[go: up one dir, main page]

CN1437581A - Glucagon antagonists/inverse agonists - Google Patents

Glucagon antagonists/inverse agonists Download PDF

Info

Publication number
CN1437581A
CN1437581A CN01811591A CN01811591A CN1437581A CN 1437581 A CN1437581 A CN 1437581A CN 01811591 A CN01811591 A CN 01811591A CN 01811591 A CN01811591 A CN 01811591A CN 1437581 A CN1437581 A CN 1437581A
Authority
CN
China
Prior art keywords
alkyl
compound
cycloalkyl
independently hydrogen
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN01811591A
Other languages
Chinese (zh)
Inventor
A·S·卓根森
I·T·克里斯滕森
J·T·克德拉
P·玛德森
C·拜赫伦斯
C·萨姆斯
J·劳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
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 Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of CN1437581A publication Critical patent/CN1437581A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
    • C07C317/42—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/43—Y being a hetero atom
    • C07C323/44—X or Y being nitrogen atoms
    • 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
    • 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
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • 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
    • 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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
    • 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
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • 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
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms
    • 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
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Child & Adolescent Psychology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Indole Compounds (AREA)

Abstract

拮抗胰高血糖素对胰高血糖素受体作用的一类新化合物。由于它们的胰高血糖素受体拮抗作用，所述化合物可适于治疗和/或预防受益于胰高血糖素拮抗作用的任何疾病和病症例如高血糖、1型糖尿病、2型糖尿病、脂质代谢障碍和肥胖症。A new class of compounds that antagonize the action of glucagon on the glucagon receptor. Due to their glucagon receptor antagonism, the compounds may be suitable for the treatment and/or prevention of any disease and condition benefiting from glucagon antagonism such as hyperglycemia, type 1 diabetes, type 2 diabetes, lipid Metabolic disorders and obesity.

Description

胰高血糖素拮抗剂/反向激动剂Glucagon antagonist/inverse agonist

发明领域field of invention

本发明涉及拮抗胰高血糖素肽激素对胰高血糖素受体的作用的活性剂。更具体来说，本发明涉及胰高血糖素拮抗剂或反向激动剂。The present invention relates to agents that antagonize the action of the glucagon peptide hormone on the glucagon receptor. More specifically, the invention relates to glucagon antagonists or inverse agonists.

发明背景Background of the invention

胰高血糖素是与胰岛素合作起作用的重要激素类物质，其介导血液中葡萄糖量的内环境稳定性调节。当血糖水平下降时，胰高血糖素主要通过刺激一些细胞(主要是肝细胞)释放葡萄糖来起作用。胰高血糖素的作用与胰岛素的作用相反，胰岛素在血糖水平增加时刺激细胞摄取并贮存葡萄糖。胰高血糖素和胰岛素都是肽类激素。Glucagon is an important hormone that cooperates with insulin to mediate the homeostasis regulation of the amount of glucose in the blood. Glucagon works primarily by stimulating some cells, mainly liver cells, to release glucose when blood sugar levels drop. The action of glucagon is opposite to that of insulin, which stimulates the uptake and storage of glucose by cells when blood glucose levels increase. Glucagon and insulin are both peptide hormones.

胰高血糖素是在胰腺的α胰岛细胞中产生的，胰岛素是在β胰岛细胞中产生的。糖尿病是常见的葡萄糖代谢障碍。该疾病的特征是高血糖，并且可分为胰岛素依赖型的1型糖尿病和非胰岛素依赖型的2型糖尿病。1型糖尿病患者表现出高血糖和低胰岛素血，并且对该型疾病的常规治疗是提供胰岛素。然而，在某些1型或2型糖尿病中，绝对或相对高的胰高血糖素水平导致高血糖。在健康的对照动物以及1型或2型糖尿病动物模型中，用选择性和特异性抗体除去循环的胰高血糖素能导致血糖水平下降(Brand等人，Diabetologia 37，985(1994)；Diabetes 43，[suppl 1]，172A(1994)；Am.J.Physio.269，E469-E477(1995)；Diabetes 44[suppl 1]，134A(1995)；Diabetes45，1076(1996))。这些研究表明，抑制胰高血糖素或拮抗胰高血糖素的作用可用作糖尿病常规抗高血糖治疗的辅助治疗。可通过提供拮抗剂或反向激动剂，即抑制或阻止胰高血糖素引起的反应的物质来抑制胰高血糖素的作用。拮抗剂可以是肽类或非肽类物质。Glucagon is produced in the alpha islet cells of the pancreas and insulin is produced in the beta islet cells. Diabetes mellitus is a common disorder of glucose metabolism. The disease is characterized by hyperglycemia and can be divided into insulin-dependent type 1 diabetes and non-insulin-dependent type 2 diabetes. Patients with type 1 diabetes exhibit hyperglycemia and hypoinsulinemia, and the usual treatment for this type of disease is to provide insulin. However, in some type 1 or type 2 diabetes, absolute or relatively high glucagon levels lead to hyperglycemia. In healthy control animals as well as in animal models of type 1 or type 2 diabetes, removal of circulating glucagon with selective and specific antibodies resulted in a decrease in blood glucose levels (Brand et al., Diabetologia 37, 985 (1994); Diabetes 43 , [suppl 1], 172A (1994); Am. J. Physio. 269, E469-E477 (1995); Diabetes 44 [suppl 1], 134A (1995); Diabetes 45, 1076 (1996)). These studies suggest that inhibition of glucagon or antagonism of the action of glucagon could be used as an adjunct to conventional antihyperglycemic therapy in diabetes. The action of glucagon can be inhibited by providing an antagonist or inverse agonist, a substance that inhibits or prevents the response elicited by glucagon. Antagonists can be peptidic or non-peptidic substances.

天然胰高血糖素是具有29个氨基酸的肽，其序列如下：His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-NH2.Native glucagon is a 29 amino acid peptide with the following sequence: His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg -Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-NH 2 .

胰高血糖素通过结合并激活其受体来实施其作用，其受体是7-跨膜G蛋白偶联受体家族的胰高血糖素-分泌素分支(Jelinek等人，Science 259，1614，(1993))。受体通过激活腺苷酰环化酶第二信使系统来行使功能，并且结果是提高cAMP水平。Glucagon exerts its action by binding to and activating its receptor, the glucagon-secretin branch of the 7-transmembrane G protein-coupled receptor family (Jelinek et al., Science 259, 1614, (1993)). The receptor functions by activating the adenylyl cyclase second messenger system and, as a result, increases cAMP levels.

几篇出版物公开了起胰高血糖素拮抗剂作用的肽。大概特征确定得最充分的拮抗剂是DesHis1[Glu9]-胰高血糖素酰胺(Unson等人，Peptides 10，1171(1989)；Post等人，Proc.Natl.Acad.Sci.USA90，1662(1993))。其他拮抗剂是DesHis1，Phe6[Glu9]-胰高血糖素酰胺(Azizh等人，Bioorganic & Medicinal Chem.Lett.16，1849(1995))和NLeu9，Ala11，16-胰高血糖素酰胺(Unson等人，J.Biol.Chem.269(17)，12548(1994))。Several publications disclose peptides that act as glucagon antagonists. Probably the best characterized antagonist is DesHis 1 [Glu 9 ]-glucagon amide (Unson et al., Peptides 10, 1171 (1989); Post et al., Proc. Natl. Acad. Sci. USA90, 1662 (1993)). Other antagonists are DesHis 1 , Phe 6 [Glu 9 ]-glucagon amide (Azizh et al., Bioorganic & Medicinal Chem. Lett. 16, 1849 (1995)) and NLeu 9 , Ala 11,16 -glucagon Sulfonamide (Unson et al., J. Biol. Chem. 269(17), 12548(1994)).

肽激素的肽拮抗剂经常是非常有效的。然而，已知由于被生理酶降解它们通常不是口服有效的，并且体内分布不佳。因此，肽激素的口服有效的非肽类拮抗剂一般是优选的。在非肽类胰高血糖素拮抗剂当中，发现喹喔啉衍生物(2-苯乙烯基-3-[3-(二甲基氨基)丙基甲基氨基]-6，7-二氯喹喔啉将胰高血糖素从大鼠肝脏受体上替换下来(Collins，J.L.等人，Bioorganic and Medicinal Chemistry Letters2(9)：915-918(1992))。WO 94/14426公开了用作胰高血糖素拮抗剂的醌茜素—包含一对连接的9，10-蒽二酮基的一种天然产物及其合成类似物。US专利4,359,474公开了1-苯基吡唑衍生物的胰高血糖素拮抗特性。US专利4,374,130公开了用作胰高血糖素拮抗剂的取代的乙硅烷环己烷(disilacyclohexanes)。WO98/04528(BayerCorporation)公开了用作胰高血糖素拮抗剂的取代的吡啶和联苯。US专利5,776,954(Merck & Co.，Inc.)公开了用作胰高血糖素拮抗剂的取代的吡啶基吡咯，WO98/21957、WO98/22108、WO98/22109和US 5,880,139(Merck & Co.，Inc.)公开了用作胰高血糖素拮抗剂的2，4-二芳基-5-吡啶基咪唑。此外，WO97/16442和US专利5,837,719(Merck & Co.，Inc.)公开了用作胰高血糖素拮抗剂的2，5-取代的芳基吡咯。WO98/24780、WO98/24782、WO99/24404和WO99/32448(Amgen Inc.)公开了具有胰高血糖素拮抗活性的取代的嘧啶酮和吡啶酮化合物以及取代的嘧啶化合物。Madsen等人(J.Med.Chem.1998(41)5151-7)公开了一系列用作竞争性人胰高血糖素受体拮抗剂的2-(苯并咪唑-2-基硫基)-1-(3，4-二羟基苯基)-1-乙酮。Peptide antagonists of peptide hormones are often very potent. However, they are generally known not to be orally available due to degradation by physiological enzymes, and to distribute poorly in the body. Orally active non-peptide antagonists of peptide hormones are therefore generally preferred. Among the non-peptide glucagon antagonists, the quinoxaline derivative (2-styryl-3-[3-(dimethylamino)propylmethylamino]-6,7-dichloroquinoxa Glucagon displaces glucagon from the rat liver receptor (Collins, J.L. et al., Bioorganic and Medicinal Chemistry Letters 2(9):915-918 (1992)). WO 94/14426 discloses the use of glucagon Quinalizarin antagonists - a natural product containing a pair of linked 9,10-anthracendione groups and its synthetic analogues. US Patent No. 4,359,474 discloses 1-phenylpyrazole derivatives of glucagon Antagonistic properties. US Patent No. 4,374,130 discloses substituted disilacyclohexanes (disilacyclohexanes) for use as glucagon antagonists. WO98/04528 (Bayer Corporation) discloses substituted pyridines and biphenyls for use as glucagon antagonists. Benzene. US Patent 5,776,954 (Merck & Co., Inc.) discloses substituted pyridylpyrroles as glucagon antagonists, WO98/21957, WO98/22108, WO98/22109 and US 5,880,139 (Merck & Co. , Inc.) discloses 2,4-diaryl-5-pyridyl imidazoles used as glucagon antagonists. In addition, WO97/16442 and US Patent 5,837,719 (Merck & Co., Inc.) disclose the use of 2,5-substituted arylpyrroles as glucagon antagonists. WO98/24780, WO98/24782, WO99/24404 and WO99/32448 (Amgen Inc.) disclose substituted arylpyrroles having glucagon antagonistic activity Pyrimidinones and pyridone compounds and substituted pyrimidine compounds. Madsen et al. (J.Med.Chem.1998 (41) 5151-7) disclose a series of 2- (benzimidazol-2-ylthio)-1-(3,4-dihydroxyphenyl)-1-ethanone.

WO99/01423和WO00/39088(Novo Nordisk A/S)公开了用作胰高血糖素拮抗剂/反向激动剂的不同系列的亚烷基酰肼。WO99/01423 and WO00/39088 (Novo Nordisk A/S) disclose different series of alkylene hydrazides useful as glucagon antagonists/inverse agonists.

这些已知的胰高血糖素拮抗剂与本发明化合物在结构上不同。定义These known glucagon antagonists differ structurally from the compounds of the present invention. definition

下面是用于描述本发明化合物的术语的详细定义：The following are detailed definitions of terms used to describe the compounds of the present invention:

“卤素”是指选自F、Cl、Br和I。"Halogen" means selected from F, Cl, Br and I.

本文所用术语“C1-6-烷基”是指具有1-6个碳原子的饱和直链或支链烃基。代表性实例包括但不限于甲基、乙基、正丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、正己基、异己基等。The term "C 1-6 -alkyl" as used herein refers to a saturated straight or branched chain hydrocarbon radical having 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl base, n-hexyl, isohexyl, etc.

本文所用术语“C2-6-链烯基”是指具有2-6个碳原子和至少一个双键的直链或支链烃基。这样的基团的实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、异丙烯基、1，3-丁二烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、3-甲基-2-丁烯基、1-己烯基、2-己烯基、3-己烯基、2，4-己二烯基、5-己烯基等。The term "C 2-6 -alkenyl" as used herein refers to a straight or branched chain hydrocarbon radical having 2 to 6 carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, Butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl and the like.

本文所用术语“C2-6-炔基”是指具有2-6个碳原子和至少一个三键的直链或支链烃基。这样的基团的实例包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、2，4-己二炔基等。The term " C2-6 -alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical having 2 to 6 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2 -pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2,4 -hexadiynyl and the like.

本文所用术语“C1-6-烷氧基”是指基团-O-C1-6-烷基，其中C1-6-烷基如上所定义。代表性实例是甲氧基、乙氧基、正丙氧基、异丙氧基、丁氧基、仲丁氧基、叔丁氧基、戊氧基、异戊氧基、己氧基、异己氧基等。The term "C 1-6 -alkoxy" as used herein refers to the group -OC 1-6 -alkyl, wherein C 1-6 -alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyl Oxygen etc.

本文所用术语“C1-6-链烷酰基”是指基团-C(O)H或-C(O)-C1-5-烷基。代表性实例是甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、己酰基等。The term "C 1-6 -alkanoyl" as used herein refers to the group -C(O)H or -C(O)-C 1-5 -alkyl. Representative examples are formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, and the like.

本文所用术语“C3-8-环烷基”是指具有3-8个碳原子的饱和碳环基团。代表性实例是环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。The term " C3-8 -cycloalkyl" as used herein refers to a saturated carbocyclic group having 3-8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

本文所用术语“C4-8-环烯基”是指具有4-8个碳原子、含有1或2个双键的非芳族碳环基团。代表性实例是1-环戊烯基、2-环戊烯基、3-环戊烯基、1-环己烯基、2-环己烯基、3-环己烯基、2-环庚烯基、3-环庚烯基、2-环辛烯基、1，4-环辛二烯基等。The term " C4-8 -cycloalkenyl" as used herein refers to a non-aromatic carbocyclic group having 4-8 carbon atoms containing 1 or 2 double bonds. Representative examples are 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cycloheptenyl Alkenyl, 3-cycloheptenyl, 2-cyclooctenyl, 1,4-cyclooctadienyl and the like.

本文所用术语“杂环基”代表含有一个或多个选自氮、氧和硫的杂原子，并任选含有一个或两个双键的非芳族3-10元环。代表性实例是吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氮杂环丙烷基、四氢呋喃基等。The term "heterocyclyl" as used herein denotes a non-aromatic 3-10 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds. Representative examples are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl, and the like.

本文所用术语“芳基”包括芳族碳环系，例如苯基、联苯基、萘基、蒽基、菲基、芴基、茚基、戊搭烯基(pentalenyl)、薁基等。芳基还包括上述碳环系的部分氢化衍生物。这样的部分氢化衍生物的非限制性实例有1，2，3，4-四氢萘基、1，4-二氢萘基等。The term "aryl" as used herein includes aromatic carbocyclic ring systems such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, and the like. Aryl also includes partially hydrogenated derivatives of the aforementioned carbocyclic systems. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, and the like.

本文所用术语“亚芳基”包括二价芳族碳环系，例如亚苯基、亚联苯基、亚萘基、亚蒽基、亚菲基、亚芴基、亚茚基、亚戊搭烯基、亚薁基等。亚芳基还包括上述碳环系的部分氢化衍生物。这样的部分氢化衍生物的非限制性实例有1，2，3，4-四氢亚萘基、1，4-二氢亚萘基等。The term "arylene" as used herein includes divalent aromatic carbocyclic ring systems such as phenylene, biphenylene, naphthylene, anthracenylene, phenanthrylene, fluorenylene, indenylene, pentylene, alkenyl, azulene, etc. Arylene also includes partially hydrogenated derivatives of the aforementioned carbocyclic systems. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthylene, 1,4-dihydronaphthylene, and the like.

本文所用术语“芳氧基”是指基团-O-芳基，其中芳基如上所定义。The term "aryloxy" as used herein refers to the group -O-aryl, wherein aryl is as defined above.

本文所用术语“芳酰基”是指基团-C(O)-芳基，其中芳基如上所定义。The term "aroyl" as used herein refers to the group -C(O)-aryl, wherein aryl is as defined above.

本文所用术语“杂芳基”包括含有一个或多个选自氮、氧和硫的杂原子的杂芳环系，例如呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、异噁唑基、异噻唑基、1，2，3-三唑基、1，2，4-三唑基、吡喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、1，2，3-三嗪基、1，2，4-三嗪基、1，3，5-三嗪基、1，2，3-噁二唑基、1，2，4-噁二唑基、1，2，5-噁二唑基、1，3，4-噁二唑基、1，2，3-噻二唑基、1，2，4-噻二唑基、1，2，5-噻二唑基、1，3，4-噻二唑基、四唑基、噻二嗪基、吲哚基、异吲哚基、苯并呋喃基、苯并噻吩基、吲唑基、苯并咪唑基、苯并噻唑基、苯并异噻唑基、苯并噁唑基、苯并异噁唑基、嘌呤基、喹唑啉基、喹嗪基、喹啉基、异喹啉基、喹喔啉基、萘啶基(naphthyridinyl)、蝶啶基、咔唑基、氮杂_基、二氮杂_基、吖啶基等。杂芳基还包括上述杂环系的部分氢化衍生物。这样的部分氢化衍生物的非限制性实例有2，3-二氢苯并呋喃基、吡咯啉基、吡唑啉基、二氢吲哚基、噁唑烷基、噁唑啉基、氧杂氮杂_基(oxazepinyl)等。The term "heteroaryl" as used herein includes heteroaryl ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, Isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2 , 3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1 , 2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl Oxadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazole Base, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinazinyl, quinolinyl, isoquinolyl, quinoxaline Base, naphthyridinyl (naphthyridinyl), pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, etc. Heteroaryl also includes partially hydrogenated derivatives of the aforementioned heterocyclic ring systems. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuryl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxa Azapine-base (oxazepinyl) and so on.

“芳基-C1-6-烷基”、“杂芳基-C1-6-烷基”、“芳基-C2-6链烯基”等是指被如上所定义的芳基或杂芳基取代的C1-6-烷基或C2-6-链烯基，例如： "Aryl-C 1-6 -alkyl", "heteroaryl-C 1-6 -alkyl", "aryl-C 2-6 alkenyl" and the like refer to aryl as defined above or Heteroaryl-substituted C 1-6 -alkyl or C 2-6 -alkenyl, for example:

本文所用术语“任选取代的”是指基团未取代或者被一个或多个特定取代基取代。当所述基团被一个以上取代基取代时，取代基可相同或不同。The term "optionally substituted" as used herein means that the group is unsubstituted or substituted with one or more specified substituents. When the group is substituted with more than one substituent, the substituents may be the same or different.

一些上述定义的术语可能在结构式中出现一次以上，在出现时，每一术语应当是彼此独立的。Some of the above-defined terms may appear more than once in the formula, and when present, each term should be independent of the other.

此外，当使用术语“独立地为”和“独立地选自”时，应当理解，所述的基团可相同或不同。发明描述Furthermore, when the terms "independently of" and "independently selected from" are used, it should be understood that the stated groups may be the same or different. Description of the invention

本发明是基于下述意想不到的发现：下面公开的通式(I)化合物拮抗胰高血糖素的作用。The present invention is based on the unexpected discovery that the compounds of general formula (I) disclosed below antagonize the action of glucagon.

这些化合物的有利之处在于，对胰高血糖素受体有选择性，并且对胰高血糖素受体表现出的结合亲和力比对在结构上相关的GIP(胃抑制肽)受体和GLP-1受体的结合亲和力高。Advantageously, these compounds are selective for the glucagon receptor and exhibit a higher binding affinity for the glucagon receptor than the structurally related GIP (gastric inhibitory peptide) receptor and GLP- 1 has a high binding affinity to the receptor.

因此，本发明涉及通式(I)化合物：其中R1、R2、R3、R4和R5独立地为氢或C1-6-烷基，A是-C(O)-、-CH(OR6)-或-CHF-，其中R6是氢或C1-6-烷基，Z是亚芳基或衍生自含有1或2个选自氮、氧和硫的5或6元杂芳环的二价基团，其可任选被1或2个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR9、-NR9R10和C1-6-烷基的R7和R8取代，其中R9和R10独立地为氢或C1-6-烷基，X是-(CH2)q-(CR12R13)r-(CH2)s-，

Figure A0181159100242
Figure A0181159100243
或
Figure A0181159100245
其中r是0或1，q和s独立地为0、1、2或3，R11、R12、R13和R14独立地为氢、C1-6-烷基或C3-8环烷基，D是其中R15、R16、R17和R18独立地为·氢、卤素、-CN，-CHF2，-CF3，-OCF3，-OCHF2，-OCH2CF3，-OCF2CHF2，-S(O)2CF3，-SCF3，-NO2，-OR21，-NR21R22，-SR21，-NR21S(O)2R22，-S(O)2NR21R22，-S(O)NR21R22，-S(O)R21，-S(O)2R21，-C(O)NR21R22，-OC(O)NR21R22，-NR21C(O)R22，-CH2C(O)NR21R22，-OCH2C(O)NR21R22，-OC(O)R21，-C(O)R21或-C(O)OR21，·C1-6-烷基、C2-6-链烯基或C2-6炔基，所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR21、-NR21R22和C1-6-烷基的取代基取代，·C3-8环烷基、C4-8环烯基、杂环基、C3-8环烷基-C1-6-烷基、C3-8-环烷基-C1-6-烷氧基、C3-8环烷氧基、C3-8环烷基-C1-6烷硫基、C3-8-环烷硫基、C3-8环烷基-C2-6链烯基、C3-8-环烷基-C2-6-炔基、C4-8-环烯基-C1-6烷基、C4-8-环烯基-C2-6-链烯基、C4-8-环烯基-C2-6-炔基、杂环基-C1-6烷基、杂环基-C2-6-链烯基、杂环基-C2-6-炔基、芳基、芳氧基、芳氧基羰基、芳酰基、芳基-C1-6-烷氧基、芳基-C1-6-烷基、芳基-C2-6-链烯基、芳基-C2-6-炔基、杂芳基、杂芳基-C1-6-烷基、杂芳基-C2-6-链烯基或杂芳基-C2-6-炔基，其中所述环部分可任选被一个或多个选自卤素、-C(O)OR21、-CN、-CF3、-OCF3、-NO2、-OR21、-NR21R22和C1-6-烷基的取代基取代，其中R21和R22独立地为氢、C1-6-烷基、芳基-C1-6-烷基或芳基，或者当连接在同一氮原子上时，R21和R22与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环，或者当处于相邻位置时，R16-R18中的两个基团可一起形成桥基团-(CR23R24)a-O-(CR25R26)c-O-，其中a是0、1或2，c是1或2，R23、R24、R25和R26独立地为氢、C1-6-烷基或氟，R19和R20独立地为氢、C1-6-烷基、C3-8-环烷基或C3-8-环烷基-C1-6-烷基，E是 或 其中R27和R28独立地为氢、卤素、-CN、-CF3、-OR32、-NR32R33、C1-6-烷基、C3-8-环烷基、C4-8-环烯基或芳基，其中所述芳基可任选被一个或多个选自卤素、-CN、-CF3、-NO2、-OR32、-NR32R和C1-6-烷基的取代基取代，其中R32和R33独立地为氢或C1-6-烷基，或者当连接在同一氮原子上时，R32和R33与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环，R29、R30和R31独立地为■氢、卤素、-CHF2，-CF3，-OCF3，-OCHF2，-OCH2CF3，-OCF2CHF2，-SCF3，-OR34，-NR34R35，-SR34，-S(O)R34，-S(O)2R34，-C(O)NR34R35，-OC(O)NR34R35，-NR34C(O)R35，-OCH2C(O)NR34R35，-C(O)R34或-C(O)OR34，■C1-6-烷基、C2-6-链烯基或C2-6-炔基，所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，■C3-8-环烷基、C4-8环烯基、杂环基、C3-8-环烷基-C1-6-烷基、C3-8环烷基-C2-6-链烯基、C3-8-环烷基-C2-6-炔基、C4-8-环烯基-C1-6烷基、C4-8-环烯基-C2-6-链烯基、C4-8-环烯基-C2-6-炔基、杂环基-C1-6-烷基、杂环基-C2-6-链烯基、杂环基-C2-6-炔基、芳基、芳氧基、芳酰基、芳基-C1-6-烷氧基、芳基-C1-6-烷基、芳基-C2-6-链烯基、芳基-C2-6-炔基、杂芳基、杂芳基-C1-6-烷基、杂芳基-C2-6-链烯基或杂芳基-C2-6-炔基，其中所述环部分可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，其中R34和R35独立地为氢、C1-6-烷基或芳基，或者当连接在同一氮原子上时，R34和R35与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环，或者当连接在同一环碳原子或不同的环碳原子上时，R29、R30和R31当中的两个基团可一起形成基团-O-(CH2)t-CR36R37-(CH2)l-O-、-(CH2)t-CR36R37(CH2)l-或-S-(CH2)t-CR36R37-(CH2)l-S-，其中t和l独立地为0、1、2、3、4或5，R36和R37独立地为氢或C1-6-烷基，以及通式(I)化合物的旋光或几何异构体或互变异构形式，包括这些异构体或互变异构形式的混合物，或它们的可药用盐。Therefore, the present invention relates to compounds of general formula (I): wherein R 1 , R 2 , R 3 , R 4 and R 5 are independently hydrogen or C 1-6 -alkyl, A is -C(O)-, -CH(OR 6 )- or -CHF-, wherein R 6 is hydrogen or C 1-6 -alkyl, Z is arylene or a divalent group derived from a 5 or 6 membered heteroaromatic ring containing 1 or 2 selected from nitrogen, oxygen and sulfur, which can be optionally is optionally substituted by 1 or 2 R 7 and R 8 selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 9 , -NR 9 R 10 and C 1-6 -alkyl, wherein R 9 and R 10 are independently hydrogen or C 1-6 -alkyl, X is -(CH 2 ) q -(CR 12 R 13 ) r -(CH 2 ) s -,
Figure A0181159100242
Figure A0181159100243
or
Figure A0181159100245
wherein r is 0 or 1, q and s are independently 0, 1, 2 or 3, R 11 , R 12 , R 13 and R 14 are independently hydrogen, C 1-6 -alkyl or C 3-8 ring Alkyl, D is wherein R 15 , R 16 , R 17 and R 18 are independently hydrogen, halogen, -CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3 , -SCF 3 , -NO 2 , -OR 21 , -NR 21 R 22 , -SR 21 , -NR 21 S(O) 2 R 22 , -S(O) 2 NR 21 R 22 , -S(O)NR 21 R 22 , -S(O)R 21 , -S(O) 2 R 21 , -C(O)NR 21 R 22 , -OC(O)NR 21 R 22 , -NR 21 C(O)R 22 , -CH 2 C(O)NR 21 R 22 , -OCH 2 C(O)NR 21 R 22 , -OC(O)R 21 , -C(O)R 21 or -C(O)OR 21 , C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 alkynyl, which may optionally be replaced by one or more selected from halogen, Substituents of -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 21 , -NR 21 R 22 and C 1-6 -alkyl, C 3-8 cycloalkyl, C 4-8 Cycloalkenyl, heterocyclyl, C 3-8 cycloalkyl-C 1-6 -alkyl, C 3-8 -cycloalkyl-C 1-6 -alkoxy, C 3-8 cycloalkoxy , C 3-8 cycloalkyl-C 1-6 alkylthio, C 3-8 -cycloalkylthio, C 3-8 cycloalkyl-C 2-6 alkenyl, C 3-8 -cycloalkane Base-C 2-6 -alkynyl, C 4-8 -cycloalkenyl-C 1-6 alkyl, C 4-8 -cycloalkenyl-C 2-6 -alkenyl, C 4-8 -cycloalkenyl Alkenyl-C 2-6 -alkynyl, heterocyclyl-C 1-6 alkyl, heterocyclyl-C 2-6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, aryl, Aryloxy, aryloxycarbonyl, aroyl, aryl-C 1-6 -alkoxy, aryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, aryl- C 2-6 -alkynyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heteroaryl-C 2-6 -alkenyl or heteroaryl-C 2-6 -alkynyl, wherein The ring moiety can optionally be replaced by one or more selected from halogen, -C(O)OR 21 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 21 , -NR 21 R 22 and C Substituents of 1-6 -alkyl, wherein R 21 and R 22 are independently hydrogen, C 1-6 -alkyl, aryl-C 1-6 -alkyl or aryl, or when attached to the same nitrogen Atomic, R and R and said nitrogen atom may together form a 3- 8-membered heterocyclic ring, or when in adjacent positions, two groups in R 16 -R 18 can together form a bridging group -(CR 23 R 24 ) a -O-(CR 25 R 26 ) c -O -, wherein a is 0, 1 or 2, c is 1 or 2, R 23 , R 24 , R 25 and R 26 are independently hydrogen, C 1-6 -alkyl or fluorine, R 19 and R 20 are independently is hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or C 3-8 -cycloalkyl-C 1-6 -alkyl, E is or wherein R 27 and R 28 are independently hydrogen, halogen, -CN, -CF 3 , -OR 32 , -NR 32 R 33 , C 1-6 -alkyl, C 3-8 -cycloalkyl, C 4- 8 -cycloalkenyl or aryl, wherein the aryl can be optionally replaced by one or more selected from halogen, -CN, -CF 3 , -NO 2 , -OR 32 , -NR 32 R and C 1-6 - substituent substitution of alkyl, wherein R 32 and R 33 are independently hydrogen or C 1-6 -alkyl, or when attached to the same nitrogen atom, R 32 and R 33 and said nitrogen atom may form together A 3-8 membered heterocyclic ring optionally containing 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing 1 or 2 double bonds, R 29 , R 30 and R 31 are independently Hydrogen, Halogen, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -SCF 3 , -OR 34 , -NR 34 R 35 , -SR 34 , -S(O)R 34 , -S(O) 2 R 34 , -C(O)NR 34 R 35 , -OC(O)NR 34 R 35 , -NR 34 C(O)R 35 , -OCH 2 C(O)NR 34 R 35 , -C(O)R 34 or -C(O)OR 34 , C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl , the group can optionally be replaced by one or more selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl Substituent substitution, C 3-8 -cycloalkyl, C 4-8 cycloalkenyl, heterocyclyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 cycloalkyl -C 2-6 -alkenyl, C 3-8 -cycloalkyl-C 2-6 -alkynyl, C 4-8 -cycloalkenyl-C 1-6 alkyl, C 4-8 -cycloalkene Base-C 2-6 -alkenyl, C 4-8 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -chain Alkenyl, heterocyclyl-C 2-6 -alkynyl, aryl, aryloxy, aroyl, aryl-C 1-6 -alkoxy, aryl-C 1-6 -alkyl, aryl -C 2-6 -alkenyl, aryl-C 2-6 -alkynyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heteroaryl-C 2-6 -alkenyl or Heteroaryl-C 2-6 -alkynyl, wherein the ring moiety can be optionally replaced by one or more selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 is substituted with a substituent of C 1-6 -alkyl, wherein R 34 and R 35 are independently hydrogen, C 1-6 -alkyl or aryl, or when attached to the same nitrogen atom, R 34 and R and said nitrogen atom may together form a 3-8 membered heterocyclic ring optionally containing 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing 1 or 2 double bonds, or When connected to the same ring carbon atom or different ring carbon atoms, two groups among R 29 , R 30 and R 31 may together form the group -O-(CH 2 ) t -CR 36 R 37 -( CH 2 ) l -O-, -(CH 2 ) t -CR 36 R 37 (CH 2 ) l -or -S-(CH 2 ) t -CR 36 R 37 -(CH 2 ) l -S-, where t and l are independently 0, 1, 2, 3, 4 or 5, R 36 and R 37 are independently hydrogen or C 1-6 -alkyl, and optical or geometric isomers of compounds of general formula (I) or tautomeric forms, including mixtures of these isomers or tautomeric forms, or pharmaceutically acceptable salts thereof.

