,3H),4.28-4.47(m,1H),2.42(t,J=7.1Hz,2H),1.79-1.89(m,1H),1.58-1.72(m,1H),1.22-1.46(m,1H),0.71-0.99(m,6H).MS(M+1)：472.HPLC 99%.
化合物4-23
(S)-3-(4-(((4-(苯並[d]噁唑-2-基)苯基)(環戊基)甲基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-(((4-(benzo[d]oxazol-2-yl)phenyl)(cyclopentyl)methyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.12(d,J=8.3Hz,2H),7.98(t,J=5.6Hz,1H),7.73-7.80(m,2H),7.62(d,J=8.3Hz,2H),7.49(d,J=8.8Hz,2H),7.36-7.43(m,2H),6.79(d,J=7.8Hz,1H),6.57(d,J=8.8Hz,2H),4.28(t,J=8.6Hz,1H),4.02(q,J=6.8Hz,2H),3.35-3.42(m,2H),2.45-2.49(m,2H),2.16-2.28(m,1H),1.91-1.99(m,1H),1.37-1.68(m,5H),1.19-1.32(m,2H),1.11-1.16(t,J=7.3Hz,3H).MS(M+1)：512.HPLC 96%.
化合物4-24
(S)-3-(4-(((4-(苯並[d]噁唑-2-基)苯基)(環戊基)甲基)胺基)苯甲醯胺基)丙酸((S)-3-(4-(((4-(benzo[d]oxazol-2-yl)phenyl)(cyclopentyl)methyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.12(d,J=8.3Hz,2H),7.97(t,J=5.4Hz,1H),7.71-7.81(m,2H),7.62(d,J=8.3Hz,2H),7.50(d,J=8.8Hz,2H),7.35-7.45(m,2H),6.78(d,J=8.3Hz,1H),6.57(d,J=8.8Hz,2H),4.28(t,J=8.6Hz,1H),3.33-3.40(m,2H),2.42(t,J=7.3Hz,2H),2.16-2.28(m,1H),1.90-2.00(m,1H),1.36-1.68(m,5H),1.16-1.33(m,2H).MS(M+1)：484.HPLC 99%.
化合物4-25
(S)-3-(4-((1-(4-(苯並[d]噻唑-2-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.12(d,J=7.8Hz,1H),7.95-8.06(m,4H),7.47-7.56(m,5H),7.41-7.47(m,1H),6.68(d,J=7.8Hz,1H),6.58(d,J=8.8Hz,2H),4.25(t,J=7.6Hz,1H),4.02(q,J=7.3Hz,2H),3.36-3.43(m,2H),2.45-2.50(m,2H),1.99-2.10(m,1H),1.14(t,J=7.1Hz,3H),1.04(d,J=6.8Hz,3H),0.83(d,J=6.8Hz,3H).MS(M+1)：502.HPLC 98%.
化合物4-26
(S)-3-(4-((1-(4-(苯並[d]噻唑-2-基)苯基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)phenyl)-2-methylpropyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 12.1(br.s.,1H),8.12(d,J=7.3Hz,1H),7.93-8.07(m,4H),7.39-7.60(m,6H),6.67(d,J=7.8Hz,1H),6.58(d,J=8.3Hz,2H),4.26(t,J=7.6Hz,1H),3.28-3.37(m,2H),2.42(t,J=7.1Hz,2H),2.00-2.11(m,1H),1.04(d,J=6.4Hz,3H),0.83(d,J=6.4Hz,3H).MS(M+1)：474.HPLC 99%.
化合物4-27
(S)-3-(6-((1-(4-(苯並[d]噻唑-2-基)苯基)-2-甲基丙基)胺基)菸鹼醯胺基)丙酸乙酯(ethyl(S)-3-(6-((1-(4-(benzo[d]thiazol-2-yl)phenyl)-2-methylpropyl)amino)nicotinamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.39(d,J=2.4Hz,1H),8.08-8.18(m,2H),7.99-8.06(m,3H),7.74(dd,J=8.8,2.4Hz,1H),7.49-7.60(m,4H),7.40-7.47(m,1H),6.59(d,J=8.8Hz,1H),4.79-4.90(m,1H),4.00-4.05(m,2H),3.37-3.44(m,2H),3.21-3.28(m,1H),2.42(t,J=6.8Hz,1H),2.10(d,J=7.3Hz,1H),1.12-1.16(m,3H),1.00(d,J=6.4Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：503.HPLC 98%.
化合物4-28
(S)-3-(6-((1-(4-(苯並[d]噻唑-2-基)苯基)-2-甲基丙基)胺基)菸鹼醯胺基)丙酸((S)-3-(6-((1-(4-(benzo[d]thiazol-2-yl)phenyl)-2-methylpropyl)amino)nicotinamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 12.09(br.s.,1H),8.39(d,J=2.0Hz,1H),8.09-8.16(m,2H),7.98-8.07(m,3H),7.75(dd,J=8.8,2.4Hz,1H),7.50-7.59(m,4H),7.40-7.48(m,1H),6.59(d,J=8.8Hz,1H),4.85(br.s.,1H),3.34-3.42(m,2H),2.44(t,J=7.1Hz,2H),2.03-2.17(m,1H),1.00(d,J=6.4Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：475.HPLC 99%.
化合物4-29