另一方面，本发明涉及通式(I’)化合物其中R1、R2、R3、R4和R5独立地为氢或C1-6-烷基，A是-C(O)-、-CH(OR6)-或-CHF-，其中R6是氢或C1-6-烷基，Z是亚芳基或衍生自含有1或2个选自氮、氧和硫的杂原子的5或6元杂芳环的二价基团，其可任选被1或2个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR9、-NR9R10和C1-6-烷基的R7和R8取代，其中R9和R10独立地为氢或C1-6-烷基，X是-(CH2)q-(CR12R13)r-(CH2)s-  ，

Figure A0181159100282
或 其中r是0或1，q和s独立地为0、1、2或3，R11、R12、R13和R14独立地为氢、C1-6-烷基或C3-8环烷基，D是
Figure A0181159100291
或
Figure A0181159100293
其中R15、R16、R17和R18独立地为·氢、卤素、-CN，-CH2CN，-CHF2，-CF3，-OCF3，-OCHF2，-OCH2CF3，-OCF2CHF2，-S(O)2CF3，-SCF3，-NO2，-OR21，-NR21R22，-SR21，-NR21S(O)2R22，-S(O)2NR21R22，-S(O)NR21R22，-S(O)R21，-S(O)2R21，-C(O)NR21R22，-OC(O)NR21R22-NR21C(O)R22，-CH2C(O)NR21R22，-OCH2C(O)NR21R22，-CH2OR21，-CH2NR21R22，-OC(O)R21，-C(O)R21或-C(O)OR21，·C1-6-烷基、C2-6-链烯基或C2-6-炔基，所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR21、-NR21R22和C1-6-烷基的取代基取代，·C3-8环烷基、C4-8-环烯基、杂环基、C3-8环烷基-C1-6-烷基、C3-8-环烷基-C1-6-烷氧基、C3-8环烷氧基、C3-8-环烷基-C1-6-烷硫基、C3-8-环烷硫基、C3-8-环烷基-C2-6-链烯基、C3-8环烷基-C2-6-炔基、C4-8-环烯基-C1-6-烷基、C4-8-环烯基-C2-6-链烯基、C4-8-环烯基-C2-6-炔基、杂环基-C1-6-烷基、杂环基-C2-6-链烯基、杂环基-C2-6-炔基、芳基、芳氧基、芳氧基羰基、芳酰基、芳基-C1-6-烷氧基、芳基-C1-6-烷基、芳基-C2-6-链烯基、芳基-C2-6-炔基、杂芳基、杂芳基-C1-6-烷基、杂芳基-C2-6-链烯基或杂芳基-C2-6-炔基，其中所述环部分可任选被一个或多个选自卤素、-C(O)OR21、-CN、-CF3、-OCF3、-NO2、-OR21、-NR21R22和C1-6-烷基的取代基取代，其中R21和R22独立地为氢、C1-6-烷基、芳基-C1-6-烷基或芳基，或者当连接在同一氮原子上时，R21和R22与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环，或者当处于相邻位置时，R15-R18中的两个基团可一起形成桥基团-(CR23R24)a-O-(CR25R26)c-O-，其中a是0、1或2，c是1或2，R23、R24、R25和R26独立地为氢、C1-6-烷基或氟，R19和R20独立地为氢、C1-6-烷基、C3-8-环烷基或C3-8-环烷基-C1-6-烷基，E是
Figure A0181159100301
Figure A0181159100302
或 其中R27和R28独立地为氢、卤素、-CN、-CF3、-OR32、-NR32R33、C1-6-烷基、C3-8-环烷基、C4-8-环烯基或芳基，其中所述芳基可任选被一个或多个选自卤素、-CN、-CF3、-NO2、-OR32、-NR32R33和C1-6-烷基的取代基取代，其中R32和R33独立地为氢或C1-6-烷基，或者当连接在同一氮原子上时，R32和R33与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环，R29、R30和R31独立地为■氢、卤素、-CHF2，-CF3，-OCF3，-OCHF2，-OCH2CF3，-OCF2CHF2，-SCF3，-OR34，-NR34R35，-SR34，-S(O)R34，-S(O)2R34，-C(O)NR34R35，-OC(O)NR34R35，-NR34C(O)R35，-OCH2C(O)NR34R35，-C(O)R34或-C(O)OR34，■C1-6-烷基、C2-6链烯基或C2-6-炔基，所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，■C3-8-环烷基、C4-8-环烯基、杂环基、C3-8-环烷基-C1-6-烷基、C3-8-环烷基-C2-6-链烯基、C3-8-环烷基-C2-6-炔基、C4-8-环烯基-C1-6-烷基、C4-8-环烯基-C2-6-链烯基、C4-8-环烯基-C2-6-炔基、杂环基-C1-6-烷基、杂环基-C2-6-链烯基、杂环基-C2-6-炔基、芳基、芳氧基、芳酰基、芳基-C1-6-烷氧基、芳基-C1-6-烷基、芳基-C2-6-链烯基、芳基-C2-6-炔基、杂芳基、杂芳基-C1-6-烷基、杂芳基-C2-6-链烯基或杂芳基-C2-6-炔基，其中所述环部分可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，其中R34和R35独立地为氢、C1-6-烷基或芳基，或者当连接在同一氮原子上时，R34和R35与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环，或者当连接在同一环碳原子或不同的环碳原子上时，R29、R30和R31当中的两个基团可一起形成基团-O-(CH2)t-CR36R37-(CH2)l-O-、-(CH2)t-CR36R37-(CH2)l-或-S-(CH2)t-CR36R37-(CH2)l-S-，其中t和l独立地为0、1、2、3、4或5，R36和R37独立地为氢或C1-6-烷基，以及通式(I’)化合物的旋光或几何异构体或互变异构形式，包括这些异构体或互变异构形式的混合物，或它们的可药用盐。In another aspect, the present invention relates to compounds of general formula (I') wherein R 1 , R 2 , R 3 , R 4 and R 5 are independently hydrogen or C 1-6 -alkyl, A is -C(O)-, -CH(OR 6 )- or -CHF-, wherein R is hydrogen or C 1-6 -alkyl, Z is arylene or a divalent group derived from a 5- or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, It may optionally be replaced by 1 or 2 R 7 and R selected from halogen , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 9 , -NR 9 R 10 and C 1-6 -alkyl 8 substitution, wherein R 9 and R 10 are independently hydrogen or C 1-6 -alkyl, X is -(CH 2 ) q -(CR 12 R 13 ) r -(CH 2 ) s - ,
Figure A0181159100282
or wherein r is 0 or 1, q and s are independently 0, 1, 2 or 3, R 11 , R 12 , R 13 and R 14 are independently hydrogen, C 1-6 -alkyl or C 3-8 ring Alkyl, D is
Figure A0181159100291
or
Figure A0181159100293
wherein R 15 , R 16 , R 17 and R 18 are independently hydrogen, halogen, -CN, -CH 2 CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3 , -SCF 3 , -NO 2 , -OR 21 , -NR 21 R 22 , -SR 21 , -NR 21 S(O) 2 R 22 , -S (O) 2 NR 21 R 22 , -S(O)NR 21 R 22 , -S(O)R 21 , -S(O) 2 R 21 , -C(O)NR 21 R 22 , -OC(O )NR 21 R 22 -NR 21 C(O)R 22 , -CH 2 C(O)NR 21 R 22 , -OCH 2 C(O)NR 21 R 22 , -CH 2 OR 21 , -CH 2 NR 21 R 22 , -OC(O)R 21 , -C(O)R 21 or -C(O)OR 21 , C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 - Alkynyl, said group can be optionally replaced by one or more selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 21 , -NR 21 R 22 and C 1-6 -alk Substituent substituent of the group, C 3-8 cycloalkyl, C 4-8 -cycloalkenyl, heterocyclyl, C 3-8 cycloalkyl-C 1-6 -alkyl, C 3-8 -cyclo Alkyl-C 1-6 -alkoxy, C 3-8 cycloalkoxy, C 3-8 -cycloalkyl-C 1-6 -alkylthio, C 3-8 -cycloalkylthio, C 3-8 -cycloalkyl-C 2-6 -alkenyl, C 3-8- cycloalkyl-C 2-6 -alkynyl, C 4-8 -cycloalkenyl-C 1-6 -alkyl, C 4-8 -cycloalkenyl-C 2-6 -alkenyl, C 4-8 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl -C 2-6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C 1-6 -alkoxy, aryl Base-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl, heteroaryl, heteroaryl-C 1-6 -alkyl, hetero Aryl-C 2-6 -alkenyl or heteroaryl-C 2-6 -alkynyl, wherein the ring moiety can be optionally replaced by one or more selected from halogen, -C(O)OR 21 , - Substituents of CN, -CF 3 , -OCF 3 , -NO 2 , -OR 21 , -NR 21 R 22 and C 1-6 -alkyl, wherein R 21 and R 22 are independently hydrogen, C 1- 6 -Alkyl, aryl-C 1-6 -alkyl or aryl, or when attached to the same nitrogen atom, R 21 and R 22 and said nitrogen atom can form together optionally containing 1 or 2 optional Additional heteroatoms from nitrogen, oxygen and sulfur, and optionally 3-8 membered heterocyclic rings containing 1 or 2 double bonds, or when in adjacent positions, two groups in R 15 -R 18 can be Together form a bridging group -(CR 23 R 24 ) a -O-(CR 25 R 26 ) c -O-, where a is 0, 1 or 2, c is 1 or 2, R 23 , R 24 , R 25 and R 26 are independently hydrogen, C 1-6 -alkyl or fluoro, R 19 and R 20 are independently hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or C 3-8 - Cycloalkyl-C 1-6 -alkyl, E is
Figure A0181159100301
Figure A0181159100302
or wherein R 27 and R 28 are independently hydrogen, halogen, -CN, -CF 3 , -OR 32 , -NR 32 R 33 , C 1-6 -alkyl, C 3-8 -cycloalkyl, C 4- 8 -cycloalkenyl or aryl, wherein the aryl can be optionally replaced by one or more selected from halogen, -CN, -CF 3 , -NO 2 , -OR 32 , -NR 32 R 33 and C 1- Substituents of 6 -alkyl, wherein R 32 and R 33 are independently hydrogen or C 1-6 -alkyl, or when connected to the same nitrogen atom, R 32 and R 33 and the nitrogen atom can be together Forming a 3-8 membered heterocyclic ring optionally containing 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing 1 or 2 double bonds, R 29 , R 30 and R 31 are independently ■Hydrogen, Halogen, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -SCF 3 , -OR 34 , -NR 34 R 35 , -SR 34 , -S(O)R 34 , -S(O) 2 R 34 , -C(O)NR 34 R 35 , -OC(O)NR 34 R 35 , -NR 34 C(O)R 35 , -OCH 2 C(O)NR 34 R 35 , -C(O)R 34 or -C(O)OR 34 , C 1-6 -alkyl, C 2-6 alkenyl or C 2-6 -alkynyl , the group can optionally be replaced by one or more selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl Substituent substitution, C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl, heterocyclyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 -cyclo Alkyl-C 2-6 -alkenyl, C 3-8 -cycloalkyl-C 2-6 -alkynyl, C 4-8 -cycloalkenyl-C 1-6 -alkyl, C 4-8 -Cycloalkenyl-C 2-6 -alkenyl, C 4-8 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2- 6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, aryl, aryloxy, aroyl, aryl-C 1-6 -alkoxy, aryl-C 1-6 -alkyl , aryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heteroaryl-C 2-6 -chain Alkenyl or heteroaryl-C 2-6 -alkynyl, wherein the ring moiety can be optionally replaced by one or more selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and substituents of C 1-6 -alkyl, wherein R 34 and R 35 are independently hydrogen, C 1-6 -alkyl or aryl, or when attached to the same nitrogen atom , R34 and R35 and said nitrogen atom may together form a 3-8 membered heteroatom optionally containing 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing 1 or 2 double bonds ring, or when attached to the same ring carbon atom or different ring carbon atoms, two of R 29 , R 30 and R 31 may together form the group -O-(CH 2 ) t -CR 36 R 37 -(CH 2 ) l -O-, -(CH 2 ) t -CR 36 R 37 -(CH 2 ) l -or -S-(CH 2 ) t -CR 36 R 37 -(CH 2 ) l - S-, wherein t and l are independently 0, 1, 2, 3, 4 or 5, R36 and R37 are independently hydrogen or C1-6 -alkyl, and the optical activity of the compound of general formula (I') Or geometric isomers or tautomeric forms, including mixtures of these isomers or tautomeric forms, or pharmaceutically acceptable salts thereof.

另一方面，本发明涉及通式(I″)化合物其中R1、R2、R3、R4和R5独立地为氢或C1-6-烷基，A是-C(O)-、-CH(OR6)-或-CHF-，其中R6是氢、C1-6-烷基或卤素，Z是亚芳基或衍生自含有1或2个选自氮、氧和硫的杂原子的5或6元杂芳环的二价基团，其可任选被1或2个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR9、-NR9R10和C1-6-烷基的R7和R8取代，其中R9和R10独立地为氢或C1-6-烷基，X是-(CH2)q-(CR12R13)r-(CH2)s-，

Figure A0181159100323
或 其中r是0或1，q和s独立地为0、1、2或3，R11、R12、R13和R14独立地为氢或C1-6-烷基，D是
Figure A0181159100334
或
Figure A0181159100336
其中R15、R16、R17和R18独立地为·氢、卤素、-CN，-CH2CN，-CHF2，-CF3，-OCF3，-OCHF2，-OCH2CF3，-OCF2CHF2，-OS(O)2CF3，-SCF3，-NO2，-OR21，-NR21R22，-SR21，-NR21S(O)2R22，-S(O)2NR21R22，-S(O)NR21R22，-S(O)R21，-S(O)2R21，-OS(O)2R21，-C(O)NR21R22，-OC(O)NR21R22，-NR21C(O)R22，-CH2C(O)NR21R22，-OCH2C(O)NR21R22，-CH2OR21，-CH2NR21R22，-OC(O)R21，-C(O)R21或-C(O)OR21，·C1-6-烷基、C2-6-链烯基或C2-6-炔基，所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR21、-NR21R22和C1-6-烷基的取代基取代，·C3-8-环烷基、C4-8-环烯基、杂环基、C3-8-环烷基-C1-6-烷基、C3-8-环烷基-C1-6-烷氧基、C3-8环烷氧基、C3-8环烷基-C1-6-烷硫基、C3-8-环烷硫基、C3-8-环烷基-C2-6-链烯基、C3-8-环烷基-C2-6-炔基、C4-8-环烯基-C1-6-烷基、C4-8-环烯基-C2-6链烯基、C4-8-环烯基-C2-6-炔基、杂环基-C1-6-烷基、杂环基-C2-6-链烯基、杂环基-C2-6-炔基、芳基、芳氧基、芳氧基羰基、芳酰基、芳基-C1-6-烷氧基、芳基-C1-6-烷基、芳基-C2-6-链烯基、芳基-C2-6-炔基、杂芳基、杂芳基-C1-6-烷基、杂芳基-C2-6-链烯基或杂芳基-C2-6-炔基，其中所述环部分可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR21、-NR21R22和C1-6-烷基的取代基取代，其中R21和R22独立地为氢、C1-6-烷基或芳基，或者当连接在同一氮原子上时，R21和R22与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环，或者当处于相邻位置时，R15-R18中的两个基团可一起形成桥基团-(CR23R24)a-O-(CR25R26)c-O-，其中a是0、1或2，c是1或2，R23、R24、R25和R26独立地为氢、C1-6-烷基或氟，R19和R20独立地为氢、C1-6-烷基、C3-8-环烷基或C3-8-环烷基-C1-6-烷基，E是
Figure A0181159100341
Figure A0181159100351
或
Figure A0181159100352
其中R27和R28独立地为氢、卤素、-CN、-CF3、-OR32、-NR32R33、C1-6-烷基、C3-8-环烷基、C4-8-环烯基或芳基，其中所述芳基可任选被一个或多个选自卤素、-CN、-CF3、-NO2、-OR32、-NR32R33和C1-6-烷基的取代基取代，其中R32和R33独立地为氢或C1-6-烷基，或者当连接在同一氮原子上时，R32和R33与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环，R29、R30和R31独立地为■氢、-CHF2，-CF3，-OCF3，-OCHF2，-OCH2CF3，-OCF2CHF2，-SCF3，-OR34，-NR34R35，-SR34，-S(O)R34，-S(O)2R34，-C(O)NR34R35，-OC(O)NR34R35，-NR34C(O)R35，-OCH2C(O)NR34R35，-C(O)R34或-C(O)OR34，■C1-6-烷基、C2-6-链烯基或C2-6-炔基，所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，■C3-8-环烷基、C4-8-环烯基、杂环基、C3-8环烷基-C1-6-烷基、C3-8-环烷基-C2-6-链烯基、C3-8-环烷基-C2-6-炔基、C4-8-环烯基-C1-6-烷基、C4-8-环烯基-C2-6-链烯基、C4-8-环烯基-C2-6-炔基、杂环基-C1-6-烷基、杂环基-C2-6-链烯基、杂环基-C2-6-炔基、芳基、芳氧基、芳酰基、芳基-C1-6-烷氧基、芳基-C1-6-烷基、芳基-C2-6-链烯基、芳基-C2-6-炔基、杂芳基、杂芳基-C1-6-烷基、杂芳基-C2-6-链烯基或杂芳基-C2-6-炔基，其中所述环部分可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，其中R34和R35独立地为氢、C1-6-烷基或芳基，或者当连接在同一氮原子上时，R34和R35与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环，或者当连接在同一环碳原子或不同的环碳原子上时，R29、R30和R31当中的两个基团可一起形成基团-O-(CH2)t-CR36R37-(CH2)l-O-、-(CH2)t-CR36R37(CH2)l-或-S-(CH2)t-CR36R37-(CH2)l-S-，其中t和l独立地为0、1、2、3、4或5，R36和R37独立地为氢或C1-6-烷基，以及通式(I″)化合物的旋光或几何异构体或互变异构形式，包括这些异构体或互变异构形式的混合物，或它们的可药用盐。In another aspect, the present invention relates to compounds of general formula (I") wherein R 1 , R 2 , R 3 , R 4 and R 5 are independently hydrogen or C 1-6 -alkyl, A is -C(O)-, -CH(OR 6 )- or -CHF-, wherein R6 is hydrogen, C1-6 -alkyl or halogen, Z is arylene or a divalent radical derived from a 5- or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur group, which may optionally be replaced by 1 or 2 R 7 selected from the group consisting of halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 9 , -NR 9 R 10 and C 1-6 -alkyl and R 8 substituted, wherein R 9 and R 10 are independently hydrogen or C 1-6 -alkyl, X is -(CH 2 ) q -(CR 12 R 13 ) r -(CH 2 ) s -,
Figure A0181159100323
or wherein r is 0 or 1, q and s are independently 0, 1, 2 or 3, R 11 , R 12 , R 13 and R 14 are independently hydrogen or C 1-6 -alkyl, D is
Figure A0181159100334
or
Figure A0181159100336
wherein R 15 , R 16 , R 17 and R 18 are independently hydrogen, halogen, -CN, -CH 2 CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -OS(O) 2 CF 3 , -SCF 3 , -NO 2 , -OR 21 , -NR 21 R 22 , -SR 21 , -NR 21 S(O) 2 R 22 , -S (O) 2 NR 21 R 22 , -S(O)NR 21 R 22 , -S(O)R 21 , -S(O) 2 R 21 , -OS(O) 2 R 21 , -C(O) NR 21 R 22 , -OC(O)NR 21 R 22 , -NR 21 C(O)R 22 , -CH 2 C(O)NR 21 R 22 , -OCH 2 C(O)NR 21 R 22 ,- CH 2 OR 21 , -CH 2 NR 21 R 22 , -OC(O)R 21 , -C(O)R 21 or -C(O)OR 21 , C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl, said group may optionally be selected from one or more halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 21 , -NR 21 Substitution of R 22 and a substituent of C 1-6 -alkyl, C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl, heterocyclyl, C 3-8 -cycloalkyl-C 1 -6 -alkyl, C 3-8 -cycloalkyl-C 1-6 -alkoxy, C 3-8 cycloalkoxy, C 3-8 cycloalkyl-C 1-6 -alkylthio, C 3-8 -cycloalkylthio, C 3-8 -cycloalkyl-C 2-6 -alkenyl, C 3-8 -cycloalkyl-C 2-6 -alkynyl, C 4-8 - Cycloalkenyl-C 1-6 -alkyl, C 4-8 -cycloalkenyl-C 2-6 alkenyl, C 4-8 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl- C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl -C 1-6 -alkoxy, aryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl, heteroaryl, heteroaryl -C 1-6 -alkyl, heteroaryl-C 2-6 -alkenyl or heteroaryl-C 2-6 -alkynyl, wherein the ring moiety can optionally be selected from one or more Halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 21 , -NR 21 R 22 and C 1-6 -alkyl substituents, wherein R 21 and R 22 are independently hydrogen, C 1-6 -Alkyl or aryl, or when attached to the same nitrogen atom, R 21 and R 22 and said nitrogen atom may together form an additional group optionally containing 1 or 2 selected from nitrogen, oxygen and sulfur , and optionally a 3-8 membered heterocyclic ring containing 1 or 2 double bonds, or when in adjacent positions, two groups in R 15 -R 18 can together form a bridging group -(CR 23 R 24 ) a -O-(CR 25 R 26 ) c -O-, wherein a is 0, 1 or 2, c is 1 or 2, R 23 , R 24 , R 25 and R 26 are independently hydrogen, C 1-6 -alkyl or fluorine, R 19 and R 20 are independently hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or C 3-8 -cycloalkyl-C 1-6 -Alkyl, E is
Figure A0181159100341
Figure A0181159100351
or
Figure A0181159100352
wherein R 27 and R 28 are independently hydrogen, halogen, -CN, -CF 3 , -OR 32 , -NR 32 R 33 , C 1-6 -alkyl, C 3-8 -cycloalkyl, C 4- 8 -cycloalkenyl or aryl, wherein the aryl can be optionally replaced by one or more selected from halogen, -CN, -CF 3 , -NO 2 , -OR 32 , -NR 32 R 33 and C 1- Substituents of 6 -alkyl, wherein R 32 and R 33 are independently hydrogen or C 1-6 -alkyl, or when connected to the same nitrogen atom, R 32 and R 33 and the nitrogen atom can be together Forming a 3-8 membered heterocyclic ring optionally containing 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing 1 or 2 double bonds, R 29 , R 30 and R 31 are independently Hydrogen, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -SCF 3 , -OR 34 , -NR 34 R 35 , -SR 34 , - S(O)R 34 , -S(O) 2 R 34 , -C(O)NR 34 R 35 , -OC(O)NR 34 R 35 , -NR 34 C(O)R 35 , -OCH 2 C (O)NR 34 R 35 , —C(O)R 34 or —C(O)OR 34 , C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl, Said groups may be optionally substituted with one or more selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl C 3-8 -cycloalkyl, C 4-8-cycloalkenyl, heterocyclyl, C 3-8 -cycloalkyl-C 1-6 - alkyl, C 3-8 -cycloalkyl -C 2-6 -alkenyl, C 3-8 -cycloalkyl-C 2-6 -alkynyl, C 4-8 -cycloalkenyl-C 1-6 -alkyl, C 4-8 -cyclo Alkenyl-C 2-6 -alkenyl, C 4-8 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 - Alkenyl, heterocyclyl-C 2-6 -alkynyl, aryl, aryloxy, aroyl, aryl-C 1-6 -alkoxy, aryl-C 1-6 -alkyl, aryl Base-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heteroaryl-C 2-6 -alkenyl or heteroaryl-C 2-6 -alkynyl, wherein the ring moiety can be optionally replaced by one or more selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , - Substituents of NR 34 R 35 and C 1-6 -alkyl, wherein R 34 and R 35 are independently hydrogen, C 1-6 -alkyl or aryl, or when attached to the same nitrogen atom, R 34 and R 35 and said nitrogen atom may together form a 3-8 membered heterocyclic ring optionally containing 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing 1 or 2 double bonds, Or when connected to the same ring carbon atom or different ring carbon atoms, two groups among R 29 , R 30 and R 31 may together form the group -O-(CH 2 ) t -CR 36 R 37 - (CH 2 ) l -O-, -(CH 2 ) t -CR 36 R 37 (CH 2 ) l -or -S-(CH 2 ) t -CR 36 R 37 -(CH 2 ) l -S-, wherein t and l are independently 0, 1, 2, 3, 4 or 5, R 36 and R 37 are independently hydrogen or C 1-6 -alkyl, and the optical or geometric isotropy of the compound of general formula (I") isomers or tautomeric forms, including mixtures of these isomers or tautomeric forms, or pharmaceutically acceptable salts thereof.

在一个实施方案中，R1、R2、R3、R4和R5是氢。In one embodiment, R1 , R2 , R3 , R4 and R5 are hydrogen.

在一个实施方案中，A是-CHF-。In one embodiment, A is -CHF-.

在另一个实施方案中，A是-CH(OR6)-，其中R6的定义同式(I)中所述，例如是-CH(OH)-。In another embodiment, A is -CH(OR 6 )-, wherein R 6 is as defined in formula (I), for example is -CH(OH)-.

在一个实施方案中，Z是其中R7和R8的定义同式(I)中所述，例如是

Figure A0181159100362
在一个实施方案中，X是
Figure A0181159100363
-(CH2)s-，
Figure A0181159100371
或其中q是0或1，r是0或1，s是0、1或2，且R12和R13独立地为氢或C1-6-烷基。In one embodiment, Z is Wherein R 7 and R 8 are as defined in the formula (I), for example is
Figure A0181159100362
In one embodiment, X is
Figure A0181159100363
-( CH2 ) s- ,
Figure A0181159100371
or wherein q is 0 or 1, r is 0 or 1, s is 0, 1 or 2, and R 12 and R 13 are independently hydrogen or C 1-6 -alkyl.

在另一个实施方案中，X是-C(O)NH-、-C(O)NHCH2-、-C(O)NHCH(CH3)-、-C(O)NHC(CH3)2-、-C(O)NHCH2CH2-、-C(O)CH2-、-C(O)CH2CH2-、-C(O)CH＝CH-、-(CH2)s-、-C(O)-、-C(O)O-或-NHC(O)-，其中s是0或1。In another embodiment, X is -C(O)NH-, -C(O) NHCH2- , -C(O)NHCH( CH3 )-, -C(O)NHC( CH3 ) 2- , -C(O)NHCH 2 CH 2 -, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -C(O)CH=CH-, -(CH 2 ) s -, -C(O)-, -C(O)O- or -NHC(O)-, wherein s is 0 or 1 .

在另一个实施方案中，X是-C(O)NH-、-C(O)NHCH2-、-C(O)NHCH(CH3)-、-C(O)NHCH2CH2-、-C(O)CH2-、-C(O)CH＝CH-、-(CH2)s-、-C(O)-、-C(O)O-或-NHC(O)-，其中s是0或1In another embodiment, X is -C(O)NH-, -C(O) NHCH2- , -C(O)NHCH( CH3 )-, -C( O ) NHCH2CH2- , - C(O)CH 2 -, -C(O)CH=CH-, -(CH 2 ) s -, -C(O)-, -C(O)O- or -NHC(O)-, where s is 0 or 1

在另一个实施方案中，X是-C(O)NH-、-C(O)NHCH2-、-C(O)NHCH(CH3)-、-C(O)NHCH2CH2-、-C(O)CH2-、-CH2-、-C(O)-或-NHC(O)-。In another embodiment, X is -C(O)NH-, -C(O) NHCH2- , -C(O)NHCH( CH3 )-, -C( O ) NHCH2CH2- , - C(O) CH2- , -CH2- , -C(O)- or -NHC(O)-.

在另一个实施方案中，X是-C(O)NH-、-C(O)NHCH2-、-C(O)NHCH(CH3)-、-C(O)CH2-或-C(O)-，例如-C(O)NH-。In another embodiment, X is -C(O)NH-, -C(O) NHCH2- , -C(O)NHCH( CH3 )-, -C(O) CH2- or -C( O)-, eg -C(O)NH-.

在一个实施方案中，D是

Figure A0181159100373
或
Figure A0181159100375
其中R15、R16、R17、R18、R19和R20的定义同式(I)中所述。In one embodiment, D is
Figure A0181159100373
or
Figure A0181159100375
The definitions of R 15 , R 16 , R 17 , R 18 , R 19 and R 20 are the same as those described in formula (I).

在另一个实施方案中，D是

Figure A0181159100381
其中R15、R16和R17的定义同式(I)中所述。In another embodiment, D is
Figure A0181159100381
Wherein R 15 , R 16 and R 17 are as defined in formula (I).

在一个实施方案中，R15、R16和R17独立地为氢、卤素、-CN、-NO2、-CF3、-OCF3-、-SCF3、C1-6-烷基、C1-6-烷氧基、-S-C1-6-烷基、-C(O)OR21、-C(O)R21、-CH2OR21、-C(O)NR21R22、-S(O)R21、-S(O)2R21、-S(O)2CF3、-S(O)2NR21R22、C3-8-环烷基、C3-8-环烷基-C1-6-烷氧基或C3-8-环烷基-C1-6-烷硫基，或芳基、杂芳基或芳氧基，其可任选被-CF3、-OCF3、C1-6-烷基、卤素或-C(O)OR21取代，或者当处于相邻位置时，R15、R16和R17当中的两个基团可一起形成桥基团-(CR23R24)a-O-(CR25R26)c-O-，其中R21和R22独立地为氢或C1-6-烷基，且a、c、R23、R24、R25和R26的定义同式(I)中所述。In one embodiment, R 15 , R 16 and R 17 are independently hydrogen, halogen, -CN, -NO 2 , -CF 3 , -OCF 3 -, -SCF 3 , C 1-6 -alkyl, C 1-6 -Alkoxy, -SC 1-6 -Alkyl, -C(O)OR 21 , -C(O)R 21 , -CH 2 OR 21 , -C(O)NR 21 R 22 , - S(O)R 21 , -S(O) 2 R 21 , -S(O) 2 CF 3 , -S(O) 2 NR 21 R 22 , C 3-8 -cycloalkyl, C 3-8 - Cycloalkyl-C 1-6 -alkoxy or C 3-8 -cycloalkyl-C 1-6 -alkylthio, or aryl, heteroaryl or aryloxy, which may optionally be replaced by -CF 3 , -OCF 3 , C 1-6 -alkyl, halogen or -C(O)OR 21 substituted, or when in adjacent positions, two groups among R 15 , R 16 and R 17 can form together Bridging group -(CR 23 R 24 ) a -O-(CR 25 R 26 ) c -O-, wherein R 21 and R 22 are independently hydrogen or C 1-6 -alkyl, and a, c, R The definitions of 23 , R 24 , R 25 and R 26 are the same as those in formula (I).

在另一个实施方案中，R15、R16和R17独立地为氢、卤素、-CN、-CF3、-OCF3或C1-6-烷氧基，或者R15和R16一起形成桥基团-CF2-O-CF2-O-，且R17是氢。In another embodiment, R 15 , R 16 and R 17 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3 or C 1-6 -alkoxy, or R 15 and R 16 together form The bridging group -CF2 -O- CF2 -O-, and R17 is hydrogen.

在另一个实施方案中，R15、R16和R17独立地为氢、卤素、-CN、-CF3、-OCF3或C1-6-烷氧基。In another embodiment, R 15 , R 16 and R 17 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3 or C 1-6 -alkoxy.

在另一个实施方案中，D是

Figure A0181159100382
或
Figure A0181159100383
其中R15、R16、R19和R20的定义同式(I)中所述。In another embodiment, D is
Figure A0181159100382
or
Figure A0181159100383
The definitions of R 15 , R 16 , R 19 and R 20 are the same as those in formula (I).

在另一个实施方案中，D是

Figure A0181159100384
其中R15和R16都是氢，且R19是C1-6烷基、C3-8-环烷基或C3-8-环烷基-C1-6-烷基。In another embodiment, D is
Figure A0181159100384
wherein R 15 and R 16 are both hydrogen, and R 19 is C 1-6 alkyl, C 3-8 -cycloalkyl or C 3-8 -cycloalkyl-C 1-6 -alkyl.

在另一个实施方案中，D是

Figure A0181159100391
其中R15和R16都是氢，且R19和R20都是C1-6-烷基。In another embodiment, D is
Figure A0181159100391
wherein R 15 and R 16 are both hydrogen, and R 19 and R 20 are both C 1-6 -alkyl.

在一个实施方案中，E

Figure A0181159100392
或 其中R27、R28、R29、R30和R31的定义同式(I)中所述。In one embodiment, E
Figure A0181159100392
or The definitions of R 27 , R 28 , R 29 , R 30 and R 31 are the same as those described in formula (I).

在另一个实施方案中，E是其中R27和R28的定义同式(I)中所述。In another embodiment, E is Wherein R 27 and R 28 are as defined in formula (I).

在另一个实施方案中，E是

Figure A0181159100396
其中R27和R28的定义同式(I)中所述。In another embodiment, E is
Figure A0181159100396
Wherein R 27 and R 28 are as defined in formula (I).

在一个实施方案中，R27和R28独立地为氢、C1-6-烷基、C3-8-环烷基、C4-8-环烯基或苯基，其中所述苯基可任选如式(I)中所述被取代。In one embodiment, R 27 and R 28 are independently hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl or phenyl, wherein said phenyl Can be optionally substituted as described in formula (I).

在另一个实施方案中，R27和R28独立地为氢、C1-6-烷基、C3-8-环烷基或C4-8-环烯基。In another embodiment, R 27 and R 28 are independently hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl.

在另一个实施方案中，R27是氢，且R28是C1-6-烷基或C3-8-环烷基，例如叔丁基、环己基或环己烯基。In another embodiment, R 27 is hydrogen and R 28 is C 1-6 -alkyl or C 3-8 -cycloalkyl, eg tert-butyl, cyclohexyl or cyclohexenyl.

在另一个实施方案中，E是

Figure A0181159100401
其中R29、R30和R31的定义同式(I)中所述。In another embodiment, E is
Figure A0181159100401
The definitions of R 29 , R 30 and R 31 are the same as those described in formula (I).

在另一个实施方案中，E是

Figure A0181159100402
其中R29、R30和R31的定义同式(I)中所述。In another embodiment, E is
Figure A0181159100402
The definitions of R 29 , R 30 and R 31 are the same as those described in formula (I).

在一个实施方案中，R29、R30和R31独立地为■氢、-CHF2，-CF3，-OCF3，-OCHF2，-OCH2CF3，-OCF2CHF2，-SCF3，-OR34，-NR34R35，-SR34，-S(O)R34，-S(O)2R34，-C(O)NR34R35，-OC(O)NR34R35，-NR34C(O)R35，-OCH2C(O)NR34R35，-C(O)R34或-C(O)OR34，■C1-6-烷基、C2-6-链烯基或C2-6-炔基，其中所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，■C3-8-环烷基或C4-8-环烯基，其中所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的基团取代，其中R34和R35独立地为氢、C1-6-烷基或芳基，或者当连接在同一氮原子上时，R34和R35与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环。In one embodiment, R 29 , R 30 and R 31 are independently hydrogen, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -SCF 3 , -OR 34 , -NR 34 R 35 , -SR 34 , -S(O)R 34 , -S(O) 2 R 34 , -C(O)NR 34 R 35 , -OC(O)NR 34 R 35 , -NR 34 C(O)R 35 , -OCH 2 C(O)NR 34 R 35 , -C(O)R 34 or -C(O)OR 34 , C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl, wherein said group can be optionally replaced by one or more selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , - Substituents of OR 34 , -NR 34 R 35 and C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl, wherein said groups can optionally be replaced by one or multiple groups selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl, wherein R 34 and R 35 independently hydrogen, C 1-6 -alkyl or aryl, or when attached to the same nitrogen atom, R 34 and R 35 and said nitrogen atom can form together optionally containing 1 or 2 selected from nitrogen, Additional heteroatoms of oxygen and sulfur, and optionally 3-8 membered heterocyclic rings containing 1 or 2 double bonds.