(S)-3-(6-((1-(4-(苯[d]噁唑-2-基)苯基)-2-甲基丙基)胺基)菸鹼醯胺基)丙酸乙酯(ethyl (S)-3-(6-((1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylpropyl)amino)nicotinamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.39(s,1H),8.07-8.20(m,3H),7.72-7.82(m,3H),7.58(d,J=8.3Hz,3H),7.33-7.45(m,2H),6.60(d,J=8.8Hz,1H),3.99-4.07(m,2H),3.41(q,J=6.7Hz,2H),2.04-2.15(m,1H),1.14(t,J=7.1Hz,3H),1.00(d,J=6.4Hz,3H),0.82(d,J=6.4Hz,3H).MS(M+1)：487.HPLC 98%.
化合物4-30
(S)-3-(6-((1-(4-(苯並[d]噁唑-2-基)苯基)-2-甲基丙基)胺基)菸鹼醯胺基)丙酸((S)-3-(6-((1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylpropyl)amino)nicotinamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.39(d,J=2.4Hz,1H),8.13(d,J=8.3Hz,3H),7.69-7.83(m,3H),7.51-7.62(m,3H),7.34-7.44(m,2H),6.59(d,J=8.8Hz,1H),3.37(q,J=6.4Hz,2H),2.43(t,J=7.1Hz,2H),2.05-2.16(m,1H),1.00(d,J=6.4Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：459.HPLC 97%.
化合物5-1
(S)-3-(4-((3-甲基-1-(4-(3-苯基-1,2,4-噁二唑-5-基)苯基)丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((3-methyl-1-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenyl)butyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.04-8.16(m,4H),8.00(t,J=5.4Hz,1H),7.66(d,J=7.8Hz,2H),7.55-7.62(m,3H),7.46-7.54(m,2H),6.77(d,J=7.8Hz,1H),6.57(d,J=8.8Hz,2H),4.55-4.62(m,1H),4.02(q,J=7.3Hz,2H),3.36-3.43(m,2H),2.46-2.50(m,2H),1.66-1.82(m,2H),1.46-1.55(m,1H),1.14(t,J=7.1Hz,3H),0.96(d,J=6.4Hz,3H),0.91(d,J=5.9Hz,3H).MS(M+1)：527.HPLC 98%.
化合物5-2
(S)-3-(4-((3-甲基-1-(4-(3-苯基-1,2,4-噁二唑-5-基)苯基)丁基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((3-methyl-1-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.12(d,J=7.8Hz,2H),8.08(dd,J=7.6,2.2Hz,2H),7.98(t,J=5.4Hz,1H),7.66(d,J=8.3Hz,2H),7.56-7.62(m,3H),7.51(d,J=8.8Hz,2H),6.76(d,J=7.8Hz,1H),6.56(d,J=8.8Hz,2H),4.55-4.63(m,1H),3.35-3.40(m,2H),2.43(t,J=7.1Hz,2H),1.65-1.83(m,2H),1.45-1.57(m,1H),0.97(d,J=6.4Hz,3H),0.91(d,J=6.4Hz,3H).MS(M+1)：499.HPLC95%.
化合物5-3
(S)-3-(4-((2-甲基-1-(4-(3-苯基-1,2,4-噁二唑-5-基)苯基)丙基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((2-methyl-1-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenyl)propyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.12(d,J=8.3Hz,2H),8.05-8.09(m,2H),8.00(s,1H),7.55-7.65(m,5H),7.50(d,J=8.8Hz,2H),6.71(d,J=7.8Hz,1H),6.58(d,J=8.8Hz,2H),4.30(s,1H),4.02(q,J=7.2Hz,2H),3.39(q,J=6.5Hz,2H),2.46-2.50(m,2H),2.05(d,J=6.8Hz,1H),1.13(t,J=7.1Hz,3H),1.04(d,J=6.4Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：513.HPLC 99%.
化合物5-4
(S)-3-(4-((2-甲基-1-(4-(3-苯基-1,2,4-噁二唑-5-基)苯基)丙基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((2-methyl-1-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenyl)propyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.13(d,J=7.8Hz,2H),8.06-8.10(m,2H),7.98(t,J=5.4Hz,1H),7.57-7.66(m,5H),7.50(d,J=8.8Hz,2H),6.70(d,J=7.8Hz,1H),6.57(d,J=8.8Hz,2H),4.31(t,J=7.6Hz,1H),3.35-3.40(m,2H),2.42(t,J=7.3Hz,2H),2.00-2.11(m,1H),1.04(d,J=6.4Hz,3H),0.82(d,J=6.8Hz,3H).MS(M+1)：485.HPLC 99%.
化合物5-5
3-(4-(((1S)-2-甲基-1-(4-(3-苯基-1,2,4-噁二唑-5-基)苯基)丁基)胺基)苯甲醯胺基)丙酸乙酯(ethyl3-(4-(((1S)-2-methyl-1-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenyl)butyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 7.96-8.15(m,5H),7.46-7.68(m,7H),6.71(d,J=8.3Hz,1H),6.54-6.76(m,2H),4.30-4.50(m,1H),4.02(q,J=7.3Hz,2H),3.36-3.44(m,2H),2.41-2.50(m,2H),1.77-1.90(m,1H),1.55-1.73(m,1H),1.22-1.48(m,1H),1.09-1.17(m,3H),0.70-0.98(m,6H).MS(M+1)：527.HPLC95%.
化合物5-6
3-(4-(((1S)-2-甲基-1-(4-(3-苯基-1,2,4-噁二唑-5-基)苯基)丁基)胺基)苯甲醯胺基)丙酸(3-(4-(((1S)-2-methyl-1-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenyl)butyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 7.96-8.17(m,5H),7.41-7.68(m,7H),6.49-6.74(m,3H),4.29-4.50(m,1H),3.33(q,J=7.3Hz,2H),2.27-2.35(m,2H),1.60-1.90(m,1H),1.06-1.44(m,2H),0.72-0.98(m,6H).MS(M+1)：499.HPLC 97%.
化合物5-7
(S)-3-(4-((1-(4-(3-苯基-1,2,4-噁二唑-5-基)苯基)戊基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((1-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenyl)pentyl)amino)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 7.97-8.18(m,5H),7.45-7.69(m,7H),6.79(d,J=7.3Hz,1H),6.55(d,J=8.3Hz,2H),4.52(q,J=7.2Hz,1H),4.02(q, J=7.3Hz,2H),3.38-3.43(m,2H),2.46-2.50(m,2H),1.65-1.90(m,2H),1.23-1.47(m,4H),1.14(t,J=7.1Hz,3H),0.85(t,J=6.8Hz,3H).MS(M+1)：527.HPLC96%.
化合物5-8
(S)-3-(4-((1-(4-(3-苯基-1,2,4-噁二唑-5-基)苯基)戊基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenyl)pentyl)amino)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 7.94-8.18(m,5H),7.43-7.69(m,7H),6.77(d,J=7.3Hz,1H),6.45-6.59(m,2H),4.53(d,J=6.8Hz,1H),3.29-3.39(m,2H),2.32(t,J=7.1Hz,2H),1.63-1.90(m,2H),1.20-1.48(m,4H),0.86(t,J=7.1Hz,3H).MS(M+1)：499.HPLC 97%.
實施例5：表6和表7所示化合物之合成
以下揭示合成化合物6-1、6-2和化合物7-1至7-4之反應式。
反應式V
將苯並唑(benzoazoles)(16.5mmol)、4-溴苯甲醛(13.7mmol)、Pd(OAc)2(1.37mmol)、Cu(OAc)2(2.75mmol)、和K2CO3(27.5mmol)溶於甲苯(50mL)並隔夜回流，再過濾並減壓濃縮。濃縮後產物以管柱層析純化，獲得4-(苯並[d]噁唑-2-基)苯甲醛(4-(benzo[d]oxazol-2-yl)benzaldehyde)(2.50g,85%)。
將4-(苯並[d]噁唑-2-基)苯甲醛(2.50g,14mmol)溶解於THF(50mL)，並冷卻至-78℃，再滴入異丙基氯化鎂(isopropylmagnesium chloride)(2M，溶於THF，10mL)和二甲鋅(4.2mmol)，滴入時間應超過30分鐘。反應於-78℃攪拌2小時，再加入飽和氯化銨溶液終止反應。而後以乙酸乙酯萃取反應物，再以硫酸鎂乾燥有機層，過濾濃縮後，以矽膠層析法純化，獲得1-(4-(苯並[d]噁唑-2-基)苯基)-2-甲基丙醇(1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylpropan-1-ol)(2.58g,69%)。
於圓底錐形瓶中加入4-羥基苯甲酸乙酯(1.66g,10mmol)、1-(4-(苯並[d]噁唑-2-基)苯基)-2-甲基丙醇(2.40g,9mmol)、三正丁基膦(tri-n-butylphosphine)(2.02g,10mmol)、和THF(10mL)，並於室溫滴入1,1'-(偶氮二羰基)二哌啶(1,1'-(Azodicarbonyl)dipiperidine(ADDP))(2.52g,10mmol)，滴入時間應超過3分鐘，再攪拌3小時。反應物減壓乾燥後，以急速層析法(矽膠，15%乙酸乙酯溶於己烷)純化，獲得4-(1-(4-(苯並[d]噁唑-2-基)苯基)-2-甲基丙氧)苯甲酸乙酯(ethyl4-(1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylpropoxy)benzoate)(2.24g,60%)。
將4-(1-(4-(苯並[d]噁唑-2-基)苯基)-2-甲基丙氧)苯甲酸乙酯(2.10g,5mmol)溶於二噁烷(10ml)，並加入2.5M LiOH溶液(10mL)，再加熱至80℃攪拌5小時。冷卻至室溫後，加入1M HCl溶液，並以乙酸乙酯萃取2次，合併有機層以硫酸鎂乾燥，過濾濃縮後獲得白色結晶之酸性產物(1.78g,92%)。
將4-(1-(4-(苯並[d]噁唑-2-基)苯基)-2-甲基丙氧)苯甲酸(4-(1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylpropoxy)benzoic acid)(1.78g,4.6mmol)溶於THF(50mL)，再加入HOBt(1.40g,9.2mmol)、EDCI(1.76g,9.2mmol)、3-胺基氯化丙酸乙酯(ethyl 3-aminopropanoate hydrochloride)(1.41g,9.2mmol)和DIPEA(1.92g,9.2mmol)，並於室溫隔夜攪拌。反應物以乙酸乙酯和鹽水萃取，再乾燥、過濾、以及減壓濃縮。而後，濃縮物以矽膠管柱層析(15%乙酸乙酯溶於己烷)純化，獲得3-(4-(1-(4-(苯並[d]噁唑-2-基)苯基)-2-甲基丙氧)苯甲醯胺基)丙酸乙酯(ethyl3-(4-(1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylpropoxy)benzamido)propanoate)(1.43g,64%)。