在另一个实施方案中，R29、R30和R31独立地为氢、C1-6-烷氧基、卤素、-CF3、-OCF3或-NR34R35，其中R34和R35的定义同式(I)中所述，或C1-6-烷基、C3-8-环烷基或C4-8-环烯基，其中所述基团可任选如式(I)中所述被取代。In another embodiment, R 29 , R 30 and R 31 are independently hydrogen, C 1-6 -alkoxy, halogen, -CF 3 , -OCF 3 or -NR 34 R 35 , wherein R 34 and R 35 is as defined in formula (I), or C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl, wherein said group can optionally be as in formula ( substituted as described in I).

在另一个实施方案中，R29、R30和R31独立地为氢或C1-6-烷基、C3-8-环烷基或C4-8-环烯基，其中所述基团可任选如式(I)中所述被取代。In another embodiment, R 29 , R 30 and R 31 are independently hydrogen or C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl, wherein said group The groups can be optionally substituted as described in formula (I).

在另一个实施方案中，R29、R30和R31独立地为氢或C1-6-烷基、C3-8-环烷基或C4-8-环烯基，■所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，■其中R34和R35独立地为氢、C1-6-烷基或芳基，■或者当连接在同一氮原子上时，R34和R35与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环。In another embodiment, R 29 , R 30 and R 31 are independently hydrogen or C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl, said group may be optionally substituted by one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl, ■wherein R 34 and R 35 are independently hydrogen, C 1-6 -alkyl or aryl, ■or when attached to the same nitrogen atom, R 34 and R 35 and the nitrogen atom can form together optionally containing A 3-8 membered heterocyclic ring with 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing 1 or 2 double bonds.

在另一个实施方案中，R29和R31都是氢，且R30不是氢。In another embodiment, R 29 and R 31 are both hydrogen, and R 30 is not hydrogen.

在另一个实施方案中，R29和R31都是氢，且R30是C3-8-环烷基或C4-8-环烯基，■所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，■其中R34和R35独立地为氢、C1-6烷基或芳基，■或者当连接在同一氮原子上时，R34和R35与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环。In another embodiment, both R 29 and R 31 are hydrogen, and R 30 is C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl, said groups may optionally be replaced by one or more Substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl, wherein R 34 and R 35 are independently is hydrogen, C 1-6 alkyl or aryl, or when connected on the same nitrogen atom, R 34 and R 35 and the nitrogen atom can form together optionally containing 1 or 2 selected from nitrogen, oxygen and an additional heteroatom of sulfur, and optionally a 3-8 membered heterocyclic ring containing 1 or 2 double bonds.

在另一个实施方案中，R29和R31都是氢，且R30是C4-8-环烯基，■所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，■其中R34和R35独立地为氢、C1-6-烷基或芳基，■或者当连接在同一氮原子上时，R34和R35与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环。In another embodiment, both R 29 and R 31 are hydrogen, and R 30 is C 4-8 -cycloalkenyl, said group may optionally be selected from one or more of halogen, -CN, - Substituents of CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl, wherein R 34 and R 35 are independently hydrogen, C 1-6 - Alkyl or aryl, or when attached to the same nitrogen atom, R34 and R35 and said nitrogen atom may together form optionally containing 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur, And optionally a 3-8 membered heterocyclic ring containing 1 or 2 double bonds.

在另一个实施方案中，R29和R31都是氢，且R30是环己烯基，■所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，■其中R34和R35独立地为氢、C1-6-烷基或芳基，■或者当连接在同一氮原子上时，R34和R35与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环。In another embodiment, both R 29 and R 31 are hydrogen, and R 30 is cyclohexenyl, said group may optionally be selected from one or more of halogen, -CN, -CF 3 , - Substituents of OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl, wherein R 34 and R 35 are independently hydrogen, C 1-6 -alkyl or aryl or when attached to the same nitrogen atom, R34 and R35 and said nitrogen atom may together form optionally containing 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing 3-8 membered heterocycle with 1 or 2 double bonds.

在另一个实施方案中，R30被一个C1-6-烷基取代基例如叔丁基或甲基取代。In another embodiment, R 30 is substituted with a C 1-6 -alkyl substituent such as tert-butyl or methyl.

在另一个实施方案中，R29、R30和R31独立地为氢、C1-6-烷基、C3-8-环烷基或C4-8-环烯基。In another embodiment, R 29 , R 30 and R 31 are independently hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl.

在另一个实施方案中，R29和R31都是氢，且R30是C1-6-烷基、C3-8-环烷基或C4-8-环烯基，例如叔丁基、环己基或环己烯基。In another embodiment, both R 29 and R 31 are hydrogen, and R 30 is C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl, for example tert-butyl , cyclohexyl or cyclohexenyl.

在一个实施方案中，本发明提供了式(I1)化合物：

Figure A0181159100421
其中R1、R2、R3、R4、R5、R6、R7、R8、X、D和E的定义同式(I)或任一上述实施方案中所述。在一个实施方案中，本发明涉及式(I2)化合物：
Figure A0181159100431
其中R1、R2、R3、R4、R5、R6、R7、R8、D和E的定义同式(I)或任一上述实施方案中所述。In one embodiment, the present invention provides a compound of formula (I 1 ):
Figure A0181159100421
Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, D and E are as defined in formula (I) or any one of the above embodiments. In one embodiment, the invention relates to compounds of formula (I 2 ):
Figure A0181159100431
Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , D and E are as defined in formula (I) or any one of the above embodiments.

在一个实施方案中，本发明涉及式(I3)化合物：

Figure A0181159100432
其中R1、R2、R3、R4、R5、R6、R7、R8、R15、R16、R17、R29、R30、和R31的定义同式(I)或任一上述实施方案中所述。In one embodiment, the invention relates to compounds of formula (I 3 ):
Figure A0181159100432
Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 15 , R 16 , R 17 , R 29 , R 30 , and R 31 are as defined in formula (I) Or as described in any of the above embodiments.

在式(I1)、(I2)和(I3)的一个实施方案中，R1、R2、R3、R4、R5、R6、R7和R8是氢。In one embodiment of formulas (I 1 ), (I 2 ) and (I 3 ), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are hydrogen.

在一个实施方案中，本发明涉及式(I4)化合物：

Figure A0181159100433
其中R1、R2、R3、R4、R5、R7、R8、X、D和E的定义同式(I)或任一上述实施方案中所述。In one embodiment, the invention relates to compounds of formula (I 4 ):
Figure A0181159100433
Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , X, D and E are as defined in formula (I) or any one of the above embodiments.

在一个实施方案中，本发明涉及式(I5)化合物：

Figure A0181159100441
其中R1、R2、R3、R4、R5、R7、R8、D和E的定义同式(I)或任一上述实施方案中所述。In one embodiment, the invention relates to compounds of formula (I 5 ):
Figure A0181159100441
Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , D and E are as defined in formula (I) or any one of the above embodiments.

在式(I4)和(I5)的一个实施方案中，R1、R2、R3、R4、R5、R7和R8是氢。In one embodiment of formulas (I 4 ) and (I 5 ), R 1 , R 2 , R 3 , R 4 , R 5 , R 7 and R 8 are hydrogen.

本发明化合物可具有一个或多个不对称中心，其任何旋光异构体，不论是分离的、纯的或部分纯化的旋光异构体，还是其外消旋混合物，都包括在本发明范围内。The compounds of the present invention may have one or more asymmetric centers, and any optical isomer thereof, whether isolated, pure or partially purified, or a racemic mixture thereof, is included within the scope of the present invention .

此外，当分子中存在双键或全不饱和或部分不饱和环系时，可形成几何异构体。任何几何异构体，不论是分离的、纯的或部分纯化的几何异构体，还是其混合物，都包括在本发明范围内。同样，具有其旋转受限制的键的分子也可形成几何异构体。它们也包括在本发明范围内。In addition, geometric isomers may form when double bonds or fully or partially unsaturated ring systems are present in the molecule. Any geometric isomer, whether isolated, pure or partially purified, or a mixture thereof, is included within the scope of the present invention. Likewise, molecules with bonds whose rotation is restricted can also form geometric isomers. They are also included in the scope of the present invention.

此外，某些本发明化合物可以以不同的互变异构形式存在，并且本发明化合物所能够形成的任何互变异构形式都包括在本发明范围内。In addition, some of the compounds of the present invention may exist in different tautomeric forms, and any tautomeric forms that the compounds of the present invention are capable of forming are included within the scope of the present invention.

本发明还包括本发明化合物的可药用盐。这样的盐包括可药用酸加成盐、可药用金属盐、铵盐和烷基化铵盐。酸加成盐包括无机酸以及有机酸的盐。合适的无机酸的代表性实例包括盐酸、氢溴酸、氢碘酸、磷酸、硫酸、硝酸等。合适的有机酸的代表性实例包括甲酸、乙酸、三氯乙酸、三氟乙酸、丙酸、苯甲酸、肉桂酸、柠檬酸、富马酸、乙醇酸、乳酸、马来酸、苹果酸、丙二酸、扁桃酸、草酸、苦味酸、丙酮酸、水杨酸、琥珀酸、甲磺酸、乙磺酸、酒石酸、抗坏血酸、扑酸(pamoic acid)、二亚甲基水杨酸、乙二磺酸、葡萄糖酸、柠康酸、天冬氨酸、硬脂酸、棕榈酸、EDTA、羟基乙酸、对氨基苯甲酸、谷氨酸、苯磺酸、对甲苯磺酸等。可药用无机酸或有机酸加成盐的其它实例包括在J.Pharm.Sci.1977，66，2中列出的可药用盐，该文献引入本发明以作参考。金属盐的实例包括锂盐、钠盐、钾盐、镁盐等。铵盐和烷基化铵盐的实例包括铵盐、甲基铵盐、二甲基铵盐、三甲基铵盐、乙基铵盐、羟基乙基铵盐、二乙基铵盐、正丁基铵盐、仲丁基铵盐、叔丁基铵盐、四甲基铵盐等。The present invention also includes pharmaceutically acceptable salts of the compounds of the present invention. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric, and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, propionic acid, Diacid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, dimethylene salicylic acid, ethylene glycol Sulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Other examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium salts, sodium salts, potassium salts, magnesium salts, and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, n-butylammonium Ammonium salts, butyl ammonium salts, tert-butyl ammonium salts, tetramethyl ammonium salts, etc.

还作为可药用酸加成盐包括在本发明范围内的是本发明化合物所能够形成的水合物。Also included within the scope of the invention as pharmaceutically acceptable acid addition salts are hydrates which the compounds of the invention are able to form.

此外，可药用盐包括碱性氨基酸盐例如赖氨酸盐、精氨酸盐和鸟氨酸盐。In addition, pharmaceutically acceptable salts include basic amino acid salts such as lysine salts, arginine salts and ornithine salts.

酸加成盐可作为直接的化合物合成产物获得。或者，可将游离碱溶解在含有适当酸的合适的溶剂中，并通过将溶剂蒸发或者将盐和溶剂分离开来分离出盐。Acid addition salts may be obtained as direct compound synthesis products. Alternatively, the free base may be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporation of the solvent or separation of the salt and solvent.

使用本领域技术人员众所周知的方法，本发明化合物可与标准低分子量溶剂形成溶剂化物。这样的溶剂化物也包括在本发明范围内。The compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to those skilled in the art. Such solvates are also included within the scope of this invention.

本发明还包括本发明化合物的前药，其给药后通过代谢过程发生化学转化，形成药理活性物质。一般情况下，这样的前药是通式(I)化合物的官能衍生物，其在体内易于转化成所需的式(I)化合物。“前药设计”，ed.H.Bundgaard，Elsevier，1985中描述了选择和制备合适的前药衍生物的常规方法。The present invention also includes prodrugs of the compounds of the present invention, which undergo chemical conversion through metabolic processes after administration to form pharmacologically active substances. In general, such prodrugs are functional derivatives of compounds of general formula (I), which are readily converted in vivo to the desired compound of formula (I). General methods for selecting and preparing suitable prodrug derivatives are described in "Prodrug Design", ed. H. Bundgaard, Elsevier, 1985 .

本发明还包括本发明化合物的活性代谢物。The present invention also includes active metabolites of the compounds of the present invention.

本发明化合物能拮抗胰高血糖素的作用，因此可用于治疗和/或预防受益于这样的拮抗作用的病症和疾病。The compounds of the invention are capable of antagonizing the action of glucagon and are therefore useful in the treatment and/or prevention of conditions and diseases which would benefit from such antagonism.

因此，本发明化合物可用于治疗和/或预防高血糖、IGT(葡萄糖耐量异常)、胰岛素抗性综合征、综合征X、1型糖尿病、2型糖尿病、高脂血症、异常脂血症、高甘油三酯血症、高脂蛋白血症、高胆固醇血症、包括动脉粥样硬化在内的动脉硬化、胰高血糖素瘤、急性胰腺炎、心血管疾病、高血压、心肥大、胃肠道障碍、肥胖症、作为肥胖症后果的糖尿病、糖尿病性异常脂血症。Therefore, the compounds of the present invention are useful for the treatment and/or prevention of hyperglycemia, IGT (impaired glucose tolerance), insulin resistance syndrome, syndrome X, type 1 diabetes, type 2 diabetes, hyperlipidemia, dyslipidemia, Hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, arteriosclerosis including atherosclerosis, glucagonoma, acute pancreatitis, cardiovascular disease, hypertension, cardiac hypertrophy, gastric Intestinal disorders, obesity, diabetes as a consequence of obesity, diabetic dyslipidemia.

此外，本发明化合物可用作确定具有胰高血糖素受体缺陷的患者的诊断剂，用作提高胃酸分泌和逆转由于施用胰高血糖素而引起的肠可动性不足的治疗剂。In addition, the compounds of the present invention are useful as diagnostic agents for identifying patients with glucagon receptor deficiency, as therapeutic agents for increasing gastric acid secretion and for reversing intestinal insufficiency caused by the administration of glucagon.

因此，另一方面，本发明涉及用作药物的本发明化合物。Thus, in another aspect, the invention relates to compounds of the invention for use as a medicament.

本发明还涉及药物组合物，其中包含至少一种本发明化合物作为活性组分和一种或多种可药用载体或赋形剂。The present invention also relates to pharmaceutical compositions comprising at least one compound of the present invention as active ingredient together with one or more pharmaceutically acceptable carriers or excipients.

药物组合物优选呈单位剂型，其中包含约0.05mg-约1000mg、优选约0.1mg-约500mg、特别优选约0.5mg-约200mg本发明化合物。The pharmaceutical composition is preferably in unit dosage form comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg, particularly preferably from about 0.5 mg to about 200 mg, of a compound of the invention.

此外，本发明还涉及本发明化合物在制备用于治疗和/或预防能受益于胰高血糖素拮抗作用的病症或疾病的药物组合物中的应用。Furthermore, the present invention relates to the use of the compounds according to the invention for the preparation of pharmaceutical compositions for the treatment and/or prophylaxis of disorders or diseases which benefit from glucagon antagonism.

本发明还涉及治疗和/或预防能受益于胰高血糖素拮抗作用的病症或疾病的方法，所述方法包括给有此需要的个体施用有效量的本发明化合物。The present invention also relates to methods of treating and/or preventing conditions or diseases that would benefit from glucagon antagonism, said methods comprising administering to an individual in need thereof an effective amount of a compound of the present invention.

在优选的本发明实施方案中，本发明化合物可用于制备治疗和/或预防任何胰高血糖素介导的病症和疾病的药物。In a preferred embodiment of the invention, the compounds of the invention are useful in the manufacture of a medicament for the treatment and/or prophylaxis of any glucagon-mediated conditions and diseases.

在优选的本发明实施方案中，本发明化合物可用于制备治疗和/或预防高血糖的药物。In a preferred embodiment of the invention, the compounds of the invention can be used for the preparation of medicaments for the treatment and/or prevention of hyperglycemia.

在优选的本发明实施方案中，本发明化合物可用于制备降低哺乳动物血糖的药物。In a preferred embodiment of the invention, the compounds of the invention are useful in the manufacture of a medicament for lowering blood sugar in mammals.

在另一优选的本发明实施方案中，本发明化合物可用于制备治疗和/或预防IGT的药物组合物。In another preferred embodiment of the invention, the compounds of the invention can be used for the preparation of pharmaceutical compositions for the treatment and/or prevention of IGT.

在另一优选的本发明实施方案中，本发明化合物可用于制备和/或预防2型糖尿病的药物组合物。In another preferred embodiment of the invention, the compounds of the invention can be used for the preparation and/or prevention of pharmaceutical compositions for type 2 diabetes.

在另一优选的本发明实施方案中，本发明化合物可用于制备延迟或预防从IGT向2型糖尿病转化的进程的药物组合物。In another preferred embodiment of the invention, the compounds of the invention can be used for the preparation of pharmaceutical compositions for delaying or preventing the progression from IGT to type 2 diabetes.

在另一优选的本发明实施方案中，本发明化合物可用于制备延迟或预防从非胰岛素需要性2型糖尿病向胰岛素需要性2型糖尿病转化的进程的药物组合物。In another preferred embodiment of the invention, the compounds of the invention can be used for the preparation of pharmaceutical compositions for delaying or preventing the progression from non-insulin-requiring type 2 diabetes to insulin-requiring type 2 diabetes.

在另一优选的本发明实施方案中，本发明化合物可用于制备治疗和/或预防1型糖尿病的药物组合物。这样的治疗和/或预防通常伴随胰岛素治疗。In another preferred embodiment of the present invention, the compounds of the present invention can be used for the preparation of pharmaceutical compositions for the treatment and/or prevention of type 1 diabetes. Such treatment and/or prophylaxis is usually accompanied by insulin therapy.

在另一优选的本发明实施方案中，本发明化合物可用于制备治疗和/或预防肥胖症的药物组合物。In another preferred embodiment of the invention, the compounds of the invention can be used for the preparation of pharmaceutical compositions for the treatment and/or prevention of obesity.

在另一优选的本发明实施方案中，本发明化合物可用于制备治疗和/或预防脂质代谢障碍例如异常脂血症的药物组合物。In another preferred embodiment of the invention, the compounds of the invention can be used for the preparation of pharmaceutical compositions for the treatment and/or prevention of lipid metabolism disorders such as dyslipidemia.

在另一优选的本发明实施方案中，本发明化合物可用于制备治疗和/或预防食欲调节或能量消耗紊乱的药物组合物。In another preferred embodiment of the invention, the compounds according to the invention can be used for the preparation of pharmaceutical compositions for the treatment and/or prevention of appetite regulation or energy expenditure disorders.

在本发明的另一方面，本发明化合物与饮食和/或锻炼联合采用。In another aspect of the invention, the compounds of the invention are administered in combination with diet and/or exercise.

在本发明的另一方面，本发明化合物与一种或多种其它活性物质以任意合适的比例联合施用。这样的其它活性剂选自抗糖尿病剂、抗高脂血症剂、抗肥胖剂、抗高血压剂、和治疗糖尿病导致的或与糖尿病有关的并发症的活性剂。In another aspect of the invention, the compounds of the invention are administered in combination with one or more other active substances in any suitable ratio. Such other active agents are selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents, and agents treating complications resulting from or associated with diabetes.

合适的抗糖尿病剂包括胰岛素、胰岛素类似物和衍生物，例如在EP 792 290(Novo Nordisk A/S)中公开的那些，例如NεB29-十四烷酰基des(B30)人胰岛素，在EP 214 826和EP 705 275(Novo NordiskA/S)中公开的那些，例如AspB28人胰岛素，在US 5,504,188(EliLilly)中公开的那些，例如LysB28ProB29人胰岛素，在EP 368 187(Aventis)中公开的那些，例如Lantus，所有这些文献都引入本发明以作参考，GLP-1衍生物，例如在WO98/08871(Novo Nordisk A/S)中公开的那些，该文献引入本发明以作参考，以及口服活性的降血糖剂。Suitable antidiabetic agents include insulin, insulin analogs and derivatives, such as those disclosed in EP 792 290 (Novo Nordisk A/S), e.g. NεB29 -tetradecanoyl des(B30) human insulin, described in EP 214 826 and those disclosed in EP 705 275 (Novo Nordisk A/S), such as Asp B28 human insulin, disclosed in US 5,504,188 (Eli Lilly), such as Lys B28 Pro B29 human insulin, disclosed in EP 368 187 (Aventis) those of Lantus, all of which are incorporated herein by reference, GLP-1 derivatives, such as those disclosed in WO98/08871 (Novo Nordisk A/S), which are incorporated herein by reference, and Orally active hypoglycemic agent.

口服活性的降血糖剂优选包括咪唑啉类药物、磺酰脲类药物、双胍类药物、美格列奈类药物(meglitinides)、噁二唑烷二酮类药物、噻唑烷二酮类药物、葡萄糖苷酶抑制剂、胰高血糖素拮抗剂、GLP-1激动剂、作用于β-细胞ATP依赖性钾通道的活性剂例如钾通道打开剂，如在WO97/26265、WO99/03861和WO00/37474(Novo Nordisk A/S)中公开的那些，这些文献引入本发明以作参考，或那格列奈(nateglinide)或钾通道阻断剂例如BTS-67582，胰岛素敏化剂、DPP-IV(二肽基肽酶-IV)抑制剂、PTP酶抑制剂、涉及刺激糖异生和/或糖原分解的肝脏酶的抑制剂、葡萄糖摄取调节剂、GSK-3(糖原合酶激酶-3)抑制剂，调节脂质代谢的化合物例如抗高脂血症剂和抗脂血症剂，降低食物摄取的化合物，PPAR(过氧化物酶体增殖子激活受体)和RXR(类维生素AX受体)激动剂例如ALRT-268、LG-1268或LG-1069。Orally active hypoglycemic agents preferably include imidazolines, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucose Glycosidase inhibitors, glucagon antagonists, GLP-1 agonists, agents acting on β-cell ATP-dependent potassium channels such as potassium channel openers, as described in WO97/26265, WO99/03861 and WO00/37474 (Novo Nordisk A/S), which are incorporated herein by reference, or nateglinide or potassium channel blockers such as BTS-67582, insulin sensitizers, DPP-IV (two Peptidyl peptidase-IV) inhibitors, PTPase inhibitors, inhibitors of liver enzymes involved in stimulating gluconeogenesis and/or glycogenolysis, glucose uptake regulators, GSK-3 (glycogen synthase kinase-3) Inhibitors, compounds that regulate lipid metabolism such as antihyperlipidemic and antilipidemic agents, compounds that reduce food intake, PPAR (peroxisome proliferator-activated receptor) and RXR (retinoid X receptor ) agonists such as ALRT-268, LG-1268 or LG-1069.

在一个本发明实施方案中，将本发明化合物与胰岛素或胰岛素类似物或衍生物例如NεB29-十四烷酰基des(B30)人胰岛素、AspB28人胰岛素、LysB28ProB29人胰岛素、Lantus、或包含一种或多种这些活性剂的混合制剂联合给药。In one embodiment of the invention, the compounds of the invention are combined with insulin or insulin analogs or derivatives such as NεB29 -tetradecanoyl des(B30) human insulin, Asp B28 human insulin, Lys B28 Pro B29 human insulin, Lantus, Or combined administration of mixed preparations containing one or more of these active agents.

在另一个本发明实施方案中，将本发明化合物与磺酰脲类药物例如甲苯磺丁脲、氯磺丙脲、妥拉磺脲、格列本脲、优降糖、格列吡嗪或格列齐特联合给药。In another embodiment of the present invention, the compound of the present invention is combined with a sulfonylurea drug such as tolbutamide, chlorpropamide, tolazamide, glibenclamide, glibenclamide, glipizide or glibenclamide Lizide combined administration.

在另一个本发明实施方案中，将本发明化合物与双胍类药物例如甲福明联合给药。In another embodiment of the invention, the compounds of the invention are administered in combination with a biguanide such as metformin.

在另一个本发明实施方案中，将本发明化合物与美格列奈类药物(meglitinide)例如瑞格列奈或列格列奈联合给药。In another embodiment of the present invention, the compound of the present invention is administered in combination with a meglitinide, eg repaglinide or ligninide.

在另一个本发明实施方案中，将本发明化合物与噻唑烷二酮类胰岛素敏化剂例如曲格列酮、环格列酮、吡格列酮、rosiglitazone、isaglitazone、达格列酮、恩格列酮、CS-011/CI-1037或T174，或在WO97/41097、WO97/41119、WO97/41120、WO00/41121和WO98/45292(Dr.Reddy’s Research Foundation)中公开的化合物联合给药。In another embodiment of the invention, the compound of the invention is combined with a thiazolidinedione insulin sensitizer such as troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, daglitazone, emglitazone, CS-011/CI-1037 or T174, or compounds disclosed in WO97/41097, WO97/41119, WO97/41120, WO00/41121 and WO98/45292 (Dr. Reddy's Research Foundation) are administered in combination.

在另一个本发明实施方案中，将本发明化合物与胰岛素敏化剂例如Gl 262570、YM-440、MCC-555、JTT-501、AR-H039242、KRP-297、GW-409544、CRE-16336、AR-H049020、LY510929、MBX-102、CLX-0940、GW-501516或在下列文献中公开的化合物联合给药：WO99/19313、WO00/50414、WO00/63191、WO00/63192、WO00/63193(Dr.Reddy’s Research Foundation)和WO00/23425、WO00/23415、WO00/23451、WO00/23445、WO00/23417、WO00/23416、WO00/63153、WO00/63196、WO00/63209、WO00/63190和WO00/63189(Novo Nordisk A/S)。In another embodiment of the invention, the compound of the invention is combined with an insulin sensitizer such as G1 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or combined administration of compounds disclosed in the following documents: WO99/19313, WO00/50414, WO00/63191, WO00/63192, WO00/63193 (Dr .Reddy's Research Foundation) and WO00/23425, WO00/23415, WO00/23451, WO00/23445, WO00/23417, WO00/23416, WO00/63153, WO00/63196, WO00/63209, WO00/63190 and WO00/63189 ( Novo Nordisk A/S).

在另一个本发明实施方案中，将本发明化合物与α-葡萄糖苷酶抑制剂例如伏格列波糖、乙格列酯、米格列醇或阿卡波糖联合给药。In another embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-glucosidase inhibitor such as voglibose, emigretate, miglitol or acarbose.

在另一个本发明实施方案中，将本发明化合物与作用于β-细胞ATP依赖性钾通道的活性剂例如甲苯磺丁脲、氯磺丙脲、妥拉磺脲、格列本脲、优降糖、格列吡嗪、格列齐特、BTS67582、瑞格列奈或那格列奈联合给药。In another embodiment of the present invention, the compounds of the present invention are combined with active agents acting on β-cell ATP-dependent potassium channels such as tolbutamide, chlorpropamide, tolazamide, glibenclamide, glibenclamide, Combination administration of sugar, glipizide, gliclazide, BTS67582, repaglinide or nateglinide.

在另一个本发明实施方案中，将本发明化合物与抗高脂血症剂或抗脂血症剂例如考来烯胺、考来替泊、氯贝特、吉非贝齐、洛伐他汀、普伐他汀、辛伐他汀、丙丁酚或右旋甲状腺素联合给药。In another embodiment of the invention, the compound of the invention is combined with an antihyperlipidemic or antilipidemic agent such as cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, Combined administration of pravastatin, simvastatin, probucol, or dextrothyroxine.

在本发明的另一方面，将本发明化合物与一种以上的上述化合物联合给药，例如与下列各组化合物联合给药：甲福明和磺酰脲类药物例如格列本脲或优降糖；磺酰脲类药物和阿卡波糖；甲福明和美格列奈例如瑞格列奈；阿卡波糖和甲福明；磺酰脲类药物、甲福明和曲格列酮；磺酰脲类药物、甲福明和吡格列酮；磺酰脲类药物、甲福明和胰岛素敏化剂例如在WO00/63189或WO97/41097中公开的那些；美格列奈例如瑞格列奈、甲福明和曲格列酮；美格列奈例如瑞格列奈、甲福明和吡格列酮；美格列奈例如瑞格列奈、甲福明和胰岛素敏化剂例如在WO00/63189或WO97/41097中公开的那些；胰岛素和磺酰脲类药物；胰岛素和美格列奈例如瑞格列奈；胰岛素和甲福明；胰岛素、甲福明和美格列奈例如瑞格列奈；胰岛素、甲福明和磺酰脲类药物；胰岛素和曲格列酮；胰岛素和吡格列酮；胰岛素和胰岛素敏化剂例如在WO00/63189或WO97/41097中公开的那些；胰岛素和洛伐他汀；胰岛素类似物或衍生物、甲福明和美格列奈例如瑞格列奈；胰岛素类似物或衍生物、甲福明和磺酰脲类药物；胰岛素类似物或衍生物和曲格列酮；胰岛素类似物或衍生物和吡格列酮；胰岛素类似物或衍生物和胰岛素敏化剂例如在WO00/63189或WO97/41097中公开的那些；胰岛素类似物或衍生物和洛伐他汀等。In another aspect of the invention, the compounds of the invention are administered in combination with more than one of the above compounds, for example in combination with the following groups of compounds: metformin and a sulfonylurea such as glibenclamide or glibenclamide ; sulfonylureas and acarbose; metformin and meglitinide e.g. repaglinide; acarbose and metformin; sulfonylureas, metformin and troglitazone; Ureas, metformin and pioglitazone; sulfonylureas, metformin and insulin sensitizers such as those disclosed in WO00/63189 or WO97/41097; meglitinides such as repaglinide, metformin and tremolin glitazones; meglitazones such as repaglinide, metformin and pioglitazone; meglitazones such as repaglinide, metformin and insulin sensitizers such as those disclosed in WO00/63189 or WO97/41097; Insulin and sulfonylureas; insulin and meglitinides such as repaglinide; insulin and metformin; insulin, metformin and meglitinides such as repaglinide; insulin, metformin and sulfonylureas Insulin and troglitazone; Insulin and pioglitazone; Insulin and insulin sensitizers such as those disclosed in WO00/63189 or WO97/41097; Insulin and lovastatin; Insulin analogs or derivatives, metformin and Meg Glinides such as repaglinide; insulin analogs or derivatives, metformin and sulfonylureas; insulin analogs or derivatives and troglitazone; insulin analogs or derivatives and pioglitazone; insulin analogs or derivatives and insulin sensitizers such as those disclosed in WO00/63189 or WO97/41097; insulin analogs or derivatives and lovastatin and the like.

此外，可将本发明化合物与一种或多种抗肥胖剂或食欲调节剂联合给药。Additionally, the compounds of the present invention may be administered in combination with one or more anti-obesity or appetite-regulating agents.

这样的活性剂可选自CART(可卡因苯丙胺调节的转录)激动剂、NPY(神经肽Y)拮抗剂、MC4(melanocortin 4)激动剂、阿立新拮抗剂、TNF(肿瘤坏死因子)调节剂、CRF(促肾上腺皮质素释放因子)激动剂、CRF BP(促肾上腺皮质素释放因子结合蛋白)拮抗剂、urocortin激动剂，β3肾上腺素能激动剂例如CL-316243、AJ-9677、GW-0604、LY362884、LY377267或AZ-40140，MSH(黑素细胞刺激激素)激动剂、MCH(黑素细胞浓缩激素)拮抗剂、CCK(缩胆囊素)激动剂，血清素再摄取抑制剂例如氟西汀、赛乐特(seroxat)或西酞普兰，血清素和去甲肾上腺素再摄取抑制剂、5HT(血清素)激动剂、铃蟾肽激动剂、良姜素(galanin)拮抗剂、生长激素、生长激素释放化合物、TRH(促甲状腺素释放激素)激动剂、UCP 2或3(解偶联蛋白2或3)调节剂、leptin激动剂、DA(多巴胺)激动剂(溴隐亭、doprexin)、脂酶/淀粉酶抑制剂、PPAR抑制剂、RXR调节剂或TRβ激动剂。Such active agents may be selected from CART (cocaine-amphetamine-regulated transcription) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) modulators, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, beta3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884 , LY377267 or AZ-40140, MSH (melanocyte stimulating hormone) agonists, MCH (melanocyte concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin reuptake inhibitors such as fluoxetine, race Seroxat or citalopram, serotonin and norepinephrine reuptake inhibitors, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone Release compounds, TRH (thyrotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA (dopamine) agonists (bromocriptine, doprexin), lipase / Amylase inhibitors, PPAR inhibitors, RXR modulators, or TRβ agonists.

在一个本发明实施方案中，抗肥胖剂是leptin。In one embodiment of the invention the anti-obesity agent is leptin.

在另一个本发明实施方案中，抗肥胖剂是右旋苯丙胺或苯丙胺。In another embodiment of the invention, the anti-obesity agent is dexamphetamine or amphetamine.

在另一个本发明实施方案中，抗肥胖剂是芬氟拉明或右芬氟拉明。In another embodiment of the invention, the anti-obesity agent is fenfluramine or dexfenfluramine.

在另一个本发明实施方案中，抗肥胖剂是西布曲明。In another embodiment of the invention, the anti-obesity agent is sibutramine.

在另一个本发明实施方案中，抗肥胖剂是奥利司他。In another embodiment of the invention the anti-obesity agent is orlistat.

在另一个本发明实施方案中，抗肥胖剂是马吲哚或芬特明。In another embodiment of the invention, the anti-obesity agent is mazindol or phentermine.

此外，本发明化合物可以与一种或多种抗高血压剂联合给药。抗高血压剂的实例有β-阻断剂，例如阿普洛尔、阿替洛尔、噻吗洛尔、吲哚洛尔、普萘洛尔和美托洛尔，ACE(血管紧张素转化酶)抑制剂例如贝那普利、卡托普利、依那普利、福辛普利、赖诺普利、喹那普利和雷米普利，钙通道阻断剂例如硝苯地平、非洛地平、尼卡地平、伊拉地平、尼莫地平、地尔硫_和维拉帕米，以及α-阻断剂例如多沙唑嗪、乌拉地尔、哌唑嗪和特拉唑嗪。其它参考可参见Remington：TheScience and Practice of Pharmacy，19th Edition，Gennaro，Ed.，Mack Publishing Co.，Easton，PA，1995。In addition, the compounds of the present invention may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme ) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felopril Dipine, nicardipine, isradipine, nimodipine, diltiazem, and verapamil, and alpha-blockers such as doxazosin, urapidil, prazosin, and terazosin. Additional references may be found in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

应当理解，本发明化合物与饮食和/或锻炼、一种或多种上述化合物以及任选一种或多种其它活性物质的任意合适组合都在本发明范围内。It is to be understood that any suitable combination of a compound of the invention with diet and/or exercise, one or more of the compounds described above, and optionally one or more other active substances is within the scope of the invention.