將3-(4-(1-(4-(苯並[d]噁唑-2-基)苯基)-2-甲基丙氧)苯甲醯胺基)丙酸乙酯(1.43g,2.94mmol)溶於THF(20ml)，再加入LiOH水溶液(0.24g,10mL)，並於室溫隔夜攪拌，並以TLC監測反應。待反應完全後，以旋轉蒸發去除溶劑，再加入2M HCl溶液，並以乙酸乙酯萃取2次，合併有機層乾燥過濾後，減壓濃縮獲得3-(4-(1-(4-(苯並[d]噁唑-2-基)苯基)-2-甲基丙氧)苯甲醯胺基)丙酸(3-(4-(1-(4-(benzo[d]oxazol-2-yl)phenyl)-2-methylpropoxy)benzamido)propanoic acid)(1.21g,90%)。
化合物6-1
3-(4-(1-(4-(苯並[d]噻唑-2-基)苯基)-2-甲基丙氧)苯甲醯胺基)丙酸乙酯(Ethyl3-(4-(1-(4-(benzo[d]thiazol-2-yl)phenyl)-2-methylpropoxy)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.29(t,J=5.6Hz,1H),8.13(d,J=7.3Hz,1H),8.02-8.09(m,3H),7.65-7.71(m,2H),7.51-7.57(m,3H),7.42-7.48(m,1H),6.93-6.99(m,2H),5.26(d,J=6.4Hz,1H),4.03(q,J=7.2Hz,2H),3.38-3.46(m,2H),2.50-2.54(m,2H),2.16(dq,J=13.4,6.6Hz,1H),1.13(t,J=7.1Hz,3H),1.03(d,J=6.4Hz,3H),0.89(d,J=6.8Hz,3H).MS(M+1)：503.HPLC 98%.
化合物6-2
3-(4-(1-(4-(苯並[d]噻唑-2-基)苯基)-2-甲基丙氧)苯甲醯胺基)丙酸(3-(4-(1-(4-(Benzo[d]thiazol-2-yl)phenyl)-2-methylpropoxy)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.27(t,J=5.6Hz,1H),8.12(d,J=7.8Hz,1H),8.01-8.08(m,3H),7.70(d,J=8.8Hz,2H),7.50-7.57(m,3H),7.42-7.47(m,1H),6.93-6.99(m,2H),5.26(d,J=6.4Hz,1H),3.39-3.43(m,2H),2.45(t,J=7.1Hz,2H),2.10-2.20(m,1H),1.03(d,J=6.8Hz,3H),0.89(d,J=6.8Hz,3H).MS(M+1)：475.HPLC 98%.
於錐形瓶中加入4-(苯並[d]噻唑-2-基)酚(2.27g,10mmol)、4-(1-羥基-2-甲基丙基)苯甲酸甲酯(2.08g,10mmol)、三正丁基膦(2.02g,10mmol)、和THF(10mL)後，於室溫滴入ADDP(2.52,10mmol)，滴入時間應超過3分鐘，再攪 拌3小時。而後，將反應物減壓乾燥，並以急速層析法(15%乙酸乙酯，溶於己烷)，獲得4-(1-(4-(苯並[d]噻唑-2-基)苯氧基)-2-甲基丙基)苯甲酸甲酯(methyl4-(1-(4-(benzo[d]thiazol-2-yl)phenoxy)-2-methylpropyl)benzoate)(2.34g,56%)。
於4-(1-(4-(苯並[d]噻唑-2-基)苯氧基)-2-甲基丙基)苯甲酸甲酯(2.34g,5.6mmol)之二噁烷(10mL)溶液加入2.5M LiOH溶液(10mL)，加熱至80℃並攪拌5小時。冷卻至室溫後，加入1M HCl溶液，並以乙酸乙酯萃取2次，合併有機層以硫酸鎂乾燥，過濾濃縮後，獲得白色結晶之酸性產物(2.03g,90%)。
將4-(1-(4-(苯並[d]噻唑-2-基)苯氧基)-2-甲基丙基)苯甲酸(4-(1-(4-(benzo[d]thiazol-2-yl)phenoxy)-2-methylpropyl)benzoic acid)(2.03g,5.04mmol)溶於THF(50mL)，並加入HOBt(1.40g,9.2mmol)、EDCI(1.76g,9.2mmol)、3-胺基氯化丙酸乙酯(1.41g,9.2mmol)、和DIPEA(1.92g,9.2mmol)，再於室溫攪拌隔夜。而後以乙酸乙酯和鹽水萃取反應物，乾燥過濾後減壓蒸發，再以矽膠管柱層析(15%乙酸乙酯溶己烷於)純化，獲得3-(4-(1-(4-(苯並[d]噻唑-2-基)苯氧基)-2-甲基丙基)苯甲醯胺基)丙酸乙酯(3-(4-(1-(4-(benzo[d]thiazol-2-yl)phenoxy)-2-methylpropyl)benzamido)propanoate)(1.72g,68%)。
將乙酯(1.72g,3.42mmol)溶於THF(20mL)，再加入LiOH(0.24g)之水溶液(10mL)，於室溫隔夜攪拌，並以TLC監測反應。待反應完全後，以旋轉蒸發去除溶劑，再加入2M HCl溶液。而後以乙酸乙酯萃取反應物2次，合併有機層乾燥後，過濾並減壓濃縮，獲得3-(4-(1-(4-(苯並[d]噻唑-2-基)苯氧基)-2-甲基丙基)苯甲醯胺基)丙酸 (3-(4-(1-(4-(benzo[d]thiazol-2-yl)phenoxy)-2-methylpropyl)benzamido)propanoic acid)(1.40g,87%)。
化合物7-1
3-(4-(1-(4-(苯並[d]噁唑-2-基)苯氧基)-2-甲基丙基)苯甲醯胺基)丙酸乙酯(Ethyl3-(4-(1-(4-(benzo[d]oxazol-2-yl)phenoxy)-2-methylpropyl)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.49(s,1H),7.98-8.08(m,2H),7.79(d,J=8.3Hz,2H),7.68-7.75(m,2H),7.47(d,J=8.3Hz,2H),7.33-7.39(m,2H),7.06-7.11(m,2H),5.27(d,J=6.4Hz,1H),4.04(q,J=7.2Hz,2H),3.46(d,J=5.9Hz,2H),2.54(t,J=6.8Hz,2H),2.10-2.20(m,1H),1.15(t,J=7.1Hz,3H),1.02(d,J=6.8Hz,3H),0.87(d,J=6.8Hz,3H).MS(M+1)：487.HPLC 96%.
化合物7-2
3-(4-(1-(4-(苯並[d]噁唑-2-基)苯氧基)-2-甲基丙基)苯甲醯胺基)丙酸(3-(4-(1-(4-(Benzo[d]oxazol-2-yl)phenoxy)-2-methylpropyl)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 8.48(t,J=5.4Hz,1H),7.98-8.08(m,2H),7.80(d,J=7.8Hz,2H),7.67-7.75(m,2H),7.47(d,J=8.3Hz,2H),7.30-7.41(m,2H),7.04-7.13(m,2H),5.27(d,J=6.4Hz,1H),3.41-3.48(m,2H),2.45-2.49(m,2H),2.07-2.22(m,1H),1.02(d,J=6.8Hz,3H),0.87(d,J=6.8Hz,3H).MS(M+1)：459.HPLC 94%.
化合物7-3
3-(4-(1-(4-(苯並[d]噻唑-2-基)苯氧基)-2-甲基丙基)苯甲醯胺基)丙酸乙酯(Ethyl3-(4-(1-(4-(benzo[d]thiazol-2-yl)phenoxy)-2-methylpropyl)benzamido)propanoate)
1H NMR(400MHz,DMSO-d6)：δ 8.49(t,J=5.4Hz,1H),8.07(d,J=7.8Hz,1H),7.97(d,J=8.3Hz,1H),7.92(d,J=8.8Hz,2H),7.79(d,J=8.3Hz,2H),7.35-7.56(m,4H),7.04(d,J=8.8Hz,2H),5.24(d,J=6.4Hz,1H),4.04(q,J=7.3Hz,2H),3.41-3.52(m,2H),2.54(t,J=7.1Hz,2H),2.14(d,J=6.8Hz,1H),1.15(t,J=7.1Hz,3H),1.02(d,J=6.8Hz,3H),0.87(d,J=6.8Hz,3H).MS(M+1)：503.HPLC 99%.
化合物7-4
3-(4-(1-(4-(苯並[d]噻唑-2-基)苯氧基)-2-甲基丙基)苯甲醯胺基)丙酸(3-(4-(1-(4-(Benzo[d]thiazol-2-yl)phenoxy)-2-methylpropyl)benzamido)propanoic acid)
1H NMR(400MHz,DMSO-d6)：δ 12.19(br.s.,1H),8.49(t,J=5.4Hz,1H),8.06(d,J=7.3Hz,1H),7.98(d,J=7.8Hz,1H),7.89-7.95(m,2H),7.82(d,J=8.3Hz,2H),7.44-7.52(m,3H),7.37-7.43(m,1H),7.02-7.07(m,2H),5.23(d,J=6.4Hz,1H),3.41-3.50(m,2H),2.48-2.54(m,2H),2.09-2.19(m,1H),1.02(d,J=6.4Hz,3H),0.84-0.89(m,3H).MS(M+1)：475.HPLC 97%.
實施例1-5中，若合成之步驟與前述其他化合物相似，則不再重複說明特定化合物之詳細合成步驟。
實施例6：式(I)化合物之體外(in vitro)試驗
下文說明以2種體外試驗測試實施例1-5所製備之化合物之結果，並將結果揭示於表1-7。
升糖素cAMP抑制試驗
使用試驗套組：Cisbio cAMP Dynamic 2 kit偵測升糖素誘發之下游第二傳訊者cAMP。待測之化合物分別溶於DMSO(10mM)。為評估化合物抑制cAMP產生之能力，將待測化合物以序列稀釋之濃度給予具有升糖素受體(GCGR)過度表現之CHO-K1細胞或人類初代肝細胞(human primary hepatocyte)。 將細胞懸浮於含有0.1%(w/v)小牛血清白蛋白和800nM 3-異丁基-1-甲基黃嘌呤(IBMX)之漢克平衡鹽緩沖液(Hank's Balanced Salt solution(HBSS))，並且分置於384白色孔盤。將稀釋之化合物加入孔盤中培養30分鐘，其中DMSO最終濃度為1%。再於室溫以濃度相當於EC50(可刺激半數最大反應之藥物濃度的標記)之升糖素刺激細胞30分鐘。而後於各孔洞加入包含cAMP抗體和螢光受器之裂解緩衝液(lysis buffer)，再培養60分鐘。使用儀器：Molecular Devices SpectraMax Paradigm以及HTRF偵測匣紀錄結果，依據cAMP產生量，以非線性回歸計算化合物各自抑制cAMP產生之IC50值。
I125-升糖素結合試驗
以I125-升糖素競爭試驗(competition assay)測試各化合物之結合能力。自GCGR過度表現之CHO-K1細胞取得GCGR膜部分(membrane fraction)，並以1mg/ml之濃度保存。為評估化合物結合至GCGR之IC50，GCGR膜部分給予序列稀釋之化合物。膜部分稀釋調整為每孔7.5μg，溶於含有50Mm Tris緩衝液(pH 7.4)和0.5%(w/v)小牛血清白蛋白之70μL試驗緩衝液，並加入96孔盤中。膜部分與10μL稀釋化合物混合培養5分鐘，再於各孔洞加入20μL具有I125標記之升糖素(Perkin Elmer)，升糖素最終濃度為0.0625nM。將反應物置於25℃培養30分鐘，再移至塗佈0.5%(w/v)聚乙亞胺之過濾盤：Millipore MultiScreen GF/B Plate。過濾盤以包含50mM Tris之清洗緩衝液(pH 7.4)清洗2次，每次300μL。殘留之同位素以儀器：Hidex CHAMELEON V micro-beta counter偵測，各化合物結合至GCGR之IC50由非線性回歸計算。
表1-7揭示式(I)之172個例示化合物之結構和體外試驗活性。172個化合物均可結合至升糖素受體，並可抑制升糖素下游之cAMP之濃度，各化合物活性之差異以表中IC50表示(降低半數反應或結合之抑制劑之濃度)。
a 括號中的數字表示化合物以濃度30μM給予時之抑制率。
實施例7：比較式(I)化合物與結構近似之已知化合物之活性
挑選4種化合物用於比較結構近似之已知化合物之體外活性，與前述結構近似之已知化合物揭示於表8。
以HTRF方法偵測第二傳訊者cAMP之功能性試驗揭示給予化合物後GCGR下游訊息。HTRF cAMP試驗依以下步驟進行。預先將初代人類肝細胞和不同濃度之待測化合物共同培養，再以重組升糖素刺激，並依據cAMP產生量以非線性回歸計算IC50。
前述試驗結果揭示於表8。
結果顯示，四種式化合物式(I)相較於結構相似之已知化合物，更能抑制人類肝細胞產生cAMP。
其他實施例
本說明書所揭示之技術特徵可任意組合，個別特徵可由被用於相同、相等、或相似目的之另一特徵取代。故，若無特別說明，各特徵僅為相同或相似上位特徵之例示。
另，習知技術者可依據說明書而輕易確認本發明之重要特徵，且在不背離發明精神和範圍之前提下，變換或更動本發明，已用於不同用途或狀況。故，其他實施例亦揭露於請求項。