药物组合物pharmaceutical composition

本发明化合物可单独给药，或者与可药用载体或赋形剂联合给药，可以以单剂量或多个剂量给药。本发明药物组合物可用可药用载体或稀释剂以及其它已知的助剂和赋形剂依据常规技术例如在下述文献中公开的技术配制：Remington：The Science and Practice of Pharmacy，19 Edition，Gennaro，Ed.，Mack Publishing Co.，Easton，PA，1995。The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers or excipients, and can be administered in single or multiple doses. The pharmaceutical composition of the present invention can be formulated with pharmaceutically acceptable carriers or diluents and other known adjuvants and excipients according to conventional techniques such as those disclosed in the following documents: Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro , Ed., Mack Publishing Co., Easton, PA, 1995.

可特定地配制药物组合物以通过任意合适的途径给药，合适的给药途径有例如经口、直肠、经鼻、经肺、局部(包括颊和舌下)、透皮、脑池内、腹膜内、阴道和非胃肠道(包括皮下、肌内、鞘内、静脉内和真皮内)途径，经口途径是优选的。应当理解，优选的给药途径取决于所治疗患者的身体一般状况和年龄、所治疗病症的性质以及所选的活性组分。The pharmaceutical compositions may be specially formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, peritoneal Intravaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes, oral routes are preferred. It will be appreciated that the preferred route of administration will depend on the general condition and age of the patient being treated, the nature of the condition being treated and the active ingredient chosen.

经口给药的药物组合物包括固体剂型例如胶囊、片剂、糖锭剂、丸剂、锭剂、粉剂和粒剂。如果适当的话，可给它们提供包衣例如肠溶衣，或者依据本领域众所周知的方法将它们配制以控制活性组分的释放例如持续释放或延迟释放。Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. If appropriate, they may be provided with coatings such as enteric coatings, or they may be formulated so as to control, eg sustained or delayed release of the active ingredient according to methods well known in the art.

经口给药的液体剂型包括溶液、乳剂、悬浮液、糖浆剂和酏剂。Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

非胃肠道给药的药物组合物包括无菌水性和非水性可注射溶液、分散液、悬浮液或乳液，以及使用前重新配制成无菌可注射乳液或分散液的无菌粉末。贮药库注射剂也在本发明范围内。Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable emulsions or dispersions before use. Depot injections are also within the scope of the invention.

其它合适的给药形式包括栓剂、喷雾剂、膏剂、霜剂、凝胶剂、吸入剂、皮肤贴剂、植入物等。Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants and the like.

一般的口服剂量为约0.001-约100mg/kg体重/天，优选为约0.01-约50mg/kg体重/天，更优选为约0.05-约10mg/kg体重/天，每天分成一份或多份剂量例如1-3份剂量给药。确切剂量将取决于给药频率和方式，所治疗患者的性别、年龄、体重和身体一般状况，所治疗病症和任意伴发疾病的性质和严重程度，以及对于本领域技术人员来说显而易见的其它因素。Usual oral dosage is about 0.001 to about 100 mg/kg body weight/day, preferably about 0.01 to about 50 mg/kg body weight/day, more preferably about 0.05 to about 10 mg/kg body weight/day, divided into one or more portions per day Dosing is eg administered in 1-3 divided doses. The exact dosage will depend on the frequency and mode of administration, the sex, age, weight and general condition of the patient being treated, the nature and severity of the condition being treated and any concomitant disease, and other factors apparent to those skilled in the art. factor.

方便起见，可通过本领域技术人员已知的方法将制剂制成单位剂型。用于每天口服给药一次或多次例如1-3次的典型单位剂型可含有0.05-约1000mg、优选约0.1-约500mg、更优选约0.5mg-约200mg。The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. Typical unit dosage forms for oral administration one or more times, eg, 1-3 times per day, may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, more preferably from about 0.5 mg to about 200 mg.

对于非胃肠道给药途径例如静脉内、鞘内、肌内和类似给药，所采用的剂量一般是大约口服给药剂量的一半。For parenteral routes of administration such as intravenous, intrathecal, intramuscular and the like, the dosage employed will generally be about one-half that for oral administration.

本发明化合物一般是作为物质本身或者作为其可药用盐使用。一个实例是具有游离酸的化合物的碱加成盐。当式(I)化合物含有游离酸时，这样的盐是按照常规方法通过用等当量可药用碱处理式(I)游离酸的溶液或悬浮液制得的。代表性实例如上所述。The compounds of the present invention are generally used as substances themselves or as pharmaceutically acceptable salts thereof. An example is a base addition salt of a compound with the free acid. When the compound of formula (I) contains a free acid, such salts are prepared according to conventional methods by treating a solution or suspension of the free acid of formula (I) with an equivalent amount of a pharmaceutically acceptable base. Representative examples are described above.

对于非胃肠道给药，可使用式(I)新化合物在无菌水溶液、水性丙二醇、维生素E水溶液或芝麻油或花生油中的溶液。如果需要的话，可将这样的水溶液适当地缓冲，并首先用足量的盐水或葡萄糖使液体稀释剂等渗。水溶液特别适于静脉内、肌内、皮下和腹膜内给药。所用的无菌水介质都易于通过本领域技术人员已知的标准技术获得。For parenteral administration, solutions of the novel compounds of formula (I) in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil can be used. Such aqueous solutions can be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. Aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. All sterile aqueous media used are readily available by standard techniques known to those skilled in the art.

合适的药物载体包括惰性固体稀释剂或填充剂，无菌水溶液和各种有机溶剂。固体载体的实例有乳糖、石膏粉、蔗糖、环糊精、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸和纤维素的低级烷基醚。液体载体的实例有糖浆、花生油、橄榄油、磷脂、脂肪酸、脂肪酸胺、聚氧乙烯和水。类似地，载体或稀释剂可包括本领域已知的任何缓释材料例如单独使用或者与蜡混合的甘油一硬脂酸酯或甘油二硬脂酸酯。把通过将式(I)新化合物和可药用载体混合而形成的药物组合物以适于所公开的给药途径的不同剂型方便地给药。方便起见，可通过本领域技术人员已知的方法将制剂制成单位剂型。Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained release material known in the art such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by admixing the novel compounds of formula (I) and pharmaceutically acceptable carriers are conveniently administered in different dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art.

适于经口给药的本发明制剂可制成各含有预定量活性组分，并且可含有合适的赋形剂的离散单位例如胶囊或片剂。此外，口服制剂可以呈粉末或颗粒，在水或非水液体中的溶液或悬浮液，或水包油或油包水乳液的形式。Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may contain a suitable excipient. Furthermore, oral formulations may be in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil emulsions.

如果使用固体载体进行经口给药，制剂可以是以粉末或小丸形式置于硬明胶胶囊中的小片，或者其可以呈锭剂或糖锭剂的形式。固体载体的量可以有很大变化，但是其通常为约25mg-约1g。如果使用液体载体，制剂可以呈糖浆、乳液、软明胶胶囊或无菌注射液体例如水或非水液体悬浮液或溶液的形式。If a solid carrier is used for oral administration, the preparation may be in powder or pellet form placed in a hard gelatine capsule, or it may be in the form of a troche or lozenge. The amount of solid carrier can vary widely, but generally it will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

可通过常规制片技术制得的典型片剂可含有：核：活性化合物(化合物本身或其盐)    5.0mg乳糖Ph.Eur.                     67.8mg微晶纤维素(Avicel)              31.4mgAmberiite_IRP88*               1.0mg硬脂酸镁Ph.Eur.                 适量包衣羟丙基甲基纤维素              大约9mgMywacett 9-40 T**             大约0.9mg*Polacrillin钾NF，片剂崩解剂，Rohm and Haas。**用作膜包衣增塑剂的酰化的甘油一酯。A typical tablet, which may be made by conventional tableting techniques, may contain: Core: active compound (compound itself or its salt) 5.0 mg lactose Ph.Eur. 67.8 mg microcrystalline cellulose (Avicel) 31.4 mg Amberiite_IRP88* 1.0 mg stearic acid Magnesium Ph.Eur. qs Coating Hydroxypropyl Methylcellulose Approx. 9mg Mywacett 9-40 T** Approx. 0.9mg* Polacrillin Potassium NF, Tablet Disintegrant, Rohm and Haas. **Acylated monoglycerides used as film coating plasticizers.

如果需要的话，本发明药物组合物可含有式(I)化合物和另外的药理活性物质例如上述活性物质。The pharmaceutical compositions of the present invention may, if desired, contain the compound of formula (I) and further pharmacologically active substances such as those mentioned above.

实施例Example

下述实施例和一般方法提及了在说明书与合成方案中鉴定的中间体化合物和终产物。使用下述实施例来更详细地描述本发明化合物，但是所述的化学反应是依据其制备本发明胰高血糖素拮抗剂的一般适用性公开的。有时反应可能并不能适用于包括在本发明所公开的范围内的所有化合物。本领域技术人员能很容易认识到这样的化合物。在这些情况下，通过作一些本领域技术人员已知的常规改变，即通过适当地饱和干扰性基团、换成其它常规试剂、或对反应条件作一些常规改变，可成功地进行这些反应。或者，本文所公开的其它反应或常规反应可适于制备相应的本发明化合物。在所有制备方法中，所有原料都是已知的，或者可易于由已知的原料制得。除非另有说明，所有温度都是以摄氏度给出，并且当提到产率时，所有份数和百分比都是按重量的，当提到溶剂和稀释剂时，所有份数都是按体积计的。The following examples and general methods refer to intermediate compounds and final products identified in the specification and synthetic schemes. The following examples are used to describe the compounds of the invention in more detail, but the chemical reactions described are disclosed in terms of their general applicability to the preparation of glucagon antagonists of the invention. Sometimes a reaction may not be applicable to all compounds included within the scope of the invention disclosed. Those skilled in the art will readily recognize such compounds. In these cases, these reactions can be successfully performed by making some routine changes known to those skilled in the art, ie, by suitably saturating interfering groups, exchanging other conventional reagents, or making some routine changes to the reaction conditions. Alternatively, other or conventional reactions disclosed herein may be adapted to prepare the corresponding compounds of the invention. In all preparative methods, all starting materials are known, or can be readily prepared from known starting materials. Unless otherwise indicated, all temperatures are given in degrees Celsius, and when referring to yields, all parts and percentages are by weight, and when referring to solvents and diluents, all parts are by volume of.

在下述实施例中表示的某些NMR数据仅是所选的数据。Some of the NMR data presented in the following examples are selected data only.

在实施例和药理方法中，下述术语具有下列含义：DCM：     二氯甲烷DMF：     N，N-二甲基甲酰胺DMSO：    二甲亚砜M.p.：    熔点TFA：     三氟乙酸THF：     四氢呋喃EDAC：    1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐HOBt：    1-羟基苯并三唑HOAt：    3-羟基-3H-[1，2，3]三唑并[4，5-b]吡啶，还称为1-羟基-7-氮杂苯并三唑EGTA：    乙二醇二(β-氨基乙醚)N，N，N’N’-四乙酸BSA：     N，O-二(三甲基甲硅烷基)乙酰亚胺酸盐IBMX：    异丁基甲基黄嘌呤HPLC-MS(方法A)使用下列仪器操作：·Sciex API 100 Singles四相质谱仪·Perkin Elmer Series 200 Quard泵·Perkin Elmer Series 200自动取样器·Applied Biosystems 785A UV检测器·Sedex 55蒸发光散射检测器·Valco柱，用通过从泵定时控制的Valco驱动器开关。In the examples and pharmacological methods, the following terms have the following meanings: DCM: dichloromethane DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide M.p.: melting point TFA: trifluoroacetic acid THF: tetrahydrofuran EDAC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride HOBt: 1-Hydroxybenzotriazole HOAt: 3-Hydroxy-3H-[1,2,3]triazole [4,5-b]pyridine, also known as 1-hydroxy-7-azabenzotriazole EGTA: Ethylene glycol bis(β-aminoethyl ether) N,N,N'N'-tetraacetic acid BSA: N,O-bis(trimethylsilyl)acetimidate IBMX: Isobutylmethylxanthine HPLC-MS (Method A) was performed using the following instruments: Sciex API 100 Singles Quadrature Mass Spectrometer Perkin Elmer Series 200 Quard Pump Perkin Elmer Series 200 Autosampler Applied Biosystems 785A UV Detector Sedex 55 Evaporative Light Scattering Detector Valco column switched with Valco driver controlled by slave pump timing.

使用在Macintosh PowerPC 7200计算机上运行的Sciex Sample控制软件来进行仪器控制和获得数据。Sciex Sample control software running on a Macintosh PowerPC 7200 computer was used for instrument control and data acquisition.

HPLC泵与含有下列组分的4个洗脱剂贮器相连：A：乙腈B：水C：0.5％TFA水溶液D：0.02 M乙酸铵The HPLC pump was connected to 4 eluent reservoirs containing the following components: A: Acetonitrile B: Water C: 0.5% TFA in water D: 0.02 M Ammonium Acetate

对样本的要求是它们在可接受的溶剂例如甲醇、乙醇、乙腈、THF、水及其混合物中含有大约500μg/mL预分析的化合物(高浓度的强洗脱溶剂将干扰在低乙腈浓度下进行的色谱)。The requirement for samples is that they contain approximately 500 µg/mL of preanalyzed compound in acceptable solvents such as methanol, ethanol, acetonitrile, THF, water, and mixtures thereof (high concentrations of strong eluting solvents will interfere with low acetonitrile concentrations) color spectrum).

分析是通过在柱上注射20μL样本溶液而在室温进行的，用乙腈在0.05％TFA或0.002M乙酸铵中的梯度溶液洗脱柱。根据分析方法使用不同的洗脱条件。Analysis was performed at room temperature by injecting 20 μL of sample solution on the column, which was eluted with a gradient of acetonitrile in 0.05% TFA or 0.002M ammonium acetate. Use different elution conditions depending on the analytical method.

让从柱上流下来的洗脱液流经分流T-连接器，其将大约20μL/分钟经由大约1m.75μ石英玻璃毛细管流到API 100光谱计的API界面上。The eluate coming off the column was passed through a split T-connector which directed approximately 20 μL/min through an approximately 1 m.75 μ quartz glass capillary onto the API interface of the API 100 spectrometer.

余下的1.48mL/分钟流经UV检测器并到达ELS检测器。The remaining 1.48 mL/min flowed through the UV detector and to the ELS detector.

在LC分析期间，并行地从质谱仪、UV检测器和ELS检测器上获得检测数据。During LC analysis, detection data were obtained in parallel from the mass spectrometer, UV detector and ELS detector.

用于不同方法的LC条件、检测器设置以及质谱仪设置列在下表中。 柱 YMC ODS-A 120_s-5μ3mm×50mmid 梯度 5％-90％乙腈在0.05％TFA中的混合物，在7.5分钟内以1.5mL/分钟的速度线性增加 检测 UV：214nm ELS：40℃ MS 实验：  开始：100 amu  停止：800 amu  间距：0.2amu停留：0.571 msec 方法：扫描284次＝9.5分钟 HPLC-MS(方法B)The LC conditions, detector settings, and mass spectrometer settings used for the different methods are listed in the table below. column YMC ODS-A 120_s-5μ3mm×50mmid gradient 5%-90% acetonitrile in 0.05% TFA, ramped up linearly at 1.5 mL/min over 7.5 minutes detection UV: 214nm ELS: 40°C MS Experiment: Start: 100 amu Stop: 800 amu Spacing: 0.2amu Dwell: 0.571 msec Method: 284 scans = 9.5 minutes HPLC-MS (Method B)

使用下列仪器操作：·Hewlett Packard series 1100 G1312A Bin Pump·Hewlett Packard series 1100 Column隔室·Hewlett Packard series 1100 G13 15A DAD二极管阵列检测器·Hewlett Packard series 1100 MSDOperate with the following instruments: Hewlett Packard series 1100 G1312A Bin Pump Hewlett Packard series 1100 Column compartment Hewlett Packard series 1100 G13 15A DAD diode array detector Hewlett Packard series 1100 MSD

通过HP Chemstation软件控制仪器。The instrument is controlled by HP Chemstation software.

HPLC泵与含有下列组分的2个洗脱剂贮器相连：A：0.01％TFA水溶液B：0.01％TFA在乙腈中的溶液The HPLC pump was connected to 2 eluent reservoirs containing the following components: A: 0.01% TFA in water B: 0.01% TFA in acetonitrile

分析是通过将适当体积的样本(优选1μL)注射到柱上而在40℃进行的，用乙腈进行梯度洗脱。Analysis is carried out at 40°C by injecting an appropriate volume of sample (preferably 1 μL) onto the column with gradient elution with acetonitrile.

所用的HPLC条件、检测器设置以及质谱仪设置列在下表中。 柱 Waters Xterra MS C-18×3mmid 梯度 10-100％乙腈，在7.5分钟内以1.0mL/分钟的速度线性增加 检测 UV：210nm(从DAD的类似输出) MS 电离模式：API-ES扫描100-1000 amu，间距0.1amu HPLC-MS(方法C)The HPLC conditions, detector settings, and mass spectrometer settings used are listed in the table below. column Waters Xterra MS C-18×3mmid gradient 10-100% acetonitrile, ramped linearly at 1.0 mL/min over 7.5 minutes detection UV: 210nm (similar output from DAD) MS Ionization mode: API-ES scan 100-1000 amu, spacing 0.1amu HPLC-MS (Method C)

使用下列仪器操作：·Hewlett Packard series 1100 G1312A Bin Pump·Hewlett Packard series 1100 G13 15A DAD二极管阵列检测器·Sciex 300三四相质谱仪·Gilson 215微注射器·Sedex 55蒸发光散射检测器Operate with the following instruments: Hewlett Packard series 1100 G1312A Bin Pump Hewlett Packard series 1100 G13 15A DAD diode array detector Sciex 300 triple-quad mass spectrometer Gilson 215 microinjector Sedex 55 evaporative light scattering detector

泵和检测器是通过在Macintosh G3计算机上运行的MassChrom1.1.1软件控制的。Gilson Unipoint Version 1.90控制自动注射器。Pumps and detectors were controlled by MassChrom 1.1.1 software running on a Macintosh G3 computer. Gilson Unipoint Version 1.90 controls the autoinjector.

HPLC泵与含有下列组分的2个洗脱剂贮器相连：A：0.01％TFA水溶液B：0.01％TFA在乙腈中的溶液The HPLC pump was connected to 2 eluent reservoirs containing the following components: A: 0.01% TFA in water B: 0.01% TFA in acetonitrile

分析是通过将适当体积的样本(优选1μL)注射到柱上而在室温进行的，用乙腈进行梯度洗脱。Analysis is performed at room temperature by injecting an appropriate volume of sample (preferably 1 [mu]L) onto the column with gradient elution with acetonitrile.

所用的HPLC条件、检测器设置以及质谱仪设置列在下表中。 柱 YMC ODS-A120_s-5μ3mm×50mmid 梯度 5-90％乙腈，在7.5分钟内以1.5mL/分钟的速度线性增加 检测 210nm(从DAD的类似输出) MS 电离模式：API-ES扫描100-1000amu，间距0.1amu 制备用于下述实施例的构件构件1：(RS)-异丝氨酸乙酯盐酸盐The HPLC conditions, detector settings, and mass spectrometer settings used are listed in the table below. column YMC ODS-A120_s-5μ3mm×50mmid gradient 5-90% acetonitrile, ramped linearly at 1.5 mL/min over 7.5 minutes detection 210nm (similar output from DAD) MS Ionization mode: API-ES scan 100-1000amu, spacing 0.1amu Preparation of Building Block 1: (RS)-Isoserine ethyl ester hydrochloride used in the following examples

将粗无水乙醇(40mL)在冰浴上冷却，滴加亚硫酰氯(4mL)，同时将温度保持在5℃以下。向该冷溶液中加入(RS)-异丝氨酸(2.5g，23.79mmol)，并继续搅拌直至获得均匀溶液。移去冰浴，继续在室温搅拌17小时。将该溶液真空浓缩，获得了4.0g(100％)(RS)-异丝氨酸乙酯盐酸盐，为油状物。1H-NMR(DMSO-d6)：δ1.22(t，3H)，3.00(dm，2H)，4.15(q，2H)，4.40(dd，1H)，6.30(brs，1H)，8.32(brs，2H).13C-NMR(DMSO-d6)：δ14.7(q)，42.4(t)，61.7(t)，67.7(d)，171(s).构件2：(R)-异丝氨酸乙酯盐酸盐步骤A：(R)-(2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基)乙酸Crude absolute ethanol (40 mL) was cooled on an ice bath, and thionyl chloride (4 mL) was added dropwise while keeping the temperature below 5°C. To this cold solution was added (RS)-isoserine (2.5 g, 23.79 mmol) and stirring was continued until a homogeneous solution was obtained. The ice bath was removed and stirring was continued at room temperature for 17 hours. The solution was concentrated in vacuo to afford 4.0 g (100%) of (RS)-isoserine ethyl ester hydrochloride as an oil. 1 H-NMR (DMSO-d 6 ): δ1.22 (t, 3H), 3.00 (dm, 2H), 4.15 (q, 2H), 4.40 (dd, 1H), 6.30 (brs, 1H), 8.32 ( brs, 2H). 13 C-NMR (DMSO-d 6 ): δ14.7(q), 42.4(t), 61.7(t), 67.7(d), 171(s). Building block 2: (R)- Isoserine ethyl ester hydrochloride Step A: (R)-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-yl)acetic acid

向D-(+)-苹果酸(15.0g，0.1119mol)在无水甲苯(150mL)内的悬浮液中加入2，2-二甲氧基丙烷(50mL，0.392mmol)。将该混合物在100℃回流2小时，并真空蒸发。将残余物溶解在乙醚(150mL)中，通过快速柱色谱纯化，使用乙醚作为洗脱剂(200mL)。合并纯的级分，真空蒸发，将残余物在正己烷中搅拌。收集沉淀，用正己烷洗涤并干燥，获得了15.7g(81％)(R)-(2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基)乙酸，为固体。1H-NMR(丙酮-d6)：δ1.57(ds，6H)，2.85(m，2H)，4.80(dd，1H)，11.0(brs，1H).13C-NMR(Acetone-d6)：δ25.9(q)，26.8(q)，36.2(t)，71.5(d)，111.2(s)，170.7(s)，172.7(s).元素分析：C7H10C5的计算值：C，48.28％；H，5.79％.实测值：C，48.31％；H，6.09％.步骤B：(R)-(2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基甲基)氨基甲酸苄酯To a suspension of D-(+)-malic acid (15.0 g, 0.1119 mol) in anhydrous toluene (150 mL) was added 2,2-dimethoxypropane (50 mL, 0.392 mmol). The mixture was refluxed at 100°C for 2 hours and evaporated in vacuo. The residue was dissolved in ether (150 mL) and purified by flash column chromatography using ether as eluent (200 mL). The pure fractions were combined, evaporated in vacuo and the residue was stirred in n-hexane. The precipitate was collected, washed with n-hexane and dried to obtain 15.7 g (81%) of (R)-(2,2-dimethyl-5-oxo-[1,3]dioxolane-4- base) acetic acid, as a solid. 1 H-NMR (acetone-d 6 ): δ1.57 (ds, 6H), 2.85 (m, 2H), 4.80 (dd, 1H), 11.0 (brs, 1H). 13 C-NMR (Acetone-d 6 ): δ25.9(q), 26.8(q), 36.2(t), 71.5(d), 111.2(s), 170.7(s), 172.7(s). Elemental analysis: Calculation of C 7 H 10 C 5 Value: C, 48.28%; H, 5.79%. Found: C, 48.31%; H, 6.09%. Step B: (R)-(2,2-Dimethyl-5-oxo-[1,3 ]Dioxolan-4-ylmethyl)benzyl carbamate

将(R)-(2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基)乙酸(10.0g，57.41mmol)、三乙胺(10mL，68.89mmol)和二苯基磷酰基叠氮化物(14mL，63.15mmol)在无水甲苯(100mL)中的混合物于85℃加热和搅拌。当停止释放出气体后，继续搅拌1小时。加入无水苯甲醇(6.3mL，63.15mmol)，并继续加热17小时。真空蒸发后，将残余物在二氯甲烷、水和盐水之间分配。用二氯甲烷将水相萃取2次，用饱和碳酸氢钠将合并的有机相洗涤2次。将有机相干燥(硫酸镁)、过滤、并真空浓缩后，通过快速柱色谱纯化残余物，使用二氯甲烷洗脱。获得了6.4g(40％)(R)-(2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基甲基)氨基甲酸苄酯，为油状物。1H-NMR(丙酮-d6)：δ1.56(s，6H)，3.61(m，2H)，4.64(dd，1H)，5.08(dd，2H)，6.51(br s，1H)，7.29-7.38(m，5H).步骤C：(R)-3-苄氧基羰基氨基-2-羟基丙酸(R)-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-yl)acetic acid (10.0g, 57.41mmol), triethylamine (10mL, 68.89 mmol) and diphenylphosphoryl azide (14 mL, 63.15 mmol) in anhydrous toluene (100 mL) was heated and stirred at 85°C. Stirring was continued for 1 hour when gas evolution had ceased. Anhydrous benzyl alcohol (6.3 mL, 63.15 mmol) was added and heating was continued for 17 hours. After evaporation in vacuo, the residue was partitioned between dichloromethane, water and brine. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were washed twice with saturated sodium bicarbonate. After the organic phase was dried (magnesium sulfate), filtered and concentrated in vacuo, the residue was purified by flash column chromatography eluting with dichloromethane. 6.4 g (40%) of benzyl (R)-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylmethyl)carbamate were obtained as Oil. 1 H-NMR (acetone-d 6 ): δ1.56(s, 6H), 3.61(m, 2H), 4.64(dd, 1H), 5.08(dd, 2H), 6.51(br s, 1H), 7.29 -7.38 (m, 5H). Step C: (R)-3-benzyloxycarbonylamino-2-hydroxypropionic acid

向(R)-(2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基甲基)氨基甲酸苄酯(6.0g，25.08mmol)在乙腈(100mL)内的溶液中加入盐酸(1N，100mL)。将该混合物在40℃搅拌3小时，并真空浓缩至一半初始体积。通过过滤收集固体，并用水洗涤。将粗产物在丙酮(100mL)中搅拌5分钟，并过滤。将甲苯加到澄清且无色的滤液中，真空浓缩直至获得沉淀。通过过滤收集沉淀，干燥，获得了4.45g(87％)(R)-3-苄氧基羰基氨基-2-羟基丙酸。1H-NMR(丙酮-d6)：δ3.45(ddd，1H)，3.58(ddd，1H)，4.29(dd，1H)，5.08(s，2H)，6.41(br s，1H)，7.29-7.38(m，5H).13C-NMR(丙酮-d6)：δ45.1(t)，66.4(t)，70.4(d)，128.3(d)，128.9(d)，138.0(d)，157.2(s)，173.8(s)；HPLC-MS(方法C)：m/z＝262(M+Na+)；Rt＝2.20min.M.p.131-132℃.元素分析：C11H13NO5的计算值：C，55.23％；H，5.48％；N，5.85％.实测值：C，55.35％；H，5.72％；N，5.82％.步骤D：(R)-异丝氨酸Benzyl (R)-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylmethyl)carbamate (6.0 g, 25.08 mmol) in acetonitrile To the solution in (100 mL) was added hydrochloric acid (1N, 100 mL). The mixture was stirred at 40 °C for 3 hours and concentrated in vacuo to half the original volume. The solid was collected by filtration and washed with water. The crude product was stirred in acetone (100 mL) for 5 minutes and filtered. Toluene was added to the clear and colorless filtrate and concentrated in vacuo until a precipitate was obtained. The precipitate was collected by filtration and dried to afford 4.45 g (87%) of (R)-3-benzyloxycarbonylamino-2-hydroxypropionic acid. 1 H-NMR (acetone-d 6 ): δ3.45 (ddd, 1H), 3.58 (ddd, 1H), 4.29 (dd, 1H), 5.08 (s, 2H), 6.41 (br s, 1H), 7.29 -7.38(m, 5H). 13 C-NMR (acetone-d 6 ): δ45.1(t), 66.4(t), 70.4(d), 128.3(d), 128.9(d), 138.0(d) , 157.2(s), 173.8(s); HPLC-MS (Method C): m/z=262 (M+Na + ); R t =2.20min.Mp131-132°C. Elemental analysis: C 11 H 13 NO Calculated for 5 : C, 55.23%; H, 5.48%; N, 5.85%. Found: C, 55.35%; H, 5.72%; N, 5.82%. Step D: (R)-Isoserine

将(R)-3-苄氧基羰基氨基-2-羟基丙酸(4.4g，18.39mmol)溶解在无水乙醇(150mL)中。在氮气氛下加入披钯活性炭(10％，0.5g)，将该混合物在1个大气压下氢化17小时。过滤出催化剂，并用水洗涤。通过真空蒸发将合并的滤液和洗涤液浓缩至约20mL。通过滴加甲醇(100mL)获得了沉淀。过滤出沉淀，用甲醇洗涤并干燥，获得了1.78g(92％)(R)-异丝氨酸，为固体。1H-NMR(D2O)：δ3.07(dd，1H)，3.30(dd，1H)，4.19(dd，1H).13C-NMR(D2O)：δ43.0(t)，68.9(d)，177.5(s).M.p.200-201℃.步骤E：(R)-异丝氨酸乙酯盐酸盐(R)-3-Benzyloxycarbonylamino-2-hydroxypropionic acid (4.4 g, 18.39 mmol) was dissolved in absolute ethanol (150 mL). Palladium on activated carbon (10%, 0.5 g) was added under nitrogen atmosphere, and the mixture was hydrogenated at 1 atmosphere for 17 hours. The catalyst was filtered off and washed with water. The combined filtrate and washings were concentrated to about 20 mL by vacuum evaporation. A precipitate was obtained by the dropwise addition of methanol (100 mL). The precipitate was filtered off, washed with methanol and dried to afford 1.78 g (92%) of (R)-isoserine as a solid. 1 H-NMR (D 2 O): δ3.07 (dd, 1H), 3.30 (dd, 1H), 4.19 (dd, 1H). 13 C-NMR (D 2 O): δ43.0 (t), 68.9(d), 177.5(s). Mp 200-201°C. Step E: (R)-Isoserine ethyl ester hydrochloride

该化合物是按照类似于上述制备(RS)-异丝氨酸乙酯盐酸盐的方法制得的。1H-NMR(DMSO-d6)：δ1.22(t，3H)，2.88(dd，1H)，3.10(dd，1H)，4.14(q，2H)，4.40(m，1H)，6.32(d，1H)，8.28(br s，2H).13C-NMR(DMSO-d6)：13.9(q)，41.4(t)，60.7(t)，66.9(d)，170.9(s).构件3：(S)-2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基甲基三氟乙酸铵步骤A：(S)-(2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基)乙酸This compound was prepared in a manner similar to that described above for the preparation of (RS)-isoserine ethyl ester hydrochloride. 1 H-NMR (DMSO-d 6 ): δ1.22(t, 3H), 2.88(dd, 1H), 3.10(dd, 1H), 4.14(q, 2H), 4.40(m, 1H), 6.32( d, 1H), 8.28 (br s, 2H). 13 C-NMR (DMSO-d 6 ): 13.9(q), 41.4(t), 60.7(t), 66.9(d), 170.9(s). 3: (S)-2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylmethylammonium trifluoroacetate Step A: (S)-(2, 2-Dimethyl-5-oxo-[1,3]dioxolan-4-yl)acetic acid

向L-苹果酸(3g，22.4mmol)在甲苯(25mL)内的悬浮液中加入2，2-二甲氧基丙烷(8.5g，81mmol)。将该悬浮液加热回流20分钟。通过真空蒸发除去溶剂，获得了(S)-(2，2-二甲基-5-氧代-[1，3]-4-基)-乙酸。1H-NMR(DMSO-d6)：δ1.52(6H，d)，2.75(2H，t)，4.78(1H，t).12.52(1H，brs).步骤B：(S)-(2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基甲基)氨基甲酸苄酯To a suspension of L-malic acid (3 g, 22.4 mmol) in toluene (25 mL) was added 2,2-dimethoxypropane (8.5 g, 81 mmol). The suspension was heated to reflux for 20 minutes. The solvent was removed by evaporation in vacuo to afford (S)-(2,2-dimethyl-5-oxo-[1,3]-4-yl)-acetic acid. 1 H-NMR (DMSO-d 6 ): δ1.52 (6H, d), 2.75 (2H, t), 4.78 (1H, t). 12.52 (1H, brs). Step B: (S)-(2 , Benzyl 2-dimethyl-5-oxo-[1,3]dioxolan-4-ylmethyl)carbamate

向在甲苯(20mL)内的(S)-(2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基)乙酸(1g，5.7mmol)和三乙胺(0.66 g，6.5mmol)中加入叠氮磷酸二苯酯(phosphorazidic acid diphenyl ester)(1.7g，6.2mmol)。将该溶液加热回流1小时。加入苯甲醇(0.54g，5mmol)，并继续回流6小时。冷却后，将该溶液在乙酸乙酯(2×50mL)与碳酸氢钠水溶液(10％，2×50mL)之间分配。合并有机层，干燥(硫酸钠)，并通过真空蒸发除去溶剂，获得了976 mg(S)-(2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基甲基)氨基甲酸苄酯粗产物，为油状物。1H-NMR(DMSO-d6)：δ1.53(6H，d)，3.34(1H，m)，3.50(1H，m)，4.50(1H，d)，4.64(1H，t)，5.03(2H，d)，7.32(5H，m)步骤C：(S)-2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基甲基三氟乙酸铵To (S)-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-yl)acetic acid (1 g, 5.7 mmol) in toluene (20 mL) and Phosphorazidic acid diphenyl ester (1.7 g, 6.2 mmol) was added to triethylamine (0.66 g, 6.5 mmol). The solution was heated to reflux for 1 hour. Benzyl alcohol (0.54 g, 5 mmol) was added and reflux was continued for 6 hours. After cooling, the solution was partitioned between ethyl acetate (2 x 50 mL) and aqueous sodium bicarbonate (10%, 2 x 50 mL). The organic layers were combined, dried (sodium sulfate), and the solvent was removed by evaporation in vacuo to afford 976 mg of (S)-(2,2-dimethyl-5-oxo-[1,3]dioxolane -4-ylmethyl)carbamate benzyl ester crude product as an oil. 1 H-NMR (DMSO-d 6 ): δ1.53 (6H, d), 3.34 (1H, m), 3.50 (1H, m), 4.50 (1H, d), 4.64 (1H, t), 5.03 ( 2H,d), 7.32 (5H,m) Step C: (S)-2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylmethyltrifluoro Ammonium acetate