Claims (25)

  1. 一種如式(I)所示之化合物或其藥學上可接受之鹽類： 其中， R 1係 ； ； ；或 ； R 2係-CH 2CH 2CO 2R 5或-CH 2CH 2SO 3H；L係-X-CH(R 6)-或-CH(R 6)-X-，X係NH或O；以及Z係C或N；其中，R 3係C 1-6烷基、芳基、或雜芳基，該C 1-6烷基選擇性地經一至三鹵素取代，以及該芳基和雜芳基各自選擇性地經選自C 1-6烷基、C 3-10環烷基、芳基、經鹵素取代之C 1-6烷基、C 1-6烷氧基、和鹵素所構成之群組之一至三取代基取代；R 4係選自氫、鹵素、羥基、氰基、胺基、C 1-6烷基、C 1-6烷氧基、經鹵素取代之C 1-6烷基、和C 3-10環烷基所構成之群組之一至三取代基；R 5係氫、C 1-6烷基、C 3-10環烷基、和經鹵素取代之C 1-6烷基；以及R 6係C 1-6烷基、C 3-10環烷基、或C 1-10雜環烷基，該C 1-6烷基係選擇性地經鹵素、羥基、C 1-6烷氧基、和芳基所構成之群組之一至三取代基取代，且該C 3-10環烷基和C 1-10雜環烷基選擇性地經C 1-6烷基、C 1-6烷氧基、和鹵素所構成之群組之一至二取代基取代。
  2. 如申請專利範圍第1項所述之化合物或鹽類，其中R 1係
  3. 如申請專利範圍第2項所述之化合物或鹽類，其中L係-CH(R 6)-X-，X係NH或O。
  4. 如申請專利範圍第3項所述之化合物或鹽類，其中R 1係 。
  5. 如申請專利範圍第3項所述之化合物或鹽類，其中R 1係 。
  6. 如申請專利範圍第3項所述之化合物或鹽類，其中R 1係 。
  7. 如申請專利範圍第2項所述之化合物或鹽類，其中L係-X-CH(R 6)-，X係NH或O。
  8. 如申請專利範圍第2項所述之化合物或鹽類，其中R 3係選擇性地經苯基或吡啶基取代之C 1-6烷基。
  9. 如申請專利範圍第2項所述之化合物或鹽類，其中L係-CH(R 6)-X-，R 6係C 1-6烷基。
  10. 如申請專利範圍第1項所述之化合物或鹽類，其中R 1係 、 、或 ；R 3係選擇性地經苯基或吡啶基取代之C 1-6 烷基；L係-X-CH(R 6)-或-CH(R 6)-X-，R 6係C 1-6烷基；以及Z係C。
  11. 如申請專利範圍第1項所述之化合物或鹽類，其中R 1係
  12. 如申請專利範圍第11項所述之化合物或鹽類，其中L係-CH(R 6)-X-。
  13. 如申請專利範圍第12項所述之化合物或鹽類，其中X係NH，以及Z係N。
  14. 如申請專利範圍第12項所述之化合物或鹽類，其中R 6係C 1-6烷基。
  15. 如申請專利範圍第11項所述之化合物或鹽類，其中L係-X-CH(R 6)-，以及Z係C。
  16. 如申請專利範圍第15項所述之化合物或鹽類，其中R 6係C 1-6烷基。
  17. 如申請專利範圍第11項所述之化合物或鹽類，其中R 4係H。
  18. 如申請專利範圍第1項所述之化合物或鹽類，其中R 1係 或 ，R 4係H；以及L係-X-CH(R 6)-或-CH(R 6)-X-，R 6係C 1-6 烷基。
  19. 如申請專利範圍第1項所述之化合物或鹽類，其中R 3係C 1-6烷基、芳基、或6元雜芳基，該C 1-6烷基選擇性地經一至三鹵素取代，以及該芳基和6員雜芳基選擇性地經選自甲基、三氟甲基、乙基、丙基、異丙基、丁基、三級丁基、F、和Cl所構成之群組之一至三取代基取代。
  20. 如申請專利範圍第1項所述之化合物或鹽類，其中R 6係C 1-6烷基或C 3-10環烷基，該C 1-6烷基係選擇性地經選自氟、羥基、甲氧基、和苯基所構成之群組之一至三取代基取代。
  21. 如申請專利範圍第1項所述之化合物或鹽類，係選自化合物1-1至1-62、化合物2-1至2-48、化合物3-1至3-15、化合物4-1至4-30、化合物5-1至5-8、化合物6-1至6-2、以及化合物7-1至7-4所構成之群組中之任一者。
  22. 如申請專利範圍第21項所述之化合物或鹽類，係選自化合物1-2、化合物1-38、化合物1-39、化合物1-41、化合物1-43、化合物1-45、化合物1-47、化合物1-49、化合物2-18、化合物2-19、化合物2-27、化合物2-28、以及化合物4-27至4-30所構成之群組中之任一者。
  23. 一種醫藥組合物，包括如申請專利範圍第1項所述之化合物或鹽類以及一藥學上可接受之載劑。
  24. 一種如申請專利範圍第1項所述之化合物或鹽類用於製備降低血糖之藥物之用途。
  25. 一種如申請專利範圍第1項所述之化合物或鹽類用於製備升糖素相關疾病之藥物之用途。
TW107102333A 2017-01-24 2018-01-23 醯胺化合物及其應用 TWI676621B (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762449620P 2017-01-24 2017-01-24
US62/449,620 2017-01-24