将粗制(S)-(2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基甲基)氨基甲酸苄酯(976 mg，3.5mmol)溶解在乙醇(14mL)中，加入钯(10％披钯活性炭，300mg)和1，3-环己二烯(2.8g，35mmol)，将该反应在室温搅拌1小时，并在40℃加热10分钟。过滤后，加入TFA(0.4g，3.5mmol)，并通过蒸发除去溶剂，获得了(S)-2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基甲基三氟乙酸铵，为油状物。  1H-NMR(CDCl3)：δ1.46(6H，d)，3.40-3.70(2H，m)，4.38(1H，m)，7.25(＞4H，brs)；HPLC-MS(方法B)：m/z＝146(M+)；Rt＝0.38min.构件4：3-氨基-2-氟丙酸甲酯Crude benzyl (S)-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylmethyl)carbamate (976 mg, 3.5 mmol) Dissolved in ethanol (14 mL), added palladium (10% palladium on activated carbon, 300 mg) and 1,3-cyclohexadiene (2.8 g, 35 mmol), the reaction was stirred at room temperature for 1 hour, and heated at 40 ° C for 10 minute. After filtration, TFA (0.4 g, 3.5 mmol) was added and the solvent was removed by evaporation to give (S)-2,2-dimethyl-5-oxo-[1,3]dioxolane- 4-Ylmethylammonium trifluoroacetate as an oil. 1 H-NMR (CDCl 3 ): δ1.46 (6H, d), 3.40-3.70 (2H, m), 4.38 (1H, m), 7.25 (>4H, brs); HPLC-MS (method B): m/z = 146 (M + ); R t = 0.38 min. Building block 4: methyl 3-amino-2-fluoropropionate

将无水甲醇(5.3mL)在冰浴上冷却至-15℃，滴加亚硫酰氯(2.5mL)，同时将温度保持在5℃以下。向该冷的溶液中加入(RS)-3-氨基-2-氟丙酸(0.27g，2.52mmol)，并继续搅拌直至获得均匀溶液。移去冰浴，并继续在室温搅拌17小时。该溶液真空浓缩，进一步与无水甲醇共蒸发3次。过滤出残余物，用DCM洗涤并干燥，获得了0.13g(33％)3-氨基-2-氟丙酸甲酯盐酸盐，为固体。1H-NMR(DMSO-d6)：δ3.36(m，2H)，3.76(s，3H)，5.51(d，2H)，8.59(brs，3H).构件5：3-氨基-2(R)-甲氧基丙酸甲酯盐酸盐步骤(A)：(R)-2-羟基琥珀酸二甲酯Anhydrous methanol (5.3 mL) was cooled to -15°C on an ice bath, and thionyl chloride (2.5 mL) was added dropwise while keeping the temperature below 5°C. To this cold solution was added (RS)-3-amino-2-fluoropropionic acid (0.27 g, 2.52 mmol) and stirring was continued until a homogeneous solution was obtained. The ice bath was removed and stirring was continued at room temperature for 17 hours. The solution was concentrated in vacuo and further co-evaporated with anhydrous methanol 3 times. The residue was filtered off, washed with DCM and dried to afford 0.13 g (33%) of methyl 3-amino-2-fluoropropanoate hydrochloride as a solid. 1 H-NMR (DMSO-d 6 ): δ3.36 (m, 2H), 3.76 (s, 3H), 5.51 (d, 2H), 8.59 (brs, 3H). Building block 5: 3-amino-2( R)-Methyl methoxypropionate hydrochloride Step (A): (R)-Dimethyl 2-hydroxysuccinate

向(250mL)的冰冷溶液中加入乙酰氯(12.5mL)，将该溶液在0℃搅拌1小时。加入(R)-苹果酸(20.0g)，并将该溶液在室温搅拌16小时。通过真空蒸发除去溶剂，以定量产率获得了(R)-2-羟基琥珀酸二甲酯，为油状物。1H-NMR(CDCl3)：δ4.52(dd，1H)，3.80(s，3H)，3.71(s，3H)，3.55(bs，1H)，2.88(dd，1H)，2.80(dd，1H)步骤(B)：(R)-2-甲氧基琥珀酸二甲酯To an ice-cold solution of (250 mL) was added acetyl chloride (12.5 mL), and the solution was stirred at 0°C for 1 hr. (R)-Malic acid (20.0 g) was added and the solution was stirred at room temperature for 16 hours. The solvent was removed by evaporation in vacuo to afford (R)-dimethyl 2-hydroxysuccinate as an oil in quantitative yield. 1 H-NMR (CDCl 3 ): δ4.52(dd, 1H), 3.80(s, 3H), 3.71(s, 3H), 3.55(bs, 1H), 2.88(dd, 1H), 2.80(dd, 1H) Step (B): (R)-Dimethyl 2-methoxysuccinate

将上述(R)-2-羟基琥珀酸二甲酯再溶解在甲基碘(100mL)中，加入新制备的氧化银(30.2g)，并将该混合物在室温搅拌24小时。将该反应混合物用乙腈(200mL)稀释，经由硅藻土过滤以除去银盐和过量氢氧化银。将滤液干燥，获得了(R)-2-甲氧基琥珀酸二甲酯，为油状物(23.2g，88％)。1H-NMR(CDCl3)：δ4.20(dd，1H)，3.78(s，3H)，3.71(s，3H)，3.48(s，3H)，2.80(dd，2H).步骤(C)：(R)-2-甲氧基琥珀酸1-甲酯The above dimethyl (R)-2-hydroxysuccinate was redissolved in methyl iodide (100 mL), freshly prepared silver oxide (30.2 g) was added, and the mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with acetonitrile (200 mL), filtered through celite to remove silver salts and excess silver hydroxide. The filtrate was dried to afford (R)-dimethyl 2-methoxysuccinate as an oil (23.2 g, 88%). 1 H-NMR (CDCl 3 ): δ4.20(dd, 1H), 3.78(s, 3H), 3.71(s, 3H), 3.48(s, 3H), 2.80(dd, 2H). Step (C) : (R)-1-methyl 2-methoxysuccinate

将上述(R)-2-甲氧基琥珀酸二甲酯悬浮在2N盐酸中，加热回流30分钟，获得了澄清溶液。将溶剂真空蒸发，以定量产率获得了2(R)-甲氧基琥珀酸，为油状物。将该油状物再溶解在乙酸酐(120mL)中，并在110℃加热2小时。通过旋转蒸发除去溶剂，获得了油状物。加入冰冷的甲醇(150mL)，将该混合物在0℃搅拌3小时，然后在室温搅拌16小时。除去溶剂，获得了(R)-2-甲氧基琥珀酸1-甲酯。1H-NMR(CDCl3)：δ10.30(bs，1H)，4.19(dd，1H)，3.80(s，3H)，3.50(s，3H)，2.86(dd，1H)，2.78(dd，1H).步骤(D)：3-叔丁氧基羰基氨基-2(R)-甲氧基丙酸甲酯The above (R)-dimethyl 2-methoxysuccinate was suspended in 2N hydrochloric acid, and heated to reflux for 30 minutes to obtain a clear solution. The solvent was evaporated in vacuo to give 2(R)-methoxysuccinic acid as an oil in quantitative yield. The oil was redissolved in acetic anhydride (120 mL) and heated at 110 °C for 2 hours. Solvent was removed by rotary evaporation to give an oil. Ice-cold methanol (150 mL) was added, and the mixture was stirred at 0° C. for 3 hours, then at room temperature for 16 hours. The solvent was removed to obtain (R)-1-methyl 2-methoxysuccinate. 1 H-NMR (CDCl 3 ): δ10.30 (bs, 1H), 4.19 (dd, 1H), 3.80 (s, 3H), 3.50 (s, 3H), 2.86 (dd, 1H), 2.78 (dd, 1H). Step (D): Methyl 3-tert-butoxycarbonylamino-2(R)-methoxypropionate

不用进一步纯化，将上述(R)-2-甲氧基琥珀酸1-甲酯(5.0g，30.8mmol)溶解在亚硫酰氯(16mL)中，加热回流2小时，通过旋转蒸发除去亚硫酰氯和微量组分，然后与乙腈共蒸发。1H-NMR(CDCl3)：δ3.27(dd，1H)，3.48(dd，1H)，3.51(s，3H)，3.80(s，3H)，4.22(dd，1H).Without further purification, the above 1-methyl (R)-2-methoxysuccinate (5.0 g, 30.8 mmol) was dissolved in thionyl chloride (16 mL), heated to reflux for 2 hours, and the thionyl chloride was removed by rotary evaporation and minor components, then co-evaporated with acetonitrile. 1 H-NMR (CDCl 3 ): δ3.27(dd, 1H), 3.48(dd, 1H), 3.51(s, 3H), 3.80(s, 3H), 4.22(dd, 1H).

将纯净的酰基氯溶解在甲苯(50mL)中。加入三甲基甲硅烷基叠氮化物(5.0mL，38.2mmol)，并将该混合物在100℃加热过夜。加入叔丁醇(30mL)，继续加热16小时。将该反应混合物冷却，通过过滤除去不溶物。将有机相用水(100mL)、饱和碳酸氢钠溶液(100mL)、10％柠檬酸溶液(100mL)、水(100mL)和饱和氯化钠溶液(100mL)洗涤，然后用无水硫酸钠干燥。通过旋转蒸发除去溶剂。通过柱色谱法纯化残余的油状物，用20％乙酸乙酯/庚烷洗脱。合并纯的级分(用钼酸铵/硫酸铈/硫酸将TLC板染色)，并干燥。最终获得的3-叔丁氧基-羰基氨基-2(R)-甲氧基丙酸甲酯是600mg(9％)。Neat acid chloride was dissolved in toluene (50 mL). Trimethylsilyl azide (5.0 mL, 38.2 mmol) was added, and the mixture was heated at 100 °C overnight. Tert-butanol (30 mL) was added and heating continued for 16 hours. The reaction mixture was cooled, and insoluble materials were removed by filtration. The organic phase was washed with water (100 mL), saturated sodium bicarbonate solution (100 mL), 10% citric acid solution (100 mL), water (100 mL) and saturated sodium chloride solution (100 mL), then dried over anhydrous sodium sulfate. Solvent was removed by rotary evaporation. The residual oil was purified by column chromatography eluting with 20% ethyl acetate/heptane. Pure fractions were pooled (TLC plate stained with ammonium molybdate/cerium sulfate/sulfuric acid) and dried. The finally obtained methyl 3-tert-butoxy-carbonylamino-2(R)-methoxypropionate was 600 mg (9%).

1H-NMR(CDCl3)：δ6.93(t，1H)，3.83(t，1H)，3.64(s，3H)，3.25(s，3H)，3.18(dd，2H)，1.36(s， 1 H-NMR (CDCl 3 ): δ6.93(t, 1H), 3.83(t, 1H), 3.64(s, 3H), 3.25(s, 3H), 3.18(dd, 2H), 1.36(s,

9H).步骤(E)：3-氨基-2(R)-甲氧基丙酸甲酯盐酸盐9H). Step (E): 3-Amino-2(R)-methoxypropionic acid methyl ester hydrochloride

将3-叔丁氧基羰基氨基-2-甲氧基丙酸甲酯(500mg，2mmol)溶解在10％TFA在DCM内的溶液(20mL)中，将该反应混合物在室温搅拌30分钟。除去溶剂，将残余物与30mL1N氯化氢的乙醚溶液共蒸发2次。产量：320mg(88％)。1H-NMR(CDCl3)：δ8.25(s，3H)，4.21(dd，1H)，3.71(s，3H)，3.40(s，3H)，3.15(m，1H)，2.98(m，1H).构件6：(R)-3-(9H-芴-9-基甲氧基羰基氨基)-2-羟基丙酸((R)-Fmoc-异丝氨酸Methyl 3-tert-butoxycarbonylamino-2-methoxypropanoate (500 mg, 2 mmol) was dissolved in 10% TFA in DCM (20 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed and the residue was co-evaporated twice with 30 mL of 1N hydrogen chloride in ether. Yield: 320 mg (88%). 1 H-NMR (CDCl 3 ): δ8.25(s, 3H), 4.21(dd, 1H), 3.71(s, 3H), 3.40(s, 3H), 3.15(m, 1H), 2.98(m, 1H). Building block 6: (R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-2-hydroxypropionic acid ((R)-Fmoc-isoserine

向(R)-(2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基)乙酸(5.88g，33.8mmol)中加入甲苯(100mL)、三乙胺(4.7mL，33.8mmol)和二苯氧基磷酰基叠氮化物(8.0mL，37.2mmol)。将该反应混合物加热至100℃，并在氮气氛下于100℃搅拌1.5小时。加入9-芴甲醇(5.1g，26mmol)，并将该反应混合物回流6小时。冷却至室温后，将该混合物转移到分液漏斗中，并用水(2×50mL)洗涤。真空除去溶剂，并与乙腈(100mL)共蒸发。将残余的浅棕色油状物溶解在DCM(20mL)中，在硅胶柱上纯化，用DCM作为洗脱剂。通过蒸发除去DCM，获得了浅黄色油状物，将其再溶解在乙腈(150mL)中，并加入盐酸(1N，75mL)。将该黄色反应混合物在室温搅拌3小时。真空除去溶剂，加入甲苯(100mL)，并将该悬浮液加热回流，冷却至室温。通过过滤分离出(R)-Fmoc-异丝氨酸(3.1g，28％)，为粉末。Mp：165-166℃。1H-NMR(DMSO-d6)：δ12.5(brs，1H)，7.90(m，2H)，7.70(m，2 H)，7.50-7.30(m，4H)，5.45(brs，1H)，4.23(m，3H)，4.05(m，1H)，3.17(m，1H)；HPLC-MS (方法B)：m/z＝350(M+Na)；Rt＝3.20min.构件7：3-(叔丁基二甲基甲硅烷氧基甲基)-4-三氟甲氧基苯基胺( 3-(tert-Butyldimethylsilanyloxymethyl)-4-trifluoromethoxyphenyl amine)步骤A：5-硝基-2-三氟甲氧基苯甲酸甲酯To (R)-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-yl)acetic acid (5.88 g, 33.8 mmol) was added toluene (100 mL), Triethylamine (4.7 mL, 33.8 mmol) and diphenoxyphosphoryl azide (8.0 mL, 37.2 mmol). The reaction mixture was heated to 100°C and stirred at 100°C for 1.5 hours under nitrogen atmosphere. 9-Fluorenemethanol (5.1 g, 26 mmol) was added and the reaction mixture was refluxed for 6 hours. After cooling to room temperature, the mixture was transferred to a separatory funnel and washed with water (2 x 50 mL). The solvent was removed in vacuo and coevaporated with acetonitrile (100 mL). The residual light brown oil was dissolved in DCM (20 mL) and purified on a silica gel column using DCM as eluent. DCM was removed by evaporation to give a light yellow oil which was redissolved in acetonitrile (150 mL) and hydrochloric acid (1 N, 75 mL) was added. The yellow reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, toluene (100 mL) was added, and the suspension was heated to reflux and cooled to room temperature. (R)-Fmoc-Isoserine (3.1 g, 28%) was isolated by filtration as a powder. Mp: 165-166°C. 1 H-NMR (DMSO-d 6 ): δ12.5(brs, 1H), 7.90(m, 2H), 7.70(m, 2H), 7.50-7.30(m, 4H), 5.45(brs, 1H) , 4.23 (m, 3H), 4.05 (m, 1H), 3.17 (m, 1H); HPLC-MS (method B): m/z = 350 (M+Na); R t = 3.20 min. Building block 7: 3-(tert-Butyldimethylsilyloxymethyl)-4-trifluoromethoxyphenylamine ( 3-(tert-Butyldimethylsilyloxymethyl)-4-trifluoromethoxyphenyl amine ) Step A: 5-nitro-2 -Methyl trifluoromethoxybenzoate

在装配有温度计和分液漏斗的三颈圆底烧瓶中，将HNO3(5mL发烟硝酸，100％)在冰浴中冷却。用0.5小时将2-(三氟甲氧基)苯甲酸甲酯(5g，22.7mmol)缓慢地加到冷却的硝酸中，同时将温度保持在15℃以下。然后将该反应在60℃搅拌1小时，在室温搅拌2小时。将该反应混合物加到冰水中，分离出油状物。将该油状残余物加到水(50mL)中，用碳酸氢钠水溶液中和，然后用乙酸乙酯(25mL)萃取。再用乙酸乙酯(15mL)将水相萃取一次。将合并的有机相用饱和氯化钠(2×15mL)洗涤，干燥(硫酸镁)，并真空浓缩，获得了5.69g5-硝基-2-三氟甲氧基苯甲酸甲酯。1H-NMR(DMSO-d6)：δ3.93(3H，s)，7.82(1H，d)，8.58(1H，d)，8.67(1H，s).步骤B：5-氨基-2-三氟甲氧基苯甲酸甲酯In a three-neck round bottom flask equipped with a thermometer and a separatory funnel, HNO3 (5 mL fuming nitric acid, 100%) was cooled in an ice bath. Methyl 2-(trifluoromethoxy)benzoate (5 g, 22.7 mmol) was added slowly to the cooled nitric acid over 0.5 hours while keeping the temperature below 15°C. The reaction was then stirred at 60°C for 1 hour and at room temperature for 2 hours. The reaction mixture was added to ice water and an oil was separated. The oily residue was added to water (50 mL), neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate (25 mL). The aqueous phase was extracted once more with ethyl acetate (15 mL). The combined organic phases were washed with saturated sodium chloride (2 x 15 mL), dried (magnesium sulfate), and concentrated in vacuo to afford 5.69 g of methyl 5-nitro-2-trifluoromethoxybenzoate. 1 H-NMR (DMSO-d 6 ): δ3.93 (3H, s), 7.82 (1H, d), 8.58 (1H, d), 8.67 (1H, s). Step B: 5-amino-2- Methyl trifluoromethoxybenzoate

将5-硝基-2-三氟甲氧基苯甲酸甲酯(5.69 g，21.5mmol)溶解在99.9％乙醇(80mL)中，加入氯化亚锡(II)二水合物(24.2g，107mmol)。将该悬浮液在75℃搅拌2小时，然后真空浓缩。将残余物加到乙酸乙酯(100mL)和水(50mL)中，并用4N氢氧化钠(50mL)将pH调节至8。将液体从生成的细沉淀中倾出，用乙酸乙酯洗涤沉淀并倾出，该操作进行2次。将合并的有机相用水∶饱和氯化钠(1∶1)溶液(2×100mL)洗涤，干燥(硫酸镁)，并真空浓缩。通过柱色谱(120g二氧化硅)纯化残余物，用乙酸乙酯∶庚烷(1∶1)洗脱，获得了3.8g5-氨基-2-三氟甲氧基苯甲酸甲酯。1H-NMR(DMSO-d6)：δ3.82(3H，s)，5.63(2H，s)，6.79(1H，d)，7.07(1H，s)，7.11(1H，d).步骤C：(5-氨基-2-三氟甲氧基苯基)甲醇Dissolve methyl 5-nitro-2-trifluoromethoxybenzoate (5.69 g, 21.5 mmol) in 99.9% ethanol (80 mL), add stannous(II) chloride dihydrate (24.2 g, 107 mmol ). The suspension was stirred at 75°C for 2 hours, then concentrated in vacuo. The residue was added to ethyl acetate (100 mL) and water (50 mL), and the pH was adjusted to 8 with 4N sodium hydroxide (50 mL). The liquid was decanted from the resulting fine precipitate, which was washed with ethyl acetate and decanted twice. The combined organic phases were washed with water:saturated sodium chloride (1 :1 ) solution (2 x 100 mL), dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by column chromatography (120 g silica) eluting with ethyl acetate:heptane (1:1) to afford 3.8 g of methyl 5-amino-2-trifluoromethoxybenzoate. 1 H-NMR (DMSO-d 6 ): δ3.82 (3H, s), 5.63 (2H, s), 6.79 (1H, d), 7.07 (1H, s), 7.11 (1H, d). Step C : (5-amino-2-trifluoromethoxyphenyl)methanol

在装配有温度计和分液漏斗的三颈烧瓶中，在氮气氛下将5-氨基-2-三氟甲氧基苯甲酸甲酯(3.0g，12.8mmol)溶解在THF(20mL)中。在搅拌下用10分钟滴加冰冷的氢化锂铝(1MTHF溶液，15mL)。继续在室温搅拌1小时，将该反应混合物真空浓缩。将残余物悬浮在DCM(150mL)和水(50mL)中，并经由硅藻土过滤。将滤液在DCM与水之间分配。将合并的有机相用水(2×20mL)洗涤，干燥(硫酸镁)，并真空浓缩，获得了2.47g(5-氨基-2-三氟甲氧基苯基)甲醇。1H-NMR(DMSO-d6)：δ3.92(2H，d)，5.18(1H，t)，5.28(2H，s)，6.45(1H，d)，6.91(1H，d).步骤(D)：3-(叔丁基二甲基甲硅烷氧基甲基)-4-三氟甲氧基苯基苯胺In a three-necked flask equipped with a thermometer and a separatory funnel, methyl 5-amino-2-trifluoromethoxybenzoate (3.0 g, 12.8 mmol) was dissolved in THF (20 mL) under a nitrogen atmosphere. Ice-cold lithium aluminum hydride (1M THF solution, 15 mL) was added dropwise with stirring over 10 minutes. Stirring was continued at room temperature for 1 hour, and the reaction mixture was concentrated in vacuo. The residue was suspended in DCM (150 mL) and water (50 mL), and filtered through celite. The filtrate was partitioned between DCM and water. The combined organic phases were washed with water (2 x 20 mL), dried (magnesium sulfate), and concentrated in vacuo to afford 2.47 g of (5-amino-2-trifluoromethoxyphenyl)methanol. 1 H-NMR (DMSO-d 6 ): δ3.92 (2H, d), 5.18 (1H, t), 5.28 (2H, s), 6.45 (1H, d), 6.91 (1H, d). Step ( D): 3-(tert-butyldimethylsilyloxymethyl)-4-trifluoromethoxyphenylaniline

将(5-氨基-2-三氟甲氧基苯基)甲醇(1.2g，5.8mmol)溶解在DMF(5mL)中，加入咪唑(0.48g，7.1mmol)和叔丁基二甲基甲硅烷基氯(0.99g，6.6mmol)，并将该混合物搅拌16小时。用乙酸乙酯(50mL)和水(20mL)萃取该反应混合物。用乙酸乙酯(20mL)将水相再萃取一次。将合并的有机相用水(10mL)、柠檬酸水溶液(10mL，10％)和水(2×10mL)洗涤，干燥(硫酸镁)并真空浓缩。通过柱色谱法(110g，硅胶)纯化残余物，用乙酸乙酯和庚烷(1∶3)作为洗脱剂，获得了1.2g3-(叔丁基二甲基甲硅烷氧基甲基)-4-三氟甲氧基苯基苯胺。1H-NMR(DMSO-d6)：δ0.82(9H，s)，3.25(6H，s)，4.52(2H，s)，5.23(2H，s)，6.41(1H，d)，6.61(1H，s)，6.86(1H，d).构件8：4-环己-1-烯基苯胺Dissolve (5-amino-2-trifluoromethoxyphenyl)methanol (1.2 g, 5.8 mmol) in DMF (5 mL), add imidazole (0.48 g, 7.1 mmol) and tert-butyldimethylsilane diethyl chloride (0.99 g, 6.6 mmol), and the mixture was stirred for 16 hours. The reaction mixture was extracted with ethyl acetate (50 mL) and water (20 mL). The aqueous phase was extracted one more time with ethyl acetate (20 mL). The combined organic phases were washed with water (10 mL), aqueous citric acid (10 mL, 10%) and water (2 x 10 mL), dried (magnesium sulfate) and concentrated in vacuo. Purification of the residue by column chromatography (110 g, silica gel) using ethyl acetate and heptane (1:3) as eluent gave 1.2 g of 3-(tert-butyldimethylsilyloxymethyl)- 4-Trifluoromethoxyphenylaniline. 1 H-NMR (DMSO-d 6 ): δ0.82 (9H, s), 3.25 (6H, s), 4.52 (2H, s), 5.23 (2H, s), 6.41 (1H, d), 6.61 ( 1H, s), 6.86(1H, d). Building block 8: 4-cyclohex-1-enylaniline

该化合物是按照类似于J.v.Braun等人，J.Liebigs Ann.Chem.，472(1929)，1-89中描述的方法制得的，即将苯胺(2当量)、环己酮(1当量)在乙醇和37％盐酸中回流4-5天，然后加入乙酸乙酯、水、和氢氧化钠，用85％磷酸中和，相分离，并将有机相蒸馏。向残余物中加入催化量的硫酸，并蒸馏(180℃，5-7毫巴)。再将残余物蒸馏(120℃，3毫巴)，获得了(在残余物中)所需的4-环己-1-烯基苯胺。1HNMR(DMSO-d6)：δ1.50-1.60(m，2H)，1.60-1.70(m，2H)，2.10-2.15(m，2H)，2.20-2.30(brds，2H)，5.00(s，2H)，5.90(t，1H)，6.50(d，2H)，7.10(d，2H).构件9：4-环己基苯胺The compound was prepared in a manner similar to that described by Jv Braun et al., J. Liebigs Ann. Chem., 472(1929), 1-89, by dissolving aniline (2 eq.), cyclohexanone (1 eq.) in ethanol Reflux with 37% hydrochloric acid for 4-5 days, then add ethyl acetate, water, and sodium hydroxide, neutralize with 85% phosphoric acid, separate the phases, and distill the organic phase. A catalytic amount of sulfuric acid was added to the residue and distilled (180° C., 5-7 mbar). Subsequent distillation of the residue (120° C., 3 mbar) affords (in the residue) the desired 4-cyclohex-1-enylaniline. 1 HNMR (DMSO-d 6 ): δ1.50-1.60 (m, 2H), 1.60-1.70 (m, 2H), 2.10-2.15 (m, 2H), 2.20-2.30 (brds, 2H), 5.00 (s , 2H), 5.90(t, 1H), 6.50(d, 2H), 7.10(d, 2H). Building block 9: 4-cyclohexylaniline

该化合物是商购获得的(例如得自Lancaster或Avocado)。构件10：4-环己基环己基胺This compound is commercially available (eg from Lancaster or Avocado). Building block 10: 4-cyclohexylcyclohexylamine

该化合物的制备描述在文献中，参见H.Booth等人，J.Chem.Soc.(B)，1971，1047-1050。构件11：4-(2-甲基环己-1-烯基)苯胺和(R，S)-4-(6-甲基环己-1-烯基)苯胺

Figure A0181159100651
The preparation of this compound is described in the literature, see H. Booth et al., J. Chem. Soc. (B), 1971, 1047-1050. Building block 11: 4-(2-methylcyclohex-1-enyl)aniline and (R,S)-4-(6-methylcyclohex-1-enyl)aniline
Figure A0181159100651

将2-甲基环己酮(112g，1,0mol)、苯胺(186g，2mol)和乙醇(26mL)的混合物在室温搅拌，用30分钟加入12M盐酸(167mL)。将该深黄色溶液在85℃回流7天。将该溶液冷却，并用乙酸乙酯稀释。将该混合物在冰浴中搅拌，并用27％氢氧化钠溶液碱化(pH＝9)，将温度保持在30℃以下。分离出有机层，用盐水洗涤(3×)，用硫酸镁干燥，浓缩，获得了棕色油状物(131g)。减压除去过量苯胺。加入催化量的12M盐酸(1mL)，将该残余物在高度真空下分馏。收集在145-175℃(0.2mmHg)蒸馏出来的馏份，并进行色谱纯化(硅胶)，用30％乙酸乙酯/甲苯洗脱，获得了4-(2-甲基环己-1-烯基)苯胺和(R，S)-4-(6-甲基环己-1-烯基)苯胺的9∶1混合物(8.7g)。4-(2-甲基环己-1-烯基)苯胺：1HNMR(DMSO-d6)：δ1,53(s，3H)，1,61(m，4H)，2,00(bs，2H)，2,13(bs，2H)，4,92(s，2H)，6,50(d，2H)，6,79(d，2H)；HPLC-MS(方法B)：m/z＝188(M+)；Rt＝2,96min.(R，S)-4-(6-甲基环己-1-烯基)苯胺：1HNMR(DMSO-d6)：δ0,88(d，3H)，1,61(m，4H)，2,00(bs，2H)，2,13(bs，2H)，2,74(m，1H)，4,92(s，2H)，5,68(t，1H)，6,50(d，2H)，6,79(d，2H).构件12：4-(4-叔丁基环己-1-烯基)苯胺

Figure A0181159100661
A mixture of 2-methylcyclohexanone (112 g, 1,0 mol), aniline (186 g, 2 mol) and ethanol (26 mL) was stirred at room temperature, and 12M hydrochloric acid (167 mL) was added over 30 minutes. The dark yellow solution was refluxed at 85°C for 7 days. The solution was cooled and diluted with ethyl acetate. The mixture was stirred in an ice bath and basified (pH=9) with 27% sodium hydroxide solution, keeping the temperature below 30°C. The organic layer was separated, washed with brine (3x), dried over magnesium sulfate and concentrated to give a brown oil (131 g). Excess aniline was removed under reduced pressure. A catalytic amount of 12M hydrochloric acid (1 mL) was added and the residue was fractionally distilled under high vacuum. Fractions distilled at 145-175°C (0.2 mmHg) were collected and chromatographed (silica gel) eluting with 30% ethyl acetate/toluene to give 4-(2-methylcyclohex-1-ene 9:1 mixture of (R,S)-4-(6-methylcyclohex-1-enyl)aniline (8.7 g). 4-(2-Methylcyclohex-1-enyl)aniline: 1 HNMR (DMSO-d 6 ): δ1,53(s, 3H), 1,61(m, 4H), 2,00(bs, 2H), 2, 13(bs, 2H), 4, 92(s, 2H), 6, 50(d, 2H), 6, 79(d, 2H); HPLC-MS (Method B): m/z =188(M + ); R t =2,96 min. (R,S)-4-(6-methylcyclohex-1-enyl)aniline: 1 HNMR (DMSO-d 6 ): δ0,88( d,3H), 1,61(m,4H), 2,00(bs,2H), 2,13(bs,2H), 2,74(m,1H), 4,92(s,2H), 5,68(t,1H), 6,50(d,2H), 6,79(d,2H). Building block 12: 4-(4-tert-butylcyclohex-1-enyl)aniline
Figure A0181159100661

4-(4-叔丁基环己-1-烯基)苯胺是按照类似于制备构件11的方法，使用4-叔丁基环己酮(0.59mol)和苯胺制得的。1H NMR(DMSO-d6)：δ0,88(s，9H)，1,21(m，2H)，1,90(m，2H)，2,10-2,50(m，3H)，4,97(s,2H)，5,90(m，1H)，6,50(d，2H)，7,06(d，2H)；HPLC-MS(方法B)：m/z＝230(M+)；Rt＝4,07min.构件13：(R，S)-4-(5-甲基环己-1-烯基)苯胺和(R，S)-4-(3-甲基环己-1-烯基)苯胺

Figure A0181159100671
4-(4-tert-Butylcyclohex-1-enyl)aniline was prepared analogously to the preparation of building 11 using 4-tert-butylcyclohexanone (0.59 mol) and aniline. 1 H NMR (DMSO-d 6 ): δ0,88(s, 9H), 1,21(m, 2H), 1,90(m, 2H), 2,10-2,50(m, 3H), 4,97(s,2H), 5,90(m,1H), 6,50(d,2H), 7,06(d,2H); HPLC-MS (method B): m/z=230( M + ); R t =4,07 min. Building block 13: (R,S)-4-(5-methylcyclohex-1-enyl)aniline and (R,S)-4-(3-methyl Cyclohex-1-enyl)aniline
Figure A0181159100671

将(R，S)-3-甲基环己酮(123mL，1.0mol)、苯胺(182mL，2.0mol)、12M盐酸(167mL，2.0mol)、和乙醇(26mL)的混合物在90℃回流10天。将该溶液冷却，并用乙酸乙酯稀释。用6M氢氧化钠溶液将水层碱化(pH＝10)。分离出有机层，用盐水洗涤(3×)，用硫酸镁干燥，浓缩，获得了棕色油状物。减压除去过量苯胺。加入催化量的12M盐酸(1mL)，将残余物在高度真空下分馏。收集在123-128℃(0.15-0.20mmHg)蒸馏出来的馏份，获得了21.0g油状物。1H-NMR表明存在(R，S)-4-(5-甲基环己-1-烯基)苯胺和(R，S)-4-(3-甲基环己-1-烯基)苯胺的3∶2混合物。(R，S)-4-(5-甲基环己-1-烯基)苯胺：1HNMR(DMSO-d6)：δ1.00(d，3H)，1.45-1.95(m，3H)，2.10-2.45(m，3H)，5.04(s，2H)，5.86(t，1H)，6.48(d，2H)，7.06(d，2H).(R，S)-4-(3-甲基环己-1-烯基)苯胺：1HNMR(DMSO-d6)：δ1.00(d，3H)，1.45-1.95(m，3H)，2.10-2.45(m，3H)，5.04(s，2H)，5.75(d，1H)，6.48(d，2H)，7.06(d，2H).用于液相合成通式(Ia)和(Ib)化合物的一般方法(A)：其中R2、R3、R7、R8、A、E和D的定义同式(I)中所述。A mixture of (R,S)-3-methylcyclohexanone (123mL, 1.0mol), aniline (182mL, 2.0mol), 12M hydrochloric acid (167mL, 2.0mol), and ethanol (26mL) was refluxed at 90°C for 10 sky. The solution was cooled and diluted with ethyl acetate. The aqueous layer was basified (pH=10) with 6M sodium hydroxide solution. The organic layer was separated, washed with brine (3x), dried over magnesium sulfate, and concentrated to give a brown oil. Excess aniline was removed under reduced pressure. A catalytic amount of 12M hydrochloric acid (1 mL) was added and the residue was fractionally distilled under high vacuum. Fractions distilled at 123-128°C (0.15-0.20 mmHg) were collected to obtain 21.0 g of an oily substance. 1 H-NMR showed the presence of (R,S)-4-(5-methylcyclohex-1-enyl)aniline and (R,S)-4-(3-methylcyclohex-1-enyl) 3:2 mixture of aniline. (R,S)-4-(5-methylcyclohex-1-enyl)aniline: 1 HNMR (DMSO-d 6 ): δ1.00 (d, 3H), 1.45-1.95 (m, 3H), 2.10-2.45(m, 3H), 5.04(s, 2H), 5.86(t, 1H), 6.48(d, 2H), 7.06(d, 2H).(R, S)-4-(3-Methyl Cyclohex-1-enyl)aniline: 1 HNMR (DMSO-d 6 ): δ1.00 (d, 3H), 1.45-1.95 (m, 3H), 2.10-2.45 (m, 3H), 5.04 (s, 2H), 5.75(d, 1H), 6.48(d, 2H), 7.06(d, 2H). General method (A) for liquid phase synthesis of compounds of general formula (Ia) and (Ib): The definitions of R 2 , R 3 , R 7 , R 8 , A, E and D are the same as those in formula (I).

由一般方法(A)生成的化合物可经由酯途径或羧酸途径制得。这两条途径的唯一不同在于将苯甲酸作为酯保护起来。将酯脱保护(步骤2a)，获得了等同于羧酸途径的中间体。Compounds produced by general method (A) can be prepared via the ester route or the carboxylic acid route. The only difference between the two approaches is the protection of the benzoic acid as an ester. Deprotection of the ester (step 2a) affords an intermediate equivalent to the carboxylic acid pathway.

实施例1和2中举例说明了依据酯途径的方法，实施例3中举例说明了依据羧酸途径的方法。实施例1(一般方法(A))(R)-3-{4-[1-(4-环己基苯基)-3-(3-甲氧基-5-三氟甲基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸步骤1：4-((4-环己基苯基氨基)甲基)苯甲酸甲酯Methods based on the ester route are illustrated in Examples 1 and 2, and methods based on the carboxylic acid route are illustrated in Example 3. Example 1 (General Method (A)) (R)-3-{4-[1-(4-cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)urea methyl]benzoylamino}-2-hydroxypropionic acid Step 1: Methyl 4-((4-cyclohexylphenylamino)methyl)benzoate

将4-甲酰基苯甲酸甲酯(6.65g，40.5mmol)溶解在热的甲醇(175mL)中。向该混合物中加入4-环己基苯胺(7.1g，40.5mmol)。向所得悬浮液中加入甲醇(75mL)，并将该混合物加热回流1小时。冷却至0℃以后，将该混合物过滤，将固体用冰冷的甲醇洗涤，并在40℃真空干燥16小时，获得了10.95g4-[(4-环己基苯基亚氨基)-甲基]苯甲酸甲酯。将该化合物(10.93g，34mmol)悬浮在甲醇(200mL)中，加入冰醋酸(27mL)，然后以少量多次的方式加入氰基硼氢化钠(1.9g，30mmol)。将该混合物在室温搅拌1小时，并真空浓缩。将残余物溶解在DCM(200mL)中，用5％碳酸钠水溶液(5×80mL)洗涤，干燥(硫酸镁)，并真空浓缩。向残余物中加入乙酸乙酯(100mL)和正庚烷(200mL)，并真空浓缩至初始体积的一半。过滤出固体，用正庚烷洗涤，在40℃真空干燥16小时，获得了9.52g(87％)4-((4-环己基苯基氨基)甲基)苯甲酸甲酯。Dissolve methyl 4-formylbenzoate (6.65 g, 40.5 mmol) in hot methanol (175 mL). To this mixture was added 4-cyclohexylaniline (7.1 g, 40.5 mmol). To the resulting suspension was added methanol (75 mL), and the mixture was heated to reflux for 1 hr. After cooling to 0°C, the mixture was filtered, the solid was washed with ice-cold methanol, and dried under vacuum at 40°C for 16 hours to obtain 10.95 g of 4-[(4-cyclohexylphenylimino)-methyl]benzoic acid methyl ester. This compound (10.93 g, 34 mmol) was suspended in methanol (200 mL), glacial acetic acid (27 mL) was added, followed by sodium cyanoborohydride (1.9 g, 30 mmol) in small portions. The mixture was stirred at room temperature for 1 hour, and concentrated in vacuo. The residue was dissolved in DCM (200 mL), washed with 5% aqueous sodium carbonate (5 x 80 mL), dried (magnesium sulfate), and concentrated in vacuo. Ethyl acetate (100 mL) and n-heptane (200 mL) were added to the residue and concentrated in vacuo to half the original volume. The solid was filtered off, washed with n-heptane, and dried under vacuum at 40° C. for 16 hours to obtain 9.52 g (87%) of methyl 4-((4-cyclohexylphenylamino)methyl)benzoate.

1H-NMR(DMSO-d6)：δ1.2-1.4(5H，m)，1.65(5H，m)，2.30(1H，t)，3.84(3H，s)，4.30(2H，d)， 1 H-NMR (DMSO-d 6 ): δ1.2-1.4 (5H, m), 1.65 (5H, m), 2.30 (1H, t), 3.84 (3H, s), 4.30 (2H, d),

6.18(1H，t)，6.50(2H，d)，6.87(2H，d)，7.49(2H，d)，7.92(2H，d)；HPLC-MS(方法B)：m/z6.18(1H,t), 6.50(2H,d), 6.87(2H,d), 7.49(2H,d), 7.92(2H,d); HPLC-MS (Method B): m/z

＝324(M+1)；Rt=7.18min步骤2：4-[1-(环己基苯基)-3-(3-甲氧基-5-三氟甲基苯基)脲基甲基]苯甲酸甲酯=324(M+1); Rt =7.18min Step 2: 4-[1-(cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl ]Methyl benzoate

将5-甲氧基-3-(三氟甲基)苯胺(2.0g，10.5mmol)溶解在乙酸乙酯(10mL)中，加入无水HCl在乙酸乙酯(15mL)中的溶液，并真空除去溶剂。将该固体与甲苯(3×15mL)共蒸发。加入甲苯(75mL)和双光气(13mL)，将该反应混合物在氮气氛下回流2.5小时。真空除去过量双光气，将澄清的油状物与甲苯共蒸发。获得的异氰酸酯不用进一步纯化直接使用。5-Methoxy-3-(trifluoromethyl)aniline (2.0 g, 10.5 mmol) was dissolved in ethyl acetate (10 mL), a solution of anhydrous HCl in ethyl acetate (15 mL) was added, and vacuum Solvent was removed. The solid was co-evaporated with toluene (3 x 15 mL). Toluene (75 mL) and diphosgene (13 mL) were added and the reaction mixture was refluxed under nitrogen atmosphere for 2.5 hours. Excess diphosgene was removed in vacuo and the clear oil was coevaporated with toluene. The obtained isocyanate was used without further purification.

将上述异氰酸酯溶解在DCM(75mL)中，加入4-((4-环己基苯基氨基)-甲基)苯甲酸甲酯(2.3g，7.1mmol)。将该反应混合物在室温搅拌过夜，真空除去溶剂，通过硅胶柱色谱纯化残余的油状物，用庚烷与乙酸乙酯(7∶3)的混合物洗脱。获得了3g4-[1-(环己基苯基)-3-(3-甲氧基-5-三氟-甲基苯基)脲基甲基]苯甲酸甲酯，为油状物。1H-NMR(DMSO-d6)：δ1.22(宽峰，1H)，1.37(宽峰，4H)，1.7(宽峰，1H)，1.79(宽峰，4H)，3.77(s，3H)，3.83(s，3H)，4.98(s，2H)，6.81(s，1H)，7.18(d，2H)，7.23(d，2H)，7.42(m，3H)，7.51(s，1H)，7.90(d，2H)，8.53(s，1H)，10.01(s，1H)；HPLC-MS(方法A)：m/z＝541(M+1)；Rt＝8.98min.步骤2a：4-[1-(环己基苯基)-3-(3-甲氧基-5-三氟甲基苯基)脲基甲基]苯甲酸The above isocyanate was dissolved in DCM (75 mL) and methyl 4-((4-cyclohexylphenylamino)-methyl)benzoate (2.3 g, 7.1 mmol) was added. The reaction mixture was stirred at room temperature overnight, the solvent was removed in vacuo and the residual oil was purified by column chromatography on silica gel, eluting with a mixture of heptane and ethyl acetate (7:3). 3 g of methyl 4-[1-(cyclohexylphenyl)-3-(3-methoxy-5-trifluoro-methylphenyl)ureidomethyl]benzoate were obtained as an oil. 1 H-NMR (DMSO-d 6 ): δ1.22 (broad peak, 1H), 1.37 (broad peak, 4H), 1.7 (broad peak, 1H), 1.79 (broad peak, 4H), 3.77 (s, 3H ), 3.83(s, 3H), 4.98(s, 2H), 6.81(s, 1H), 7.18(d, 2H), 7.23(d, 2H), 7.42(m, 3H), 7.51(s, 1H) , 7.90(d, 2H), 8.53(s, 1H), 10.01(s, 1H); HPLC-MS (method A): m/z=541(M+1); Rt =8.98min. Step 2a: 4-[1-(cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoic acid

将4-[1-(环己基苯基)-3-(3-甲氧基-5-三氟甲基苯基)脲基甲基]苯甲酸甲酯(3.0g)溶解在无水乙醇(50mL)中，加入氢氧化钠(4N，15mL)，将该反应混合物在室温搅拌16小时。真空除去有机溶剂，加入水(50mL)，用盐酸(4N)将pH调节至酸性反应，然后加入乙酸乙酯(200mL)。将有机相用水(5×50mL)洗涤，干燥(硫酸镁)，过滤并真空蒸发。将残余物从乙腈(25mL)中重结晶，获得了4-[1-(环己基苯基)-3-(3-甲氧基-5-三氟甲基苯基)脲基甲基]苯甲酸(1.83g)，为晶体。1H-NMR(DMSO-d6)：δ1.22(m，1H)，1.37(m，4H)，1.70(m，1H)，1.79(m，4H)，3.77(s，3H)，4.95(s，2H)，6.81(s，1H)，7.18(d，2H)，7.23(d，2H)，7.40(d，2H)，7.42(s，1H)，7.51(s，1H)，7.89(d，2H)，8.55(s，1H)，12.90(s，1H)；HPLC-MS(方法A)：m/z＝527(M+1)；Rt＝8.23min；M.p.148-150℃.元素分析：C29H29N2F3O4的计算值：C，66.15％；H5.55％；N5.32％.实测值：C，66.65％；H5.70％；N5.33％.步骤3：(R)-3-{4-[1-(4-环己基苯基)-3-(3-甲氧基-5-三氟甲基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸乙酯Dissolve methyl 4-[1-(cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoate (3.0 g) in absolute ethanol ( 50 mL), sodium hydroxide (4N, 15 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. The organic solvent was removed in vacuo, water (50 mL) was added, the pH was adjusted to acidic reaction with hydrochloric acid (4N), and ethyl acetate (200 mL) was added. The organic phase was washed with water (5 x 50 mL), dried (magnesium sulfate), filtered and evaporated in vacuo. The residue was recrystallized from acetonitrile (25 mL) to give 4-[1-(cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzene Formic acid (1.83 g), as crystals. 1 H-NMR (DMSO-d 6 ): δ1.22 (m, 1H), 1.37 (m, 4H), 1.70 (m, 1H), 1.79 (m, 4H), 3.77 (s, 3H), 4.95 ( s, 2H), 6.81(s, 1H), 7.18(d, 2H), 7.23(d, 2H), 7.40(d, 2H), 7.42(s, 1H), 7.51(s, 1H), 7.89(d , 2H), 8.55(s, 1H), 12.90(s, 1H); HPLC-MS (method A): m/z=527(M+1); R t =8.23min; Mp148-150°C. Elemental analysis : Calculated for C29H29N2F3O4 : C, 66.15%; H5.55%; N5.32% . Found: C, 66.65%; H5.70%; N5.33% . Step 3 : (R)-3-{4-[1-(4-cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoylamino} -Ethyl 2-hydroxypropionate

将4-[1-(环己基苯基)-3-(3-甲氧基-5-三氟甲基苯基)脲基甲基]苯甲酸(420mg，0.8mmol)溶解在DMF(10mL)中，然后加入HOBt(160mg，1.2mmol)和EDAC(230mg，1.2mmol)。将该反应混合物静置30分钟，然后加入溶解在DMF(5mL)中的(R)-异丝氨酸乙酯(260mg，1.2mmol)和二异丙基乙基胺(210mL，1.2mmol)，并将该反应混合物在室温搅拌16小时。加入水(50mL)和乙酸乙酯(100mL)，将有机相用水(5×50mL)洗涤，干燥(硫酸镁)，过滤并真空蒸发。通过硅胶柱色谱纯化残余物，用庚烷与乙酸乙酯的混合物(1∶3)洗脱，获得了510mg(R)-3-{4-[1-(4-环己基苯基)-3-(3-甲氧基-5-三氟甲基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸乙酯，为无定形固体。1H-NMR(DMSO-d6)：δ1.12(t，3H)，1.22(m，1H)，1.37(m，4H)，1.70(m，1H)，1.79(宽峰，4H)，3.41(m，1H)，3.52(m，1H)，3.77(s，3H)，4.06(q，2H)，4.21(q，1H)，4.95(s，2H)，5.68(d，1H)，6.81(s，1H)，7.18(d，2H)，7.23(d，2H)，7.33(d，2H)，7.42(s，1H)，7.51(s，1H)，7.77(d，2H)，8.47(t，1H)，8.53(s，1H)；HPLC-MS(方法A)：m/z＝658(M+1)；Rt＝8.17min.步骤4：4-[1-(Cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoic acid (420 mg, 0.8 mmol) was dissolved in DMF (10 mL) , then HOBt (160 mg, 1.2 mmol) and EDAC (230 mg, 1.2 mmol) were added. The reaction mixture was left to stand for 30 minutes, then (R)-isoserine ethyl ester (260 mg, 1.2 mmol) and diisopropylethylamine (210 mL, 1.2 mmol) dissolved in DMF (5 mL) were added, and The reaction mixture was stirred at room temperature for 16 hours. Water (50 mL) and ethyl acetate (100 mL) were added and the organic phase was washed with water (5 x 50 mL), dried (magnesium sulfate), filtered and evaporated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with a mixture of heptane and ethyl acetate (1:3), afforded 510 mg of (R)-3-{4-[1-(4-cyclohexylphenyl)-3 -(3-Methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropanoic acid ethyl ester as an amorphous solid. 1 H-NMR (DMSO-d 6 ): δ1.12(t, 3H), 1.22(m, 1H), 1.37(m, 4H), 1.70(m, 1H), 1.79(broad peak, 4H), 3.41 (m, 1H), 3.52(m, 1H), 3.77(s, 3H), 4.06(q, 2H), 4.21(q, 1H), 4.95(s, 2H), 5.68(d, 1H), 6.81( s, 1H), 7.18(d, 2H), 7.23(d, 2H), 7.33(d, 2H), 7.42(s, 1H), 7.51(s, 1H), 7.77(d, 2H), 8.47(t , 1H), 8.53(s, 1H); HPLC-MS (method A): m/z = 658 (M+1); Rt = 8.17min. Step 4:

将(R)-3-{4-[1-(4-环己基苯基)-3-(3-甲氧基-5-三氟甲基苯基)脲基甲基]苯甲酰基-氨基}-2-羟基丙酸乙酯溶解在乙醇(15mL)中，并加入氢氧化钠(2N，2mL)。将该反应混合物在室温搅拌60分钟。然后真空除去乙醇，加入水(50mL)，用4N盐酸将pH调节至酸性反应。过滤并用水(5×5mL)洗涤，真空干燥，获得了460mg本标题化合物，为固体结晶。1H-NMR(DMSO-d6)：δ1.22(m，1H)，1.37(m，4H)，1.70(m，1H)，1.79(宽峰，4H)，3.37(m，1H)，3.51(m，1H)，3.77(s，3H)，4.09(t，1H)，4.95(s，2H)，6.80(s，1H)，7.18(d，2H)，7.23(d，2H)，7.33(d，2H)，7.42(s，1H)，7.51(s，1H)，7.77(d，2H)，8.47(t，1H)，8.53(s，1H)；HPLC-MS(方法A.)：m/z＝614(M+1)；Rt＝7.67min.元素分析：C32H34N3F3O6(+1.25H2O)：C，60.42％；H，5.78％；N，6.61％.实测值：C，60.25％；H，5.55％；N，6.50％.实施例2(一般方法(A))(R)-3-{4-[3-(3，5-二(三氟甲基)苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸

Figure A0181159100721
步骤2：4-[3-(3，5-二(三氟甲基)苯基)-1-(4-环己基苯基)脲基甲基]苯甲酸甲酯(R)-3-{4-[1-(4-cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoyl-amino Ethyl }-2-hydroxypropionate was dissolved in ethanol (15 mL), and sodium hydroxide (2N, 2 mL) was added. The reaction mixture was stirred at room temperature for 60 minutes. The ethanol was then removed in vacuo, water (50 mL) was added, and the pH was adjusted to an acidic reaction with 4N hydrochloric acid. Filtration and washing with water (5 x 5 mL) and drying in vacuo afforded 460 mg of the title compound as a crystalline solid. 1 H-NMR (DMSO-d 6 ): δ1.22 (m, 1H), 1.37 (m, 4H), 1.70 (m, 1H), 1.79 (broad peak, 4H), 3.37 (m, 1H), 3.51 (m, 1H), 3.77(s, 3H), 4.09(t, 1H), 4.95(s, 2H), 6.80(s, 1H), 7.18(d, 2H), 7.23(d, 2H), 7.33( d, 2H), 7.42(s, 1H), 7.51(s, 1H), 7.77(d, 2H), 8.47(t, 1H), 8.53(s, 1H); HPLC-MS (Method A.): m /z=614(M+1); Rt =7.67min. Elemental analysis: C 32 H 34 N 3 F 3 O 6 (+1.25H 2 O): C, 60.42%; H, 5.78%; N, 6.61 %. Measured value: C, 60.25%; H, 5.55%; N, 6.50%. Embodiment 2 (general method (A)) (R)-3-{4-[3-(3,5-two(three Fluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid
Figure A0181159100721
Step 2: Methyl 4-[3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoate

将4-((4-环己基苯基氨基)甲基)苯甲酸甲酯(2.38g，7.36mmol)溶解在DCM(150mL)中，加入异氰酸3，5-二(三氟甲基)苯基酯(1.36mL，8.10mmol)，并将该混合物在室温搅拌16小时。将该反应混合物周水(3×15mL)洗涤，干燥(硫酸镁)并真空浓缩，获得了4.3g4-[3-(3，5-二(三氟甲基)苯基)-1-(4-环己基苯基)脲基甲基]苯甲酸甲酯。1H-NMR(DMSO-d6)：δ1.17-1.44(m，5H)，1.66-1.82(m，5H)，3.83(s，3H)，4.98(s，2H，7.20-7.28(m，4H)，7.44(d，2H)，7.62(s，1H)，7.93(d，2H)，8.24(s，2H)，8.94(s，1H)；HPLC-MS(方法A)：m/z＝579(M+1)；Rt＝9.50min步骤2a：4-[3-(3，5-二(三氟甲基)苯基)-1-(4-环己基苯基)脲基甲基]苯甲酸Methyl 4-((4-cyclohexylphenylamino)methyl)benzoate (2.38 g, 7.36 mmol) was dissolved in DCM (150 mL) and 3,5-bis(trifluoromethyl)isocyanate was added Phenyl ester (1.36 mL, 8.10 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with water (3 x 15 mL), dried (magnesium sulfate) and concentrated in vacuo to afford 4.3 g of 4-[3-(3,5-bis(trifluoromethyl)phenyl)-1-(4 - Methylcyclohexylphenyl)ureidomethyl]benzoate. 1 H-NMR (DMSO-d 6 ): δ1.17-1.44(m, 5H), 1.66-1.82(m, 5H), 3.83(s, 3H), 4.98(s, 2H, 7.20-7.28(m, 4H), 7.44(d, 2H), 7.62(s, 1H), 7.93(d, 2H), 8.24(s, 2H), 8.94(s, 1H); HPLC-MS (Method A): m/z= 579 (M+1); R t =9.50 min Step 2a: 4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl ]benzoic acid

将4-[3-(3，5-二(三氟甲基)苯基)-1-(4-环己基苯基)脲基甲基]苯甲酸甲酯(4.2g，7.36mmol)悬浮在乙醇(80mL)中，加入氢氧化钠(4N，11mL)，并在室温搅拌16小时。将该反应混合物真空浓缩至干，向残余物中加入水(50mL)，用盐酸(4N，12mL)酸化。用乙酸乙酯将水相萃取2次(75mL和25mL)，并将合并的有机相用水洗涤(3×15mL)，干燥(硫酸镁)并真空浓缩，获得了4-[3-(3，5-二(三氟甲基)苯基)-1-(4-环己基苯基)脲基甲基]苯甲酸。1H-NMR(DMSO-d6)：δ1.32-1.43(m，5H)，1.7(m，1H)，1.75-1.85(5H)，4.98(s，2H)，7.20-7.28(m，4H)，7.4(d，2H)，7.61(d，1H)，7.88(d，2H)，8.25(s，2H)，8.93(s，1H)，12.90(s，1H)；HPLC-MS(方法B)：m/z＝565(M+1)；Rt＝8.65min；M.p.148.5-149.5℃.元素分析：C29H26F6N2O3的计算值：C，61.70％；H，4.64％；N，4.96％.实测值：C，61.54％；H，4.71％；N，4.92％.步骤3：(R)-3-{4-[3-(3，5-二(三氟甲基)苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸乙酯Methyl 4-[3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoate (4.2 g, 7.36 mmol) was suspended in Sodium hydroxide (4N, 11 mL) was added to ethanol (80 mL), and stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness in vacuo, water (50 mL) was added to the residue and acidified with hydrochloric acid (4N, 12 mL). The aqueous phase was extracted twice with ethyl acetate (75 mL and 25 mL), and the combined organic phases were washed with water (3 x 15 mL), dried (magnesium sulfate) and concentrated in vacuo to give 4-[3-(3,5 - bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid. 1 H-NMR (DMSO-d 6 ): δ1.32-1.43 (m, 5H), 1.7 (m, 1H), 1.75-1.85 (5H), 4.98 (s, 2H), 7.20-7.28 (m, 4H) ), 7.4(d, 2H), 7.61(d, 1H), 7.88(d, 2H), 8.25(s, 2H), 8.93(s, 1H), 12.90(s, 1H); HPLC-MS (Method B ): m/z = 565 (M+1); R t = 8.65 min; Mp 148.5-149.5°C. Elemental analysis: calculated for C 29 H 26 F 6 N 2 O 3 : C, 61.70%; H, 4.64%; N, 4.96%. Found: C, 61.54%; H, 4.71%; N, 4.92%. Step 3: (R)-3-{4-[3-(3,5-bis(trifluoro Methyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid ethyl ester

将4-[3-(3，5-二(三氟甲基)苯基)-1-(4-环己基苯基)脲基甲基]苯甲酸(0.22 g，0.39mmol)溶解在DMF(3mL)中，并加入1-羟基-7-氮杂苯并三唑(0.06g，0.47mmol)和EDAC(0.09g，1.2mmol)。将该混合物搅拌1.5小时，加入在DMF(2mL)中的(R)-异丝氨酸乙酯(0.10g，0.59mmol)和二异丙基乙基胺(0.10mL，0.59mmol)。将该混合物在室温搅拌16小时。将该反应混合物用水(10mL)稀释，并用乙酸乙酯(25mL)萃取。用乙酸乙酯(10mL)萃取水相。将合并的有机相用盐酸(0.2N，3×10mL)和水∶饱和氯化钠(1∶1)洗涤，干燥(硫酸镁)并真空浓缩。通过柱色谱法(35g硅胶)纯化残余物，用乙酸乙酯和正庚烷(6∶4)洗脱，获得了0.27g(R)-3-{4-[3-(3，5-二(三氟甲基)苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸乙酯。1H-NMR(DMSO-d6)：δ1.14(t，3H)，1.19-1.42(m，5H)，1.67-1.85(m，5H)，3.38-3.48(m，1H)，3.49-3.57(m，1H)，4.08(q，2H)，4.20(m，1H)，4.97(s，2H)，5.67(d，1H)，7.20-7.27(m，4H)，7.36(d，2H)，7.62(s，1H)，7.75(d，2H)，8.24(s，2H)，8.48(t，1H)，8.90(s，1H)；HPLC-MS(方法A)：m/z＝680(M+1)；Rt＝8.42min.步骤4：4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid (0.22 g, 0.39 mmol) was dissolved in DMF ( 3 mL), and added 1-hydroxy-7-azabenzotriazole (0.06 g, 0.47 mmol) and EDAC (0.09 g, 1.2 mmol). The mixture was stirred for 1.5 hours and (R)-isoserine ethyl ester (0.10 g, 0.59 mmol) and diisopropylethylamine (0.10 mL, 0.59 mmol) in DMF (2 mL) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL), and extracted with ethyl acetate (25 mL). The aqueous phase was extracted with ethyl acetate (10 mL). The combined organic phases were washed with hydrochloric acid (0.2N, 3 x 10 mL) and water: saturated sodium chloride (1:1), dried (magnesium sulfate) and concentrated in vacuo. Purification of the residue by column chromatography (35 g silica gel) eluting with ethyl acetate and n-heptane (6:4) afforded 0.27 g of (R)-3-{4-[3-(3,5-di( Trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropanoic acid ethyl ester. 1 H-NMR (DMSO-d 6 ): δ1.14(t, 3H), 1.19-1.42(m, 5H), 1.67-1.85(m, 5H), 3.38-3.48(m, 1H), 3.49-3.57 (m, 1H), 4.08(q, 2H), 4.20(m, 1H), 4.97(s, 2H), 5.67(d, 1H), 7.20-7.27(m, 4H), 7.36(d, 2H), 7.62(s, 1H), 7.75(d, 2H), 8.24(s, 2H), 8.48(t, 1H), 8.90(s, 1H); HPLC-MS (Method A): m/z=680 (M +1); Rt = 8.42min. Step 4:

将(R)-3-{4-[3-(3，5-二(三氟甲基)苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸乙酯(0.26g，0.38mmol)溶解在乙醇(96％，15mL)中，加入氢氧化钠(4N，0.57mL，2.3mmol)。在25℃搅拌1小时后，将该混合物真空蒸发，向残余物中加入水(30mL)，并用盐酸(4N，0.62mL)酸化。将水相用乙酸乙酯萃取2次(25mL和10mL)，并将合并的有机相用饱和氯化钠∶水(1∶1)洗涤，干燥(硫酸镁)并真空浓缩，获得了0.21g本标题化合物。1H-NMR(DMSO-d6)：δ1.21-1.45(m，5H)，1.66-1.86(m，5H)，3.37-3.44(m，1H)，3.53-3.60(m，1H)，4.18(t，1H)，4.95(s，2H)，7.18-7.27(m，4H)，7.45(d，2H)，7.60(s，1H)，7.78(d，2H)，8.24(s，2H)，8.44(t，1H)，8.90(s，1H)；HPLC-MS(方法B)：m/z＝652(M+1)；Rt＝7.93min.实施例3(一般方法(A))(R)-3-{4-[3-(3-溴苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸

Figure A0181159100741
步骤1：4-[(4-环己基苯基氨基)甲基]苯甲酸(R)-3-{4-[3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}- Ethyl 2-hydroxypropionate (0.26 g, 0.38 mmol) was dissolved in ethanol (96%, 15 mL), and sodium hydroxide (4N, 0.57 mL, 2.3 mmol) was added. After stirring at 25°C for 1 hour, the mixture was evaporated in vacuo, water (30 mL) was added to the residue and acidified with hydrochloric acid (4N, 0.62 mL). The aqueous phase was extracted twice with ethyl acetate (25 mL and 10 mL), and the combined organic phases were washed with saturated sodium chloride:water (1:1), dried (magnesium sulfate) and concentrated in vacuo to obtain 0.21 g of the title compound. 1 H-NMR (DMSO-d 6 ): δ1.21-1.45 (m, 5H), 1.66-1.86 (m, 5H), 3.37-3.44 (m, 1H), 3.53-3.60 (m, 1H), 4.18 (t, 1H), 4.95(s, 2H), 7.18-7.27(m, 4H), 7.45(d, 2H), 7.60(s, 1H), 7.78(d, 2H), 8.24(s, 2H), 8.44(t, 1H), 8.90(s, 1H); HPLC-MS (Method B): m/z=652(M+1); Rt =7.93min. Example 3 (General Method (A))( R)-3-{4-[3-(3-Bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid
Figure A0181159100741
Step 1: 4-[(4-Cyclohexylphenylamino)methyl]benzoic acid

将4-环己基苯胺(8.0g，53mmol)溶解在甲醇(200mL)中，分批加入4-甲酰基苯甲酸(9.4g，53mmol)在冰醋酸(12mL)中的悬浮液，将所得混合物在回流温度加热1.5小时。冷却至室温后，分批加入氰基硼氢化钠(5.0g，80mmol)在甲醇(100mL)中的混合物，并将所得混合物在室温搅拌16小时。将该混合物过滤，用水充分洗涤，在50℃真空干燥3天，获得了12.8g(78％)4-[(4-环己基苯基氨基)甲基]苯甲酸。  1H-NMR(DMSO-d6)：δ1.1-1.35(5H，m)，1.65-1.75(5H，m)，2.29(1H，m)，4.31(2H，s)，6.15(1H，bs)，6.45(2H，d)，6.89(2H，d)，7.46(2H，d)，7.88(2H，d).步骤2：4-[3-(3-溴苯基)-1-(4-环己基苯基)脲基甲基]苯甲酸4-cyclohexylaniline (8.0g, 53mmol) was dissolved in methanol (200mL), and a suspension of 4-formylbenzoic acid (9.4g, 53mmol) in glacial acetic acid (12mL) was added in portions, and the resulting mixture was Heated at reflux temperature for 1.5 hours. After cooling to room temperature, a mixture of sodium cyanoborohydride (5.0 g, 80 mmol) in methanol (100 mL) was added portionwise, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was filtered, washed well with water, and dried under vacuum at 50° C. for 3 days to obtain 12.8 g (78%) of 4-[(4-cyclohexylphenylamino)methyl]benzoic acid. 1 H-NMR (DMSO-d 6 ): δ1.1-1.35 (5H, m), 1.65-1.75 (5H, m), 2.29 (1H, m), 4.31 (2H, s), 6.15 (1H, bs ), 6.45 (2H, d), 6.89 (2H, d), 7.46 (2H, d), 7.88 (2H, d). Step 2: 4-[3-(3-bromophenyl)-1-(4 -cyclohexylphenyl)ureidomethyl]benzoic acid

将3-溴苯胺(1.4g，8.1mmol)溶解在乙醚(50mL)中，加入3.5M无水HCl在乙酸乙酯(2.3mL)中的混合物。将该混合物真空浓缩。向残余物中加入甲苯(100mL)并真空浓缩。向残余物中加入甲苯(100mL)和双光气(8.1g，41mmol)，并将所得混合物回流1.5小时。冷却后，将该混合物真空浓缩。将残余物溶解在甲苯(100mL)中并真空浓缩。将残余物溶解在DMF(30mL)中，加入4-[(4-环己基苯基氨基)甲基]苯甲酸(1.3g，4.1mmol)。将该混合物在室温搅拌16小时。向该混合物中加入乙酸乙酯(150mL)，并用水∶盐水(1∶1)(2×100mL)洗涤。将有机相用硫酸钠干燥，并真空浓缩。通过硅胶柱色谱纯化残余物，首先用乙酸乙酯∶正庚烷∶三乙胺的混合物(7∶2∶1)洗脱，然后用乙酸乙酯洗脱，最后用甲醇洗脱，获得了1.95g(94％)4-[3-(3-溴苯基)-1-(4-环己基苯基)脲基甲基]苯甲酸。1H-NMR(CDCl3)：δ1.2-1.4(5H，m)，1.7-1.8(5H，m)，4.94(2H，s)，7.1-7.25(6H，m)，7.30(2H，d)，7.44(1H，d)，7.78(1H，t)，7.83(2H，d)，8.38(1H，s)；HPLC-MS(方法B)：m/z＝507(M+1)；R1＝5.52min.步骤3：(R)-3-{4-[3-(3-溴苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸乙酯3-Bromoaniline (1.4 g, 8.1 mmol) was dissolved in diethyl ether (50 mL) and a mixture of 3.5M anhydrous HCl in ethyl acetate (2.3 mL) was added. The mixture was concentrated in vacuo. To the residue was added toluene (100 mL) and concentrated in vacuo. To the residue were added toluene (100 mL) and diphosgene (8.1 g, 41 mmol), and the resulting mixture was refluxed for 1.5 hours. After cooling, the mixture was concentrated in vacuo. The residue was dissolved in toluene (100 mL) and concentrated in vacuo. The residue was dissolved in DMF (30 mL), and 4-[(4-cyclohexylphenylamino)methyl]benzoic acid (1.3 g, 4.1 mmol) was added. The mixture was stirred at room temperature for 16 hours. Ethyl acetate (150 mL) was added to the mixture and washed with water:brine (1:1) (2 x 100 mL). The organic phase was dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting first with a mixture of ethyl acetate:n-heptane:triethylamine (7:2:1), then with ethyl acetate and finally with methanol, afforded 1.95 g (94%) 4-[3-(3-bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid. 1 H-NMR (CDCl 3 ): δ1.2-1.4 (5H, m), 1.7-1.8 (5H, m), 4.94 (2H, s), 7.1-7.25 (6H, m), 7.30 (2H, d ), 7.44(1H, d), 7.78(1H, t), 7.83(2H, d), 8.38(1H, s); HPLC-MS (method B): m/z=507(M+1); R 1 = 5.52min. Step 3: (R)-3-{4-[3-(3-bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2 -Ethyl hydroxypropionate