Publications (2)

Publication Number Publication Date
TW201838977A true TW201838977A (zh) 2018-11-01
TWI676621B TWI676621B (zh) 2019-11-11

Family

ID=62979478

Family Applications (2)

Application Number Title Priority Date Filing Date
TW107102334A TWI753995B (zh) 2017-01-24 2018-01-23 醯胺化合物及其應用
TW107102333A TWI676621B (zh) 2017-01-24 2018-01-23 醯胺化合物及其應用

Family Applications Before (1)

Application Number Title Priority Date Filing Date
TW107102334A TWI753995B (zh) 2017-01-24 2018-01-23 醯胺化合物及其應用

Country Status (25)

Country Link
US (2) US10882837B2 (zh)
EP (1) EP3573611B1 (zh)
JP (1) JP6937524B2 (zh)
KR (1) KR102378883B1 (zh)
CN (1) CN110234318A (zh)
AU (1) AU2018212473B2 (zh)
CA (1) CA3048911C (zh)
DK (1) DK3573611T3 (zh)
EA (1) EA039455B1 (zh)
ES (1) ES2907746T3 (zh)
HR (1) HRP20220232T1 (zh)
HU (1) HUE058153T2 (zh)
IL (1) IL267937B (zh)
LT (1) LT3573611T (zh)
MX (1) MX390507B (zh)
PH (1) PH12019501566B1 (zh)
PL (1) PL3573611T3 (zh)
PT (1) PT3573611T (zh)
RS (1) RS63068B1 (zh)
SA (1) SA519402283B1 (zh)
SG (1) SG11201905965QA (zh)
SI (1) SI3573611T1 (zh)
TW (2) TWI753995B (zh)
WO (2) WO2018140338A1 (zh)
ZA (1) ZA201904383B (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI787751B (zh) * 2020-03-06 2022-12-21 昊運股份有限公司 醯胺化合物的製備方法、其晶型及其鹽類

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021142186A1 (en) * 2020-01-10 2021-07-15 Alphala Co., Ltd. Pharmaceutical composition and use thereof
US20210330648A1 (en) * 2020-01-10 2021-10-28 Alphala Co., Ltd & Chung-Chin Chen Pharmaceutical composition and use thereof
JP7368548B2 (ja) 2021-07-02 2023-10-24 昊運股▲フン▼有限公司 薬学的組成物及びその使用
TW202600131A (zh) * 2024-02-22 2026-01-01 昊運股份有限公司 治療胰島素阻抗、增強胰島素敏感性、提供血糖控制或治療胰島素抗性相關疾病的方法