将4-[3-(3-溴苯基)-1-(4-环己基苯基)脲基甲基]苯甲酸(0.20g，0.39mmol)溶解在DMF(2.5mL)中，加入EDAC(0.12g，0.6mmol)和HOBt(0.089mg，0.6mmol)，并将该混合物在室温搅拌10分钟。加入溶解在DMF(2.5mL)中的(R)-异丝氨酸乙酯盐酸盐(0.10g，0.6mmol)和N，N-二异丙基乙基胺(130μL)，并将所得混合物在室温搅拌16小时。向该混合物中加入乙酸乙酯(70mL)，用水(2×100mL)洗涤，用硫酸钠将有机相干燥，并真空浓缩。通过硅胶柱色谱纯化残余物，用含有10％乙酸的乙酸乙酯∶正庚烷混合物(1∶2)洗脱。获得了100mg(R)-3-{4-[3-(3-溴苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸乙酯。HPLC-MS(方法B)：m/z＝624(M+1)；Rt＝5.33分钟。步骤4：(R)-3-{4-[3-(3-溴苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2羟基丙酸4-[3-(3-Bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid (0.20 g, 0.39 mmol) was dissolved in DMF (2.5 mL) and EDAC ( 0.12g, 0.6mmol) and HOBt (0.089mg, 0.6mmol), and the mixture was stirred at room temperature for 10 minutes. (R)-Isoserine ethyl ester hydrochloride (0.10 g, 0.6 mmol) and N,N-diisopropylethylamine (130 μL) dissolved in DMF (2.5 mL) were added, and the resulting mixture was incubated at room temperature Stir for 16 hours. To the mixture was added ethyl acetate (70 mL), washed with water (2 x 100 mL), the organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with an ethyl acetate:n-heptane mixture (1:2) containing 10% acetic acid. 100 mg of (R)-3-{4-[3-(3-bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropanoic acid ethyl ester. HPLC-MS (Method B): m/z = 624 (M+1); Rt = 5.33 min. Step 4: (R)-3-{4-[3-(3-Bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropanoic acid

将(R)-3-{4-[3-(3-溴苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基-丙酸乙酯(100mg)溶解在乙醇(10mL)中，加入1N氢氧化钠(480μL)，并将所得混合物在室温搅拌1小时。加入1N盐酸(480μL)，并将该混合物真空浓缩。将残余物悬浮在水(50mL)中并过滤，获得了38mg本标题化合物。1H-NMR(CDCl3)：δ1.2-1.4(5H，m)，1.7-1.85(5H，m).2.45(1H，s)，3.7(2H，m)，4.30(1H，m)，4.78(2H，s)，6.23(1H，s)，6.95-7.3(8H，m)，7.42(1H，s)，7.60(2H，d)；HPLC-MS(方法A)：m/z＝595(M+1)；Rt＝7.48min.实施例4(一般方法(A))(R)-3-{4-[1-(4-环己基苯基)-3-(4-三氟甲基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸

Figure A0181159100761
1H-NMR(DMSO-d6)：δ1.2-1.4(5H，m)，1.7-1.8(5H，m)，3.40(1H，m)，3.56(1H，dt)，4.18(1H，t)，4.97(2H，s)，5.5(1H，brd)7.14-7.25，(6H，m)，7.34(2H，d)，7.55(2H，d)，7.79(2H，d)，8.38(1H，s)，8.44(1H，t)；HPLC-MS(方法A)：m/z＝600(M+1)；Rt＝7.38min.实施例5(一般方法(A))(R)-3-{4-[1-(4-环己基苯基)-3-(3-三氟甲基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸 1H-NMR(400 MHz，DMSO-d6)：δ1.15-1-45(m，5H)，1.60-1.90(m，5H)，4.95(s，2H)，7.12(d，2H)，7.19(d，2H)，7.24(d，1H)，7.45(t，1H)，7.72(d，2H)，7.75(sbr，1H)，7.90(s，1H)，8.55(s，1H)，8.58(s br，1H)；HPLC-MS(方法B)：m/z＝584(M+1)；Rt＝4.99min.实施例6(一般方法(A))(R)-3-{4-[1-(4-环己基苯基)-3-(3-氟-5-三氟甲基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸
Figure A0181159100772
1H-NMR(200MHz，DMSO-d6)：δ1.15-1-45(m，5H)，1.60-1.85(m，5H)，3.25-3.65(m，3H)，4.13(t，1H)，4.95(s，2H)，7.10-7.22(m，5H)，7.30(d，2H)，7.75(m，3H)，8.45(t，1H)，8.78(s，1H)；HPLC-MS(方法A)：m/z＝602(M+1)；Rt＝7.83min.实施例7(一般方法(A))(R)-3-{4-[3-(3-氰基-5-三氟甲基苯基)-1-(4-环己-1-烯基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸 1H-NMR(200MHz，DMSO-d6)：δ1.15-1.70(m，4H)，2.12(s，2H)，2.35(s，2H)，5.00(s，2H)，6.15(s，1H)，7.10-7.40(m，6H)，7.78(m，3H)，8.20(d，2H)，8.90(s，1H)；HPLC-MS(方法A)：m/z＝607(M+1)；Rt＝7.42min.实施例8(一般方法(A))(R)-3-{4-[3-(3-氰基-5-三氟甲基苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸 1H-NMR(400MHz，DMSO-d6)：δ1.15-1.45(m，5H)，1.60-1.85(m，5)，3.45-3.60(m，3H)，4.15(t，1H)4.95(s，2H)，7.20(dd，4H)，7.35(d，2H)，7.76(d，2H)，7.88(s，1H)，8.18(s，1H)，8.21(s，1H)，8.45(t，1H)，8.95(s，1H)；HPLC-MS(方法A)：m/z＝609(M+1)；Rt＝7.58 min.实施例9(一般方法(A))(R)-3-{4-[3-(3-溴-5-三氟甲基苯基)-1-(4-环己-1-烯基苯基)脲基甲基]苯甲酰基氨基)-2-羟基丙酸 1H-NMR(DMSO-d6)：δ1.50-1.76(m，4H)，2.15(m，2H)，2.33(m，2H)，3.37(m，2H)，3.54(m，1H)，4.14(dd，1H)，4.95(s，2H)，6.17(t，1H)，7.17(d，2H)，7.33(d，2H)，7.40(d，2H)，7.46(s，1H)，7.75(d，2H)，7.91(s，1H)，8.07(s，1H)，8.44(t，1H)，8.66(s，1H).实施例10(一般方法(A))(R)-3-{4-[1-(4-环己-1-烯基苯基)-3-(3-甲氧基-5-三氟甲基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸 1H-NMR(DMSO-d6)：δ1.51-1.76(m，4H)，2.15(m，2H)，2.34(m，2H)，3.37(m，2H)，3.54(m，1H)，3.75(s，3H)，4.14(dd，1H)，4.95(s，2H)，6.16(t，3H)，6.78(s，1H)，7.16(d，2H)，7.32(d，2H)，7.38(d，2H)，7.43(s，1H)，7.76(d，2H)，8.44(t，1H)，8.51(s，1H).实施例11(一般方法(A))(R)-3-{4-[3-(3-溴苯基)-1-(4-环己-1-烯基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸
Figure A0181159100793
(R)-3-{4-[3-(3-Bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxy-propionic acid ethyl ester (100 mg) was dissolved in ethanol (10 mL), 1N sodium hydroxide (480 µL) was added, and the resulting mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (480 μL) was added, and the mixture was concentrated in vacuo. The residue was suspended in water (50 mL) and filtered to obtain 38 mg of the title compound. 1 H-NMR (CDCl 3 ): δ1.2-1.4 (5H, m), 1.7-1.85 (5H, m). 2.45 (1H, s), 3.7 (2H, m), 4.30 (1H, m), 4.78(2H,s), 6.23(1H,s), 6.95-7.3(8H,m), 7.42(1H,s), 7.60(2H,d); HPLC-MS (Method A): m/z=595 (M+1); R t =7.48min. Example 4 (General Method (A)) (R)-3-{4-[1-(4-cyclohexylphenyl)-3-(4-trifluoro Methylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid
Figure A0181159100761
1 H-NMR (DMSO-d 6 ): δ1.2-1.4 (5H, m), 1.7-1.8 (5H, m), 3.40 (1H, m), 3.56 (1H, dt), 4.18 (1H, t ), 4.97 (2H, s), 5.5 (1H, brd) 7.14-7.25, (6H, m), 7.34 (2H, d), 7.55 (2H, d), 7.79 (2H, d), 8.38 (1H, s), 8.44 (1H, t); HPLC-MS (Method A): m/z = 600 (M+1); R t = 7.38min. Example 5 (General Method (A)) (R)-3 -{4-[1-(4-cyclohexylphenyl)-3-(3-trifluoromethylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid 1 H-NMR (400 MHz, DMSO-d 6 ): δ1.15-1-45(m, 5H), 1.60-1.90(m, 5H), 4.95(s, 2H), 7.12(d, 2H), 7.19(d, 2H), 7.24(d, 1H), 7.45(t, 1H), 7.72(d, 2H), 7.75(sbr, 1H), 7.90(s, 1H), 8.55(s, 1H), 8.58 (s br, 1H); HPLC-MS (Method B): m/z = 584 (M+1); R t = 4.99min. Example 6 (General Method (A)) (R)-3-{4 -[1-(4-cyclohexylphenyl)-3-(3-fluoro-5-trifluoromethylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid
Figure A0181159100772
1 H-NMR (200MHz, DMSO-d 6 ): δ1.15-1-45(m, 5H), 1.60-1.85(m, 5H), 3.25-3.65(m, 3H), 4.13(t, 1H) , 4.95(s, 2H), 7.10-7.22(m, 5H), 7.30(d, 2H), 7.75(m, 3H), 8.45(t, 1H), 8.78(s, 1H); HPLC-MS (Method A): m/z=602(M+1); Rt =7.83min. Example 7 (General Method (A)) (R)-3-{4-[3-(3-cyano-5- Trifluoromethylphenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid 1 H-NMR (200MHz, DMSO-d 6 ): δ1.15-1.70(m, 4H), 2.12(s, 2H), 2.35(s, 2H), 5.00(s, 2H), 6.15(s, 1H ), 7.10-7.40 (m, 6H), 7.78 (m, 3H), 8.20 (d, 2H), 8.90 (s, 1H); HPLC-MS (method A): m/z=607 (M+1) ; R t =7.42min. Example 8 (General Method (A)) (R)-3-{4-[3-(3-cyano-5-trifluoromethylphenyl)-1-(4- Cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid 1 H-NMR (400MHz, DMSO-d 6 ): δ1.15-1.45(m, 5H), 1.60-1.85(m, 5), 3.45-3.60(m, 3H), 4.15(t, 1H)4.95( s, 2H), 7.20(dd, 4H), 7.35(d, 2H), 7.76(d, 2H), 7.88(s, 1H), 8.18(s, 1H), 8.21(s, 1H), 8.45(t , 1H), 8.95 (s, 1H); HPLC-MS (Method A): m/z=609 (M+1); R t =7.58 min. Example 9 (General Method (A)) (R)- 3-{4-[3-(3-Bromo-5-trifluoromethylphenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]benzoylamino)-2 -Hydroxypropionic acid 1 H-NMR (DMSO-d 6 ): δ1.50-1.76 (m, 4H), 2.15 (m, 2H), 2.33 (m, 2H), 3.37 (m, 2H), 3.54 (m, 1H), 4.14(dd, 1H), 4.95(s, 2H), 6.17(t, 1H), 7.17(d, 2H), 7.33(d, 2H), 7.40(d, 2H), 7.46(s, 1H), 7.75 (d, 2H), 7.91 (s, 1H), 8.07 (s, 1H), 8.44 (t, 1H), 8.66 (s, 1H). Example 10 (General Method (A)) (R)-3- {4-[1-(4-cyclohex-1-enylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoylamino}-2 -Hydroxypropionic acid 1 H-NMR (DMSO-d 6 ): δ1.51-1.76 (m, 4H), 2.15 (m, 2H), 2.34 (m, 2H), 3.37 (m, 2H), 3.54 (m, 1H), 3.75(s, 3H), 4.14(dd, 1H), 4.95(s, 2H), 6.16(t, 3H), 6.78(s, 1H), 7.16(d, 2H), 7.32(d, 2H), 7.38 (d, 2H), 7.43 (s, 1H), 7.76 (d, 2H), 8.44 (t, 1H), 8.51 (s, 1H). Example 11 (General Method (A)) (R)-3- {4-[3-(3-Bromophenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid
Figure A0181159100793

本标题化合物是按照一般方法(A)，并如下所述改动步骤2制得的：步骤2：4-[3-(3-溴苯基)-1-(4-环己-1-烯基苯基)脲基甲基]苯甲酸甲酯The title compound was prepared according to general method (A) and modification of Step 2 as follows: Step 2: 4-[3-(3-bromophenyl)-1-(4-cyclohex-1-enyl Methyl phenyl)ureidomethyl]benzoate

向在甲苯(20mL)内的3-溴苯甲酸(1.2g，5.7mmol)中加入三乙胺(0.91mL，6.5mmol)和二苯氧基磷酰基叠氮化物(1.3mL，6.2mmol)，并在搅拌下将该混合物加热至100℃。1小时后，加入4-[(4-环己-1-烯基苯基氨基)甲基]-苯甲酸甲酯(按照类似于实施例1，步骤1的方法制得的)(1.6g，5mmol)，并继续加热1.5小时。冷却至室温后，将该混合物与乙酸乙酯(50mL)转移到分液漏斗中。将有机混合物用饱和碳酸氢钠水溶液(2×50mL)洗涤，用乙酸乙酯(50mL)回洗。收集有机层，干燥(硫酸钠)，真空除去溶剂，获得了棕色油状物，通过硅胶柱纯化，用DCM洗脱，获得了700mg4-[3-(3-溴苯基)-1-(4-环己-1-烯基苯基)脲基甲基]苯甲酸甲酯。HPLC-MS(方法B)：m/z＝521(M+1)；Rt＝6.1分钟。本标题化合物的数据：1H-NMR(CDCl3)：δ1.54(s，2H)，1.65(s，2H)；2.15(s，2H)，2.36(s，2H)，3.56(br s，2H)，4.19(brs，1H)，4.71(s，2H)，6.09(s，1H)，6.42(s，1H)，6.90-7.18(m，6H)，7.30.7.70(m，6H)；HPLC-MS(方法B)：m/z＝592.5(M+1)；Rt＝4.73min.实施例12(一般方法(A))(R)-3-{4-[3-(3-溴-5-三氟甲基苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸

Figure A0181159100801
1H-NMR(DMSO-d6)：δ1.14-1.43(m，5H)，1.64-1.83(m，5H)，3.40-3.45(m，1H)，3.45-3.53(m，1H)，4.00(t，1H)，4.95(s，2H)，7.13-7.27(m，4H)，7.33(d，2H)，7.48(s，1H)，7.77(d，2H)，7.92(s，1H)，8.07(s，1H)，8.43(t，1H)，8.71(s，1H)；HPLC-MS(方法A)：m/z＝662(M+1)；Rt＝8.17min.实施例13(一般方法(A))(S)-反式-3-{4-[3-(3，5-二(三氟甲基)苯基)-1-(4-叔丁基环己基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸
Figure A0181159100811
步骤1：反式-4-[(4-叔丁基环己基氨基)甲基]苯甲酸甲酯
Figure A0181159100812
To 3-bromobenzoic acid (1.2 g, 5.7 mmol) in toluene (20 mL) was added triethylamine (0.91 mL, 6.5 mmol) and diphenoxyphosphoryl azide (1.3 mL, 6.2 mmol), And the mixture was heated to 100° C. with stirring. After 1 hour, 4-[(4-cyclohex-1-enylphenylamino)methyl]-benzoic acid methyl ester (prepared by a method similar to Example 1, step 1) (1.6 g, 5 mmol), and continued heating for 1.5 hours. After cooling to room temperature, the mixture was transferred to a separatory funnel with ethyl acetate (50 mL). The organic mixture was washed with saturated aqueous sodium bicarbonate (2 x 50 mL) and backwashed with ethyl acetate (50 mL). The organic layer was collected, dried (sodium sulfate) and the solvent was removed in vacuo to give a brown oil which was purified by silica gel column eluting with DCM to give 700 mg of 4-[3-(3-bromophenyl)-1-(4- Methyl cyclohex-1-enylphenyl)ureidomethyl]benzoate. HPLC-MS (Method B): m/z = 521 (M+1); Rt = 6.1 min. Data of the title compound: 1 H-NMR (CDCl 3 ): δ1.54 (s, 2H), 1.65 (s, 2H); 2.15 (s, 2H), 2.36 (s, 2H), 3.56 (br s, 2H), 4.19(brs,1H), 4.71(s,2H), 6.09(s,1H), 6.42(s,1H), 6.90-7.18(m,6H), 7.30.7.70(m,6H); HPLC - MS (Method B): m/z = 592.5 (M+1); R t = 4.73 min. Example 12 (General Method (A)) (R)-3-{4-[3-(3-Bromo -5-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid
Figure A0181159100801
1 H-NMR (DMSO-d 6 ): δ1.14-1.43 (m, 5H), 1.64-1.83 (m, 5H), 3.40-3.45 (m, 1H), 3.45-3.53 (m, 1H), 4.00 (t, 1H), 4.95(s, 2H), 7.13-7.27(m, 4H), 7.33(d, 2H), 7.48(s, 1H), 7.77(d, 2H), 7.92(s, 1H), 8.07(s, 1H), 8.43(t, 1H), 8.71(s, 1H); HPLC-MS (Method A): m/z=662(M+1); Rt =8.17min. Example 13( General Procedure (A)) (S)-trans-3-{4-[3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-tert-butylcyclohexyl)ureidomethyl ]benzoylamino}-2-hydroxypropionic acid
Figure A0181159100811
Step 1: Methyl trans-4-[(4-tert-butylcyclohexylamino)methyl]benzoate
Figure A0181159100812

将4-甲酰基苯甲酸甲酯(10.6g，64.4mmol)溶解在甲醇(200mL)中。加入4-叔丁基环己基胺的17∶83顺式/反式混合物(10.0g，64.4mmol，Aldrich)，立即沉淀出了白色晶体。将该混合物加热回流30分钟以完全形成亚胺，然后在冰浴上冷却至0℃。通过过滤收集纯的反式-4-[(4-叔丁基环己基亚氨基)甲基]苯甲酸甲酯晶体，并真空干燥过夜。产量：15.3g(78％)。1HNMR(CDCl3)，300MHz：δ8.37(s，1H)；8.06(d，2H)；7.77(d，2H)；3.92(s，3H)；3.17(m，1H)；1.83(m，4H)；1.60(m，2H)，1.09(m，3H)；0.87(s，9H).元素分析：C19H27NO2的计算值：C，75.71％；H，9.03％；N，4.65％.实测值：C，75.60％；H，9.37％；N，4.68％.Methyl 4-formylbenzoate (10.6 g, 64.4 mmol) was dissolved in methanol (200 mL). A 17:83 cis/trans mixture of 4-tert-butylcyclohexylamine (10.0 g, 64.4 mmol, Aldrich) was added and white crystals immediately precipitated. The mixture was heated to reflux for 30 minutes to complete imine formation, then cooled to 0°C on an ice bath. Pure trans-methyl 4-[(4-tert-butylcyclohexylimino)methyl]benzoate crystals were collected by filtration and dried under vacuum overnight. Yield: 15.3 g (78%). 1 HNMR (CDCl 3 ), 300MHz: δ8.37(s, 1H); 8.06(d, 2H); 7.77(d, 2H); 3.92(s, 3H); 3.17(m, 1H); 4H); 1.60 (m, 2H), 1.09 (m, 3H); 0.87 (s, 9H). Elemental analysis: Calculated for C 19 H 27 NO 2 : C, 75.71%; H, 9.03%; N, 4.65 %. Measured value: C, 75.60%; H, 9.37%; N, 4.68%.

将母液干燥，获得了4.2g(22％)白色固体，根据NMR证实其主要由亚氨基顺式异构体组成。1HNMR(CDCl3)，300MHz：δ8.36(s，1H)；8.07(d，2H)；7.81(d，2H)；3.92(s，3H)；3.54(m，1H)；1.55-1.92(m，8H)；1.14(m，1H)；0.90(s，9H).

Figure A0181159100821
The mother liquor was dried to afford 4.2 g (22%) of a white solid which by NMR consisted mainly of the imino cis isomer. 1 HNMR (CDCl 3 ), 300MHz: δ8.36(s, 1H); 8.07(d, 2H); 7.81(d, 2H); 3.92(s, 3H); 3.54(m, 1H); m, 8H); 1.14(m, 1H); 0.90(s, 9H).
Figure A0181159100821

将反式-4-[(4-叔丁基环己基亚氨基)甲基]苯甲酸甲酯(21.0g，69.2mmol)悬浮在甲醇(300mL)中，加入乙酸(50mL)。向所得澄清溶液中加入氰基硼氢化钠(3.5g，55.5mmol)，将该混合物在室温搅拌30分钟。然后通过旋转蒸发将反应混合物的体积减至三分之一，加入乙酸乙酯(500mL)。用碳酸钠溶液(5％，500mL)洗涤有机相，并用硫酸钠干燥。通过旋转蒸发除去溶剂，获得了本标题化合物，为白色固体结晶，其纯度足以进行以后的反应。产量：21.1g(100％)。1HNMR(CDCl3)，300MHz：δ7.98(d，2H)；7.38(d，2H)；3.90(s，3H)；3.86(s，2H)；2.39(m，1H)；2.01(m，2H)；1.77(m，2H)；1.51(bs，1H)；0.93-1.18(m，5H)；0.82(s，9H)；HPLC-MS(方法B：Rt＝4.87m/z＝304(M+1).步骤2：反式-4-[1-(3，5-二(三氟甲基)苯基)-3-(4-叔丁基环己基)脲基甲基]苯甲酸甲酯Methyl trans-4-[(4-tert-butylcyclohexylimino)methyl]benzoate (21.0 g, 69.2 mmol) was suspended in methanol (300 mL), and acetic acid (50 mL) was added. Sodium cyanoborohydride (3.5 g, 55.5 mmol) was added to the resulting clear solution, and the mixture was stirred at room temperature for 30 minutes. The volume of the reaction mixture was then reduced to one third by rotary evaporation and ethyl acetate (500 mL) was added. The organic phase was washed with sodium carbonate solution (5%, 500 mL) and dried over sodium sulfate. Removal of the solvent by rotary evaporation afforded the title compound as a crystalline white solid pure enough for subsequent reactions. Yield: 21.1 g (100%). 1 HNMR (CDCl 3 ), 300MHz: δ7.98(d, 2H); 7.38(d, 2H); 3.90(s, 3H); 3.86(s, 2H); 2.39(m, 1H); 2H); 1.77(m, 2H); 1.51(bs, 1H); 0.93-1.18(m, 5H); 0.82(s, 9H); HPLC-MS (Method B: R t =4.87m/z=304( M+1). Step 2: trans-methyl 4-[1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-tert-butylcyclohexyl)ureidomethyl]benzoate

将反式-4-[(4-叔丁基环己基氨基)甲基]苯甲酸甲酯(1.0g，3.3mmol)溶解在乙腈(40mL)中，加入异氰酸3，5-二(三氟甲基)苯基酯(0.9g，3.6mmol)，并将该反应混合物在室温搅拌过夜。将溶剂真空浓缩至5-10mL，通过过滤分离出结晶，获得了1.45g(81％)反式-4-[1-(3，5-二(三氟甲基)苯基)-3-(4-叔丁基环己基)脲基甲基]苯甲酸甲酯：1H-NMR(DMSO-d8)：δ9.08(s，1H)；8.25(s，2H)；7.91(d，2H)；7.60(s，1H)；7.40(d，2H)；4.65(s，2H)；4.07(宽峰，1H)；3.83(s，3H)；1.71(宽峰，4H)；1.42(宽峰，2H)；1.11(宽峰，2H)；0.93(宽峰，1H)；HPLC-MS(方法B)：m/z＝559(M+1)；Rt＝9.40min；M.p.188-190℃(CH3CN).元素分析：C28H32N2F6O3的计算值：C，60.21％；H，5.77％；N，5.02％.实测值：C，60.46％；H，5.94％；N，5.00％.步骤2a：反式-4-[1-(3，5-二(三氟甲基)苯基)-3-(4-叔丁基环己基)脲基甲基]苯甲酸Methyl trans-4-[(4-tert-butylcyclohexylamino)methyl]benzoate (1.0 g, 3.3 mmol) was dissolved in acetonitrile (40 mL), and 3,5-bis(trifluoromethane ) phenyl ester (0.9 g, 3.6 mmol), and the reaction mixture was stirred at room temperature overnight. The solvent was concentrated in vacuo to 5-10 mL and the crystals were isolated by filtration to afford 1.45 g (81%) of trans-4-[1-(3,5-bis(trifluoromethyl)phenyl)-3-( Methyl 4-tert-butylcyclohexyl)ureidomethyl]benzoate: 1 H-NMR (DMSO-d 8 ): δ9.08 (s, 1H); 8.25 (s, 2H); 7.91 (d, 2H); 7.60 (s, 1H); 7.40 (d, 2H); 4.65 (s, 2H); 4.07 (broad peak, 1H); 3.83 (s, 3H); 1.71 (broad peak, 4H); 1.42 (broad peak, 2H ); 1.11 (broad peak, 2H); 0.93 (broad peak, 1H); HPLC-MS (method B): m/z = 559 (M+1); R t = 9.40 min; Mp 188-190°C (CH 3 CN). Elemental analysis: Calculated for C 28 H 32 N 2 F 6 O 3 : C, 60.21%; H, 5.77%; N, 5.02%. Found: C, 60.46%; H, 5.94%; N, 5.00%. Step 2a: trans-4-[1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-tert-butylcyclohexyl)ureidomethyl]benzoic acid

将反式-4-[1-(3，5-二(三氟甲基)苯基)-3-(4-叔丁基环己基)脲基甲基]苯甲酸甲酯(1.4g)悬浮在无水乙醇(20mL)中，加入氢氧化钠(2N，11mL)，并将该反应混合物轻度回流2小时。真空除去乙醇，加入水(40mL)，用盐酸(4N)将pH调节至酸性反应，然后加入乙酸乙酯(200mL)。分离出有机相，用水(4×50mL)洗涤，用硫酸镁干燥，过滤并真空蒸发，获得了1.1g(85％)反式-4-[1-(3，5-二(三氟甲基)苯基)-3-(4-叔丁基环己基)脲基甲基]苯甲酸，为固体。Trans-methyl 4-[1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-tert-butylcyclohexyl)ureidomethyl]benzoate (1.4 g) was suspended in To hydroethanol (20 mL), sodium hydroxide (2N, 11 mL) was added, and the reaction mixture was gently refluxed for 2 hours. Ethanol was removed in vacuo, water (40 mL) was added, the pH was adjusted to acidic reaction with hydrochloric acid (4N), and ethyl acetate (200 mL) was added. The organic phase was separated, washed with water (4 x 50 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to afford 1.1 g (85%) of trans-4-[1-(3,5-bis(trifluoromethyl )phenyl)-3-(4-tert-butylcyclohexyl)ureidomethyl]benzoic acid as a solid.

1H-NMR(DMSO-d6)：δ12.85(s，1H)；9.08(s，1H)；8.25(s，2H)；7.89(d，2H)；7.61(s，1H)； 1 H-NMR (DMSO-d 6 ): δ12.85(s, 1H); 9.08(s, 1H); 8.25(s, 2H); 7.89(d, 2H); 7.61(s, 1H);

7.38(d，2H)；4.65(s，2H)；4.07(m，1H)；1.73(m，4H)；1.43(m，2H)；1.11(m，2H)；0.93(m，7.38(d, 2H); 4.65(s, 2H); 4.07(m, 1H); 1.73(m, 4H); 1.43(m, 2H); 1.11(m, 2H);

1H)；0.82(s，9H)；M.p.239-241℃(MeCN).元素分析：C27H30N2F6O3的计算值：C，59.55％；H，5.55％；N，5.14％.实测值：C，59.58％；H，5.65％；N，5.11％.1H); 0.82(s, 9H); Mp239-241°C (MeCN). Elemental analysis: Calculated for C 27 H 30 N 2 F 6 O 3 : C, 59.55%; H, 5.55%; N, 5.14%. Found values: C, 59.58%; H, 5.65%; N, 5.11%.

在步骤3和4之后获得了本标题化合物。  1H-NMR(DMSO-d6)：δ0.83(s，9H)，0.90-0.99(m，1H)，1.06-1.15(m，2H)，1.37-1.50(m，2H)，1.64-1.80(m，4H)，3.35-3.43(m，1H)，3.52-3.61(m，1H)，4.01-4.11(m，1H)，4.18(t，1H)，4.63(s，2H)，7.35(d，2H)，7.61(s，1H)，7.81(d，2H)，8.27(s，2H)，8.43(t，1H)，9.07(s，1H)，12.46(宽峰，1H)；HPLC-MS(方法A)：m/z＝632(M+1)；Rt＝8.00min；M.p.185-187℃.元素分析：C30H35F6N3O5的计算值：C，57.05％；H，5.59％；N，6.65％.实测值：C，57.32％；H，5.70％；N，6.27％.实施例14(一般方法(A))(R)-反式-3-{4-[3-(3，5-二(三氟甲基)苯基)-1-(4-叔丁基环己基)脲基甲基苯甲酰基氨基}-2-羟基丙酸 After steps 3 and 4 the title compound was obtained. 1 H-NMR (DMSO-d 6 ): δ0.83 (s, 9H), 0.90-0.99 (m, 1H), 1.06-1.15 (m, 2H), 1.37-1.50 (m, 2H), 1.64-1.80 (m, 4H), 3.35-3.43(m, 1H), 3.52-3.61(m, 1H), 4.01-4.11(m, 1H), 4.18(t, 1H), 4.63(s, 2H), 7.35(d , 2H), 7.61(s, 1H), 7.81(d, 2H), 8.27(s, 2H), 8.43(t, 1H), 9.07(s, 1H), 12.46 (broad peak, 1H); HPLC-MS (Method A): m/z = 632 (M+1); R t = 8.00 min; Mp 185-187°C. Elemental analysis: Calculated for C 30 H 35 F 6 N 3 O 5 : C, 57.05%; H , 5.59%; N, 6.65%. Found: C, 57.32%; H, 5.70%; N, 6.27%. Example 14 (General Method (A)) (R)-trans-3-{4-[ 3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-tert-butylcyclohexyl)ureidomethylbenzoylamino}-2-hydroxypropionic acid

1H-NMR(DMSO-d6)：δ0.82(s，9H)，0.93(m，1H)，1.11(m，2H)，1.43(m，2H)，1.71(m，4H)， 1 H-NMR (DMSO-d 6 ): δ0.82(s, 9H), 0.93(m, 1H), 1.11(m, 2H), 1.43(m, 2H), 1.71(m, 4H),

3.38(m，1H)，3.56(m，1H)，4.05(m，1H)，4.16(t，1H)，4.63(s，2H)，7.33(d，2H)，7.61(s，1H)，3.38(m, 1H), 3.56(m, 1H), 4.05(m, 1H), 4.16(t, 1H), 4.63(s, 2H), 7.33(d, 2H), 7.61(s, 1H),

7.80(d，2H)，8.26(s，2H)，8.43(t，1H)；HPLC-MS(方法A)：m/z＝632(M+1)；Rt＝8.177.80 (d, 2H), 8.26 (s, 2H), 8.43 (t, 1H); HPLC-MS (method A): m/z = 632 (M+1); Rt = 8.17

min；M.p.184-187℃.元素分析：C30H35N3F6O5(+0.5乙酸乙酯)的计算值：C，56.88％；H，5.82％；N，6.22％.实测值：C，56.63％；H，5.66％；N，6.47％.实施例15(一般方法(A))反式-(R)-3-{4-[3-(3-甲基-5-三氟甲基苯基)-1-(4-叔丁基环己基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸 1H-NMR(DMSO-d6)：δ0.82(s，9H)，0.93(m，1H)，1.11(m，2H)，1.43(m，2H)，1.71(m，4H)，2.33(s，3H)，3.38(m，1H)，3.56(m，1H)，4.05(m，1H)，4.16(t，1H)，4.63(s，2H)，7.10(s，1H)，7.33(d，2H)，7.73(s，1H)，7.80(d，2H)，8.43(t，1H)，8.62(s，1H)；HPLC-MS(方法A)：m/z＝578(M+1)；Rt＝7.45min.实施例16(一般方法(A))(RS)-3-{4-[1-(4-叔丁基苯基)-3-(4-三氟甲氧基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸

Figure A0181159100852
步骤1：4-[1-(4-叔丁基苯基)-3-(4-三氟甲氧基苯基)脲基甲基]苯甲酸min; Mp 184-187°C. Elemental analysis: Calculated for C 30 H 35 N 3 F 6 O 5 (+0.5 ethyl acetate): C, 56.88%; H, 5.82%; N, 6.22%. Found: C , 56.63%; H, 5.66%; N, 6.47%. Example 15 (General Method (A)) trans-(R)-3-{4-[3-(3-methyl-5-trifluoromethyl phenyl)-1-(4-tert-butylcyclohexyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid 1 H-NMR (DMSO-d 6 ): δ0.82(s, 9H), 0.93(m, 1H), 1.11(m, 2H), 1.43(m, 2H), 1.71(m, 4H), 2.33( s, 3H), 3.38(m, 1H), 3.56(m, 1H), 4.05(m, 1H), 4.16(t, 1H), 4.63(s, 2H), 7.10(s, 1H), 7.33(d , 2H), 7.73(s, 1H), 7.80(d, 2H), 8.43(t, 1H), 8.62(s, 1H); HPLC-MS (method A): m/z=578(M+1) ; R t =7.45min. Example 16 (General method (A)) (RS)-3-{4-[1-(4-tert-butylphenyl)-3-(4-trifluoromethoxybenzene base) ureidomethyl] benzoylamino}-2-hydroxypropionic acid
Figure A0181159100852
Step 1: 4-[1-(4-tert-Butylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoic acid