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6524619B2 (en) * 2000-01-27 2003-02-25 Chronorx, Inc. Dosage forms useful for modifying conditions and functions associated with hearing loss and/or tinnitus
US6774111B1 (en) * 2000-03-14 2004-08-10 Abbott Laboratories Carbohydrate system and a method for providing nutrition to a diabetic
AU5884101A (en) * 2000-05-26 2001-12-03 Nippon Shinyaku Co Ltd Heterocyclic compounds
JP2004530680A (ja) 2001-05-04 2004-10-07 イーライ・リリー・アンド・カンパニー ２型糖尿病治療薬製造のためのａｍｐａ受容体増強物質の使用
US7504508B2 (en) * 2002-10-04 2009-03-17 Millennium Pharmaceuticals, Inc. PGD2 receptor antagonists for the treatment of inflammatory diseases
US7989472B2 (en) * 2006-03-23 2011-08-02 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
KR20200123866A (ko) * 2007-02-09 2020-10-30 메타베이시스 테라퓨틱스, 인크. 글루카곤 수용체의 길항제
US8309580B2 (en) * 2007-11-01 2012-11-13 Takeda Pharmaceutical Company Limited Heterocyclic compound
BRPI0912245A2 (pt) * 2008-03-05 2019-09-24 Takeda Pharmaceuticals Co composto, prodroga, medicamento, métodos de suprimir produção de açúcar em um mamífero e para a profilaxia ou o tratamento de diabetes em um mamífero, e, uso do composto
PT2799428T (pt) * 2008-08-13 2017-02-17 Metabasis Therapeutics Inc Antagonistas de glicagina
WO2012107850A1 (en) * 2011-02-08 2012-08-16 Pfizer Inc. Glucagon receptor modulator
US20140256767A1 (en) 2011-10-31 2014-09-11 The Broad Institute, Inc. Direct inhibitors of keap1-nrf2 interaction as antioxidant inflammation modulators

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI787751B (zh) * 2020-03-06 2022-12-21 昊運股份有限公司 醯胺化合物的製備方法、其晶型及其鹽類
US12358881B2 (en) 2020-03-06 2025-07-15 Alphala Co., Ltd. Processes for producing amide compounds, and their crystalline and salt form

Also Published As

Publication number Publication date
US20190337915A1 (en) 2019-11-07
SI3573611T1 (sl) 2022-05-31
WO2018140339A1 (en) 2018-08-02
TWI676621B (zh) 2019-11-11
IL267937A (en) 2019-09-26
EP3573611A1 (en) 2019-12-04
JP2020506226A (ja) 2020-02-27
EP3573611A4 (en) 2020-09-09
ES2907746T3 (es) 2022-04-26
MX2019008728A (es) 2019-09-18
CN110234318A (zh) 2019-09-13
US10882837B2 (en) 2021-01-05
JP6937524B2 (ja) 2021-09-22
MX390507B (es) 2025-03-20
NZ755328A (en) 2021-06-25
AU2018212473A1 (en) 2019-07-18
EA201991570A1 (ru) 2019-12-30
PL3573611T3 (pl) 2022-06-13
EA039455B1 (ru) 2022-01-28
EP3573611B1 (en) 2022-01-12
BR112019015191A2 (pt) 2020-03-24
US11384060B2 (en) 2022-07-12
WO2018140338A1 (en) 2018-08-02
RS63068B1 (sr) 2022-04-29
PH12019501566A1 (en) 2020-03-09
TW201838967A (zh) 2018-11-01
US20190345118A1 (en) 2019-11-14
ZA201904383B (en) 2020-12-23
PT3573611T (pt) 2022-03-15
CA3048911A1 (en) 2018-08-02
SG11201905965QA (en) 2019-08-27
KR102378883B1 (ko) 2022-03-25
LT3573611T (lt) 2022-03-25
AU2018212473B2 (en) 2020-06-11
HRP20220232T1 (hr) 2022-05-13
SA519402283B1 (ar) 2022-12-25
KR20190099048A (ko) 2019-08-23
IL267937B (en) 2022-09-01
CA3048911C (en) 2021-11-09
TWI753995B (zh) 2022-02-01
DK3573611T3 (da) 2022-04-11
PH12019501566B1 (en) 2024-02-14
HUE058153T2 (hu) 2022-07-28

Similar Documents

Publication Publication Date Title
TWI676621B (zh) 醯胺化合物及其應用
EP2349982B1 (en) Acrylamido derivatives useful as inhibitors of the mitochondrial permeability transition
JP5828201B2 (ja) ナフタレン誘導体
JP2009537525A (ja) グルカゴン受容体アンタゴニスト化合物、このような化合物を含む組成物及び使用方法
TW200909400A (en) Novel sulfonyl malonamide derivative and pharmaceutical use thereof
JP2008534593A (ja) グルカゴン受容体アンタゴニスト化合物、そのような化合物を含む組成物、及びその使用方法
WO2004020393A1 (ja) ジベンジルアミン化合物及びその医薬用途
CN102656140A (zh) 用作缓激肽受体拮抗剂的2-芳基-丙酰胺衍生物以及包含其的药物组合物
TW201406736A (zh) 新穎的醯胺衍生物或其鹽
RU2648242C2 (ru) Производное имидазопиридина, используемое для лечения сахарного диабета
JP2020508981A (ja) ビアリール化合物、その製造方法及び用途
TW201602089A (zh) 多環性ｈｅｒｇ活化劑
WO2017219935A1 (zh) 联芳基脲类衍生物或其盐及其制备方法和用途
NZ755328B2 (en) Amide compounds and use thereof
CN105829304B (zh) N,n’取代哌啶胺类化合物、其制备方法及用途
HK40007074A (zh) 酰胺化合物及其应用
BR112019015191B1 (pt) Compostos de amida, composição farmacêutica que compreende os mesmos e usos dos ditos compostos para reduzir o nível glicêmico e tratar distúrbios associados ao glucagon
CN113735788B (zh) 布洛芬三唑硫醇衍生物及其在制备新冠病毒抑制剂中应用
CN101747327B (zh) 芳酰胺基噻唑类衍生物及其制备方法和用途
TW202604533A (zh) ｐ５３突變體穩定劑及其用途
CA3220193A1 (en) Novel oxazole derivative and pharmaceutical composition for preventing or treating allergic diseases comprising the same
CN105263926A (zh) 苯并噻吩化合物