将4-甲酰基苯甲酸甲酯(10.6g，64mmol)溶解在甲醇(200mL)中。加入4-叔丁基苯胺(9.61g，64mmol)，并将所得悬浮液回流15分钟。冷却至室温后，加入TFA(5.18mL，68mmol)，然后分批加入氰基硼氢化钠(3.26g，52mmol)。将所得混合物在室温搅拌2小时，并真空浓缩。将残余物在乙酸乙酯(200mL)与1N氢氧化钠水溶液(150和100mL)之间分配。将有机相干燥(硫酸镁)并真空蒸发，获得了19.0g(99％)4-[(4-叔丁基苯基氨基)甲基]苯甲酸甲酯，为固体。1H-NMR(CDCl3)：δ1.28(9H，s)，3.92(3H，s)，4.39(2H，s)，6.57(2H，d)，7.20(2H，d)，7.44  (2H，d)，8.00(2H，d ).步骤2：Methyl 4-formylbenzoate (10.6 g, 64 mmol) was dissolved in methanol (200 mL). 4-tert-Butylaniline (9.61 g, 64 mmol) was added and the resulting suspension was refluxed for 15 minutes. After cooling to room temperature, TFA (5.18 mL, 68 mmol) was added, followed by sodium cyanoborohydride (3.26 g, 52 mmol) in portions. The resulting mixture was stirred at room temperature for 2 hours, and concentrated in vacuo. The residue was partitioned between ethyl acetate (200 mL) and 1N aqueous sodium hydroxide solution (150 and 100 mL). The organic phase was dried (magnesium sulfate) and evaporated in vacuo to afford 19.0 g (99%) of methyl 4-[(4-tert-butylphenylamino)methyl]benzoate as a solid. 1 H-NMR (CDCl 3 ): δ1.28 (9H, s), 3.92 (3H, s), 4.39 (2H, s), 6.57 (2H, d), 7.20 (2H, d), 7.44 (2H, d), 8.00(2H, d). Step 2:

将上述苯甲酸甲酯(0.73g，2.44mmol)溶解在乙腈(7mL)中，加入异氰酸4-三氟甲氧基苯基酯(405μL，2.68mmol)。将所得混合物在室温搅拌3小时，然后回流1.5小时。冷却并真空浓缩后，通过硅胶柱色谱纯化残余物，首先用乙酸乙酯和庚烷的混合物(1∶6)洗脱，然后用乙酸乙酯与庚烷的混合物(1∶3)洗脱，获得了1.14g(94％)4-[1-(4-叔丁基苯基)-3-(4-三氟-甲氧基苯基)脲基甲基]苯甲酸甲酯，为油状物。1H-NMR(CDCl3)：δ1.35(9H，s)，3.91(3H，s)，4.97(2H，s)，6.30(1H，s)，7.1(4H，m)，7.32-7.43(6H，m)，7.96(2H，d).TLC：Rf＝0.11(SiO2；乙酸乙酯/庚烷(1∶6))；HPLC-MS(方法B)：m/z＝501(M+1)；Rt＝9.05min步骤2a：The above methyl benzoate (0.73 g, 2.44 mmol) was dissolved in acetonitrile (7 mL), and 4-trifluoromethoxyphenyl isocyanate (405 μL, 2.68 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours, then refluxed for 1.5 hours. After cooling and concentrating in vacuo, the residue was purified by column chromatography on silica gel, eluting first with a mixture of ethyl acetate and heptane (1:6) and then with a mixture of ethyl acetate and heptane (1:3), 1.14 g (94%) of methyl 4-[1-(4-tert-butylphenyl)-3-(4-trifluoro-methoxyphenyl)ureidomethyl]benzoate were obtained as an oil . 1 H-NMR (CDCl 3 ): δ1.35 (9H, s), 3.91 (3H, s), 4.97 (2H, s), 6.30 (1H, s), 7.1 (4H, m), 7.32-7.43 ( 6H, m), 7.96 (2H, d). TLC: Rf = 0.11 (SiO 2 ; ethyl acetate/heptane (1:6)); HPLC-MS (method B): m/z = 501 (M+ 1); R t =9.05 min Step 2a:

将上述脲基甲基苯甲酸甲酯(1.14g，2.28mmol)溶解在1，4-二氧杂环己烷(25 mL)中，并加入1N氢氧化钠水溶液(5mL)。将所得混合物在室温搅拌1小时。加入乙醇(15mL)和1N氢氧化钠水溶液(5mL)，并将所得混合物在室温搅拌16小时。将该混合物真空浓缩，在1N盐酸(100mL)与乙酸乙酯(2×50mL)之间分配。将合并的有机相干燥(硫酸镁)并真空浓缩，获得了847mg(76％)4-[1-(4-叔丁基苯基)-3-(4-三氟甲氧基苯基)脲基甲基]苯甲酸，为固体。1H-NMR(CDCl3)：δ1.33(9H，s)，3.91(3H，s)，4.97(2H，s)，6.30(1H，s)，7.1(4H，m)，7.33(2H，d)，7.43(4H，m)，8.03(2H，d).步骤3：(RS)-3-[4-[1-(4-叔丁基苯基)-3-(4-三氟甲氧基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸乙酯The above methyl ureidomethylbenzoate (1.14 g, 2.28 mmol) was dissolved in 1,4-dioxane (25 mL), and 1N aqueous sodium hydroxide solution (5 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. Ethanol (15 mL) and 1N aqueous sodium hydroxide solution (5 mL) were added, and the resulting mixture was stirred at room temperature for 16 hr. The mixture was concentrated in vacuo, partitioned between 1N hydrochloric acid (100 mL) and ethyl acetate (2 x 50 mL). The combined organic phases were dried (magnesium sulfate) and concentrated in vacuo to afford 847 mg (76%) of 4-[1-(4-tert-butylphenyl)-3-(4-trifluoromethoxyphenyl)urea Methyl]benzoic acid as a solid. 1 H-NMR (CDCl 3 ): δ1.33 (9H, s), 3.91 (3H, s), 4.97 (2H, s), 6.30 (1H, s), 7.1 (4H, m), 7.33 (2H, d), 7.43 (4H, m), 8.03 (2H, d). Step 3: (RS)-3-[4-[1-(4-tert-butylphenyl)-3-(4-trifluoromethane Oxyphenyl)ureidomethyl]benzoylamino}-2-hydroxypropanoic acid ethyl ester

向[1-(4-叔丁基苯基)-3-(4-三氟甲氧基苯基)脲基甲基]苯甲酸(1.0g，2.06mmol)在DMF(1mL)和DCM(10mL)内的溶液中加入1-羟基-7-氮杂苯并三唑(0.33g，2.47mmol)。在室温搅拌1小时，然后依次加入EDAC(0.47g，2.47mmol)、(RS)-异丝氨酸乙酯盐酸盐(0.52g，3.09mmol)和二异丙基乙基胺(1.1mL，6.18mmol)。在室温搅拌17小时后，将该反应混合物在水、盐水与乙酸乙酯之间分配。再用乙酸乙酯萃取水相。将合并的有机相用水和盐水洗涤。干燥(硫酸镁)后，并过滤，将有机相真空蒸发。通过硅胶柱色谱纯化残余物，用甲苯和乙酸乙酯的混合物(6∶4)洗脱。获得了1.2g(97％)(RS)-3-4-[1-(4-叔丁基苯基)-3-(4-三氟甲氧基苯基)脲基甲基]-苯甲酰基氨基}-2-羟基丙酸乙酯，为油状物。1H-NMR(DMSO-d6)：δ1.12(t，3H)，1.27(s，9H)，3.45(m，2H)，4.05(q，2H)，4.21(dd，1H)，4.98(s，2H)，5.67(d，1H)，7.20(dd，4H)，7.35(dd，4H)，7.55(d，2H)，5.77(d，2H)，8.42(s，1H)，8.48(t，1H)；HPLC-MS(方法B)：m/z＝602(M+1)；Rt＝3.38min.步骤4：To [1-(4-tert-butylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoic acid (1.0 g, 2.06 mmol) in DMF (1 mL) and DCM (10 mL ) was added 1-hydroxy-7-azabenzotriazole (0.33 g, 2.47 mmol). Stirred at room temperature for 1 hour, then added EDAC (0.47 g, 2.47 mmol), (RS)-isoserine ethyl ester hydrochloride (0.52 g, 3.09 mmol) and diisopropylethylamine (1.1 mL, 6.18 mmol) ). After stirring at room temperature for 17 hours, the reaction mixture was partitioned between water, brine and ethyl acetate. The aqueous phase was further extracted with ethyl acetate. The combined organic phases were washed with water and brine. After drying (magnesium sulfate) and filtration, the organic phase was evaporated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of toluene and ethyl acetate (6:4). Obtained 1.2 g (97%) of (RS)-3-4-[1-(4-tert-butylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-benzene Acylamino}-2-hydroxypropionic acid ethyl ester, an oil. 1 H-NMR (DMSO-d 6 ): δ1.12(t, 3H), 1.27(s, 9H), 3.45(m, 2H), 4.05(q, 2H), 4.21(dd, 1H), 4.98( s, 2H), 5.67(d, 1H), 7.20(dd, 4H), 7.35(dd, 4H), 7.55(d, 2H), 5.77(d, 2H), 8.42(s, 1H), 8.48(t , 1H); HPLC-MS (method B): m/z = 602 (M+1); Rt = 3.38min. Step 4:

将3-4-[1-(4-叔丁基苯基)-3-(4-三氟甲氧基苯基)脲基甲基]苯甲酰基-氨基}-2-羟基丙酸乙酯在无水乙醇(20mL)中的溶液搅拌，并加入1M氢氧化钠(6mL)。继续搅拌17小时，用盐酸将该溶液酸化。倾出溶剂，通过加热将剩余的油状物溶解在乙腈(20mL)中。在剧烈搅拌下滴加水(20mL)，将该混合物冷却至室温。过滤出沉淀，用水洗涤，干燥，获得了0.51g(43％)本标题化合物，为固体。1H-NMR(DMSO-d6)：δ1.25(s，9H)，3.50(ddd，2H)，4.18(dd，1H)，4.95(s，2H)，7.20(dd，4H)，7.39(dd，4H)，7.52(d，2H)，7.78(d，2H)，8.32(s，1H)，8.46(t，1H)；HPLC-MS(方法B)：m/z＝574(M+1)；Rt＝3.07min.元素分析：C29H30F3N3O6的计算值：C，60.73％；H，5.27％；N，7.33％.实测值：C，60.77％；H，5.37；N％，7.26％.实施例17(一般方法(A))(RS)-3-{4-[1-(4-环己-1-烯基苯基)-3-(3，5-二氯苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸步骤3：(RS)-3-{4-[1-(4-环己-1-烯基苯基)-3-(3，5-二氯苯基)脲基甲基]苯甲酰基-氨基}-2-羟基丙酸乙酯产量：0.33g(89％)。1H-NMR(CDCl3)：δ1.30(t，3H)，1.68(m，2H)，1.79(m，2H)，2.23(m，2H)，2.38(m，2H)，3.41(d，1H)，3.83(m，2H)，4.27(q，2H)，4.37(dd，1H)，4.92(s，2H)，6.20(m，1H)，6.27(s，1H)，6.51(t，1H)，6.98(s，1H)，7.04(d，2H)，7.18(d，2H)，7.33(d，2H)，7.42(d，2H)，7.68(d，2H).步骤4：(RS)-3-{4-[1-(4-环己-1-烯基苯基)-3-(3，5-二氯苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸Ethyl 3-4-[1-(4-tert-butylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoyl-amino}-2-hydroxypropionate The solution in absolute ethanol (20 mL) was stirred and 1M sodium hydroxide (6 mL) was added. Stirring was continued for 17 hours and the solution was acidified with hydrochloric acid. The solvent was decanted and the remaining oil was dissolved in acetonitrile (20 mL) by heating. Water (20 mL) was added dropwise with vigorous stirring, and the mixture was cooled to room temperature. The precipitate was filtered off, washed with water and dried to afford 0.51 g (43%) of the title compound as a solid. 1 H-NMR (DMSO-d 6 ): δ1.25 (s, 9H), 3.50 (ddd, 2H), 4.18 (dd, 1H), 4.95 (s, 2H), 7.20 (dd, 4H), 7.39 ( dd, 4H), 7.52(d, 2H), 7.78(d, 2H), 8.32(s, 1H), 8.46(t, 1H); HPLC-MS (method B): m/z=574 (M+1 ); R t = 3.07min. Elemental analysis: Calculated for C 29 H 30 F 3 N 3 O 6 : C, 60.73%; H, 5.27%; N, 7.33%. Found: C, 60.77%; H, 5.37; N%, 7.26%. Example 17 (General Method (A)) (RS)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5 -dichlorophenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid Step 3: (RS)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoyl- Yield of ethyl amino}-2-hydroxypropanoate: 0.33 g (89%). 1 H-NMR (CDCl 3 ): δ1.30(t, 3H), 1.68(m, 2H), 1.79(m, 2H), 2.23(m, 2H), 2.38(m, 2H), 3.41(d, 1H), 3.83(m, 2H), 4.27(q, 2H), 4.37(dd, 1H), 4.92(s, 2H), 6.20(m, 1H), 6.27(s, 1H), 6.51(t, 1H ), 6.98(s, 1H), 7.04(d, 2H), 7.18(d, 2H), 7.33(d, 2H), 7.42(d, 2H), 7.68(d, 2H). Step 4: (RS) -3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2-hydroxypropyl acid

将(RS)-3-{4-[1-(4-环己-1-烯基苯基)-3-(3，5-二氯苯基)脲基甲基]-苯甲酰基氨基}-2-羟基丙酸乙酯(0.99g，1.61mmol)在乙醇(15mL)和THF(15mL)中的溶液搅拌，并加入1M氢氧化钠(6mL)。将该混合物在40℃搅拌4小时，并用1N盐酸酸化。真空蒸发后，用半制备性HPLC(Gilson系统)纯化残余物。合并纯的级分，并真空蒸发，获得了0.74g(79％)本标题化合物，为固体。1H-NMR(DMSO-d6)：δ1.56(m，2H)，1.70(m，2H)，2.17(s，2H)，2.33(s，2H)，3.35(m，2H)，3.55(m，2H)，4.15(dd，1H)，4.95(s，2H)，6.20(s.1H)，7.12(s，1H)，7.18(d，2H)，7.33(d，2H)，7.40(d，2H)，7.62(s，2H)，7.76(d，2H)，8.43(t，1H)，8.55(s，1H)；HPLC-MS(方法B)：m/z＝582(M+1)；Rt＝5.13min元素分析：C29H30Cl2N3O5的计算值：C，61.86％；H，5.02％；N，7.21％.实测值：C，61.10％；H，5.05％；N，7.03％.实施例18(S)-3-{4-[1-(4-环己-1-烯基苯基)-3-(3，5-二氯苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸 (RS)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]-benzoylamino} - A solution of ethyl 2-hydroxypropionate (0.99 g, 1.61 mmol) in ethanol (15 mL) and THF (15 mL) was stirred and 1M sodium hydroxide (6 mL) was added. The mixture was stirred at 40°C for 4 hours and acidified with 1N hydrochloric acid. After evaporation in vacuo, the residue was purified by semi-preparative HPLC (Gilson system). The pure fractions were combined and evaporated in vacuo to afford 0.74 g (79%) of the title compound as a solid. 1 H-NMR (DMSO-d 6 ): δ1.56 (m, 2H), 1.70 (m, 2H), 2.17 (s, 2H), 2.33 (s, 2H), 3.35 (m, 2H), 3.55 ( m, 2H), 4.15(dd, 1H), 4.95(s, 2H), 6.20(s.1H), 7.12(s, 1H), 7.18(d, 2H), 7.33(d, 2H), 7.40(d , 2H), 7.62(s, 2H), 7.76(d, 2H), 8.43(t, 1H), 8.55(s, 1H); HPLC-MS (method B): m/z=582(M+1) ; R t = 5.13 min Elemental analysis: Calculated for C 29 H 30 Cl 2 N 3 O 5 : C, 61.86%; H, 5.02%; N, 7.21%. Found: C, 61.10%; H, 5.05% N, 7.03%. Example 18 (S)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl base]benzoylamino}-2-hydroxypropionic acid

将4-[1-(4-环己-1-烯基苯基)-3-(3，5-二氯苯基)脲基甲基]苯甲酸(130mg，0.26mmol)溶解在DMF(2mL)中，然后加入EDAC(50mg，0.26mmol)和HOBt(43mg，0.32mmol)，并将该反应混合物在室温搅拌1小时。将上述(S)-2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基甲基三氟乙酸铵粗产物溶解在DMF(1mL)中，并与二异丙基乙基胺(450mg，3.5mmol)一起加到该反应混合物中。将该混合物在室温搅拌16小时。将该反应混合物转移到硅胶柱上，并用DCM洗脱，蒸发后获得了(S)-4-[1-(4-环己-1-烯基苯基)-3-(3，5-二氯苯基)脲基甲基]-N-(2，2-二甲基-5-氧代-[1，3]二氧杂环戊烷-4-基甲基)苯甲酰胺粗产物，为油状物。将该油状物再溶解在乙腈(5mL)中，加入盐酸(1N，5mL)，并将该混合物在室温搅拌1.5小时。通过蒸发除去溶剂，通过半制备HPLC纯化粗产物(乙腈/水梯度)，获得了本标题化合物。HPLC-MS(方法B)：m/z＝582(M+1)；Rt＝5.10分钟。实施例19(一般方法(A))(R)-3-{4-[1-(4-环己-1-烯基苯基)-3-(3，5-二氯苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸

Figure A0181159100901
步骤3：(R)-3-{4-[1-(4-环己-1-烯基苯基)-3-(3，5-二氯苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸乙酯1H-NMR(丙酮-d6)：δ1.20(t，3H)，1.70(dm，4H)，2.31(dm，4H)，3.70(m，2H)，4.15(q，2H)，4.35(dd，1H)，5.02(s，2H)，6.22(m，1H)，7.00(s，1H)，7.0(d，2H)，7.40(dd，4H)，7.61(ds，2H)，7.80(d，3H)，7.89(s，1H).步骤4：Dissolve 4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoic acid (130 mg, 0.26 mmol) in DMF (2 mL ), then EDAC (50 mg, 0.26 mmol) and HOBt (43 mg, 0.32 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. The above crude (S)-2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylmethylammonium trifluoroacetate was dissolved in DMF (1 mL), and added to the reaction mixture along with diisopropylethylamine (450 mg, 3.5 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was transferred to a silica gel column and eluted with DCM to afford after evaporation (S)-4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-di Chlorophenyl)ureidomethyl]-N-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylmethyl)benzamide crude product, For oil. The oil was redissolved in acetonitrile (5 mL), hydrochloric acid (1N, 5 mL) was added, and the mixture was stirred at room temperature for 1.5 hr. The solvent was removed by evaporation and the crude product was purified by semi-preparative HPLC (acetonitrile/water gradient) to afford the title compound. HPLC-MS (Method B): m/z = 582 (M+1); Rt = 5.10 min. Example 19 (General Method (A)) (R)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureido Methyl]benzoylamino}-2-hydroxypropionic acid
Figure A0181159100901
Step 3: (R)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino }-2-Hydroxypropionic acid ethyl ester 1 H-NMR (acetone-d 6 ): δ1.20(t, 3H), 1.70(dm, 4H), 2.31(dm, 4H), 3.70(m, 2H), 4.15(q, 2H), 4.35(dd, 1H), 5.02(s, 2H), 6.22(m, 1H), 7.00(s, 1H), 7.0(d, 2H), 7.40(dd, 4H), 7.61 (ds, 2H), 7.80 (d, 3H), 7.89 (s, 1H). Step 4:

将(R)-3-{4-[1-(4-环己-1-烯基苯基)-3-(3，5-二氯苯基)脲基甲基]-苯甲酰基氨基}-2-羟基丙酸乙酯(0.60g，0.98mmol)在乙醇(5mL)和THF(5mL)中的溶液搅拌，并加入4N氢氧化钠(0.76mL，2.94mmol)。将该溶液在室温搅拌3小时，然后用1N盐酸酸化。真空蒸发，获得了油状物，将其在乙酸乙酯、水和盐水之间分配。用乙酸乙酯将水相萃取2次，用水和盐水洗涤合并的有机相。干燥(硫酸镁)，过滤，并真空蒸发，获得了0.43g(73％)本标题化合物，为固体。1H-NMR(DMSO-d6)：δ1.50-1.80(4H，m)，2.08-2.38(4H，m)，3.36-3.65(2H，m)，4.14-4.24(1H，m)，4.96(2H，m)，6.17(1H，t)，7.14(1H，t)，7.18(2H，d)，7.35(2H，d)，7.42(2H，d)，7.63(2H，d)，7.78(2H，d)，8.48(1H，t)，8.55(1H，s)；HPLC-MS(方法B)：m/z＝582(M+1)；Rt＝5.11min.实施例20(一般方法(A))(R)-3-{4-[3-(3-氯苯基)-1-(4-环己-1-烯基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸 1H-NMR(DMSO-d6)：δ1.56-1.71(m，4H)，2.15-2.33(m，4H)，3.37-3.51(m，2H)，4.14-4.17(m，1H)，4.96(s，1H)，6.17(t，1H)，7.12(dd，1H)，7.27-7.41(m，8H)，7.62(t，1H)，7.87(d，2H)，8.38-8.43(m，3H)；HPLC-MS(方法B)：m/z＝548(M+1)；Rt＝4.69min.实施例21(一般方法(A))(R)-3-{4-[1-(4-环己-1-烯基苯基)-3-苯基脲基甲基]苯甲酰基氨基-2-羟基丙酸

Figure A0181159100912
1H-NMR(DMSO-d6)：δ1.56-1.71(m，4H)，2.15-2.40(m，4H)，3.30-3.51(m，2H)，4.14-4.19(m，1H)，4.97(s，1H)，6.16(t，1H)，6.98(t，1H)，7.12-7.48(m，10H)，7.79(d，2H)，8.15(s，1H)，8.43(t，1H).实施例22(一般方法(A))(R)-3-{4-[3-苄基-1-(4-环己-1-烯基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸 1H-NMR(DMSO-d6)：δ1.50-1.75(m，4H)，1.86(s，2H)，2.08(s，2H)，3.30-3.60(m，2H)，4.13-4.20(m，1H)，4.25(d，2H)，4.87(s，2H)，6.18(t，1H)，6.55(t，1H)，7.08-7.42(m，11H)，7.77(d，2H)，8.48(t，1H).实施例23(一般方法(A))(RS)-3-{4-[1-(4-环己-1-烯基苯基)-3-(3，5-二氯苯基)脲基甲基]苯甲酰基氨基}-2-氟丙酸步骤1和2：4-[1-(4-环己-1-烯基苯基)-3-(3，5-二氯苯基)脲基甲基]苯甲酸1H-NMR(DMSO-d6)：δ1.52-1.77(m，4H)，2.10-2.23(m，2H)，2.26-2.38(m，2H)，4.95(s，2H)，6.18(t，1H)，7.14(t，1H)，7.17(d，2H)，7.34(d，2H)，7.40(d，2H)，7.64(dd，2H)，7.85(d，2H)，8.55(s，1H).元素分析：C27H24N2O3Cl2的计算值：C，65.46％；H，4.88％；N，5.65％.实测值：C，65.43％；H，5.10％；N，5.66％.步骤3：(RS)-3-{4-[1-(4-环己-1-烯基苯基)-3-(3，5-二氯苯基)脲基甲基]苯甲酰基氨基}-2-氟丙酸甲酯1H-NMR(DMSO-d6)：δ1.52-1.75(m，4H)，2.10-2.40(m，4H)，3.60-3.81(m，5H)，4.95(s，2H)，5.04-5.35(m，1H)，6.18(m，1H)，7.10-7.80(m，11H)，8.55(s，1H)，8.75(t，1H)，13.45(brs，1H).步骤4：(R)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]-benzoylamino} - A solution of ethyl 2-hydroxypropanoate (0.60 g, 0.98 mmol) in ethanol (5 mL) and THF (5 mL) was stirred, and 4N sodium hydroxide (0.76 mL, 2.94 mmol) was added. The solution was stirred at room temperature for 3 hours, then acidified with 1N hydrochloric acid. Evaporation in vacuo gave an oil which was partitioned between ethyl acetate, water and brine. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and brine. Drying (magnesium sulfate), filtering, and evaporation in vacuo afforded 0.43 g (73%) of the title compound as a solid. 1 H-NMR (DMSO-d 6 ): δ1.50-1.80 (4H, m), 2.08-2.38 (4H, m), 3.36-3.65 (2H, m), 4.14-4.24 (1H, m), 4.96 (2H,m), 6.17(1H,t), 7.14(1H,t), 7.18(2H,d), 7.35(2H,d), 7.42(2H,d), 7.63(2H,d), 7.78( 2H,d), 8.48(1H,t), 8.55(1H,s); HPLC-MS (Method B): m/z=582(M+1); Rt =5.11min. Example 20 (General Method (A))(R)-3-{4-[3-(3-chlorophenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]benzoylamino}- 2-Hydroxypropionic acid 1 H-NMR (DMSO-d 6 ): δ1.56-1.71 (m, 4H), 2.15-2.33 (m, 4H), 3.37-3.51 (m, 2H), 4.14-4.17 (m, 1H), 4.96 (s, 1H), 6.17(t, 1H), 7.12(dd, 1H), 7.27-7.41(m, 8H), 7.62(t, 1H), 7.87(d, 2H), 8.38-8.43(m, 3H ); HPLC-MS (Method B): m/z = 548 (M+1); R t = 4.69 min. Example 21 (General Method (A)) (R)-3-{4-[1-( 4-Cyclohex-1-enylphenyl)-3-phenylureidomethyl]benzoylamino-2-hydroxypropionic acid
Figure A0181159100912
1 H-NMR (DMSO-d 6 ): δ1.56-1.71 (m, 4H), 2.15-2.40 (m, 4H), 3.30-3.51 (m, 2H), 4.14-4.19 (m, 1H), 4.97 (s, 1H), 6.16(t, 1H), 6.98(t, 1H), 7.12-7.48(m, 10H), 7.79(d, 2H), 8.15(s, 1H), 8.43(t, 1H). Example 22 (General Procedure (A)) (R)-3-{4-[3-benzyl-1-(4-cyclohex-1-enylphenyl)ureidomethyl]benzoylamino} -2-Hydroxypropionic acid 1 H-NMR (DMSO-d 6 ): δ1.50-1.75 (m, 4H), 1.86 (s, 2H), 2.08 (s, 2H), 3.30-3.60 (m, 2H), 4.13-4.20 (m , 1H), 4.25(d, 2H), 4.87(s, 2H), 6.18(t, 1H), 6.55(t, 1H), 7.08-7.42(m, 11H), 7.77(d, 2H), 8.48( t, 1H). Example 23 (General Method (A)) (RS)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichloro phenyl)ureidomethyl]benzoylamino}-2-fluoropropionic acid Steps 1 and 2: 1 H-NMR of 4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl ] benzoic acid (DMSO- d 6 ): δ1.52-1.77(m, 4H), 2.10-2.23(m, 2H), 2.26-2.38(m, 2H), 4.95(s, 2H), 6.18(t, 1H), 7.14(t , 1H), 7.17(d, 2H), 7.34(d, 2H), 7.40(d, 2H), 7.64(dd, 2H), 7.85(d, 2H), 8.55(s, 1H). Elemental analysis: C Calcd for 27 H 24 N 2 O 3 Cl 2 : C, 65.46%; H, 4.88%; N, 5.65%. Found: C, 65.43%; H, 5.10%; N, 5.66%. Step 3: ( RS)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2- Methyl fluoropropionate 1 H-NMR (DMSO-d 6 ): δ1.52-1.75(m, 4H), 2.10-2.40(m, 4H), 3.60-3.81(m, 5H), 4.95(s, 2H ), 5.04-5.35(m, 1H), 6.18(m, 1H), 7.10-7.80(m, 11H), 8.55(s, 1H), 8.75(t, 1H), 13.45(brs, 1H). Step 4 :

将(RS)-3-{4-[1-(4-环己-1-烯基苯基)-3-(3，5-二氯苯基)脲基甲基]苯甲酰基氨基}-2-氟丙酸甲酯在THF和甲醇的混合物中水解，获得了本标题化合物。(RS)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}- Hydrolysis of methyl 2-fluoropropionate in a mixture of THF and methanol afforded the title compound.

1H-NMR(DMSO-d6)：δ1.59-1.72(m，4H)，2.15-2.33(m，4H)，3.58-3.81(m，2H)，4.96(s，2H)， 1 H-NMR (DMSO-d 6 ): δ1.59-1.72 (m, 4H), 2.15-2.33 (m, 4H), 3.58-3.81 (m, 2H), 4.96 (s, 2H),

5.17-5.23(m，1H)，6.18(m，1H)，7.13-7.80(m，11H)，8.54(s，1H)，8.73(t，1H)，13.45(brs，5.17-5.23(m, 1H), 6.18(m, 1H), 7.13-7.80(m, 11H), 8.54(s, 1H), 8.73(t, 1H), 13.45(brs,

1H).实施例24(一般方法(A))(R)-3-{4-[1-(4-环己基苯基)-3-(4-三氟甲硫基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸

Figure A0181159100931
步骤2：4-[1-(4-环己基苯基)-3-(4-三氟甲硫基苯基)脲基甲基]苯甲酸甲酯1H). Example 24 (General Method (A)) (R)-3-{4-[1-(4-cyclohexylphenyl)-3-(4-trifluoromethylthiophenyl)carbamide base]benzoylamino}-2-hydroxypropionic acid
Figure A0181159100931
Step 2: Methyl 4-[1-(4-cyclohexylphenyl)-3-(4-trifluoromethylthiophenyl)ureidomethyl]benzoate

将4-((4-环己基苯基氨基)甲基)苯甲酸甲酯(0.32g，1mmol)悬浮在乙腈(5mL)中，加入异氰酸4-(三氟甲硫基)苯基酯(0.24g，1.1mmol)。第一天后再加入异氰酸酯(0.05g)，第二天后再加入一部分异氰酸酯(0.05g)。在第三天停止反应，并真空浓缩。通过硅胶(30g)柱色谱纯化残余物，使用乙酸乙酯∶正庚烷(400mL1∶4和100mL1∶1)洗脱，获得了0.53g4-[1-(4-环己基苯基)-3-(4-三氟甲硫基苯基)脲基甲基]苯甲酸甲酯。1H-NMR(DMSO-d6)：δ1.16-1.43(m，5H)，1.65-1.82(m，5H)，3.84(s，3H)，4.99(s，2H)，8.62(s，1H)；HPLC-MS(方法B)：m/z＝543(M+1)；Rt＝9.35min.步骤2a：4-[1-(4-环己基苯基)-3-(4-三氟甲硫基苯基)脲基甲基]苯甲酸Suspend methyl 4-((4-cyclohexylphenylamino)methyl)benzoate (0.32 g, 1 mmol) in acetonitrile (5 mL) and add 4-(trifluoromethylthio)phenyl isocyanate (0.24 g, 1.1 mmol). Additional isocyanate (0.05 g) was added on the first day and a further portion of isocyanate (0.05 g) was added on the second day. The reaction was stopped on the third day and concentrated in vacuo. Purification of the residue by column chromatography on silica gel (30 g) eluting with ethyl acetate:n-heptane (400 mL 1:4 and 100 mL 1:1) afforded 0.53 g of 4-[1-(4-cyclohexylphenyl)-3- Methyl (4-trifluoromethylthiophenyl)ureidomethyl]benzoate. 1 H-NMR (DMSO-d 6 ): δ1.16-1.43 (m, 5H), 1.65-1.82 (m, 5H), 3.84 (s, 3H), 4.99 (s, 2H), 8.62 (s, 1H) ); HPLC-MS (Method B): m/z = 543 (M+1); R t = 9.35 min. Step 2a: 4-[1-(4-cyclohexylphenyl)-3-(4-tri Fluoromethylthiophenyl)ureidomethyl]benzoic acid

将4-[1-(4-环己基苯基)-3-(4-三氟甲硫基苯基)脲基甲基]苯甲酸甲酯(0.53g，0.98mmol)溶解在乙醇(96％，11mL)中，并加入氢氧化钠(4N，1.47mL)。将该混合物搅拌过夜。将该反应浓缩至干，加入水(15mL)，用盐酸(4N，1.6mL)酸化至pH2-3，并用乙酸乙酯(25mL)萃取。将水相再用乙酸乙酯(15mL)萃取一次，将合并的有机相用水(10mL)洗涤3次，用硫酸镁干燥，过滤并真空浓缩。从乙酸乙酯∶正庚烷中结晶，获得了0.34g4-[1-(4-环己基苯基)-3-(4-三氟-甲硫基苯基)脲基甲基]苯甲酸。1H-NMR(DMSO-d6)：δ1.5-1.42(m，5H)，1.67-1.83(m，5H)，2.45(m，1H)，5.00(s，2H)，7.15-7.25(dd，4H)，7.40(d，2H)，7.54-7.63(dd，4H)，7.88(d，2H)，7.62(s，1H)，12.90(宽峰1H)，HPLC-MS(方法B)：m/z＝529(M+1)；Rt＝8.55min；M.p.162.0-164.0℃.元素分析：C28H27F3N2O3S的计算值：C，63.62％；H，5.15％；N，5.30％.实测值：C，63.97％；H，5.28％；N，5.26％.步骤3：(R)-3-{4-[1-(4-环己基苯基)-3-(4-三氟甲硫基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸甲酯Dissolve methyl 4-[1-(4-cyclohexylphenyl)-3-(4-trifluoromethylthiophenyl)ureidomethyl]benzoate (0.53 g, 0.98 mmol) in ethanol (96% , 11 mL), and sodium hydroxide (4N, 1.47 mL) was added. The mixture was stirred overnight. The reaction was concentrated to dryness, added water (15 mL), acidified to pH 2-3 with hydrochloric acid (4N, 1.6 mL), and extracted with ethyl acetate (25 mL). The aqueous phase was extracted once more with ethyl acetate (15 mL), the combined organic phases were washed 3 times with water (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Crystallization from ethyl acetate:n-heptane afforded 0.34 g of 4-[1-(4-cyclohexylphenyl)-3-(4-trifluoro-methylthiophenyl)ureidomethyl]benzoic acid. 1 H-NMR (DMSO-d 6 ): δ1.5-1.42 (m, 5H), 1.67-1.83 (m, 5H), 2.45 (m, 1H), 5.00 (s, 2H), 7.15-7.25 (dd , 4H), 7.40 (d, 2H), 7.54-7.63 (dd, 4H), 7.88 (d, 2H), 7.62 (s, 1H), 12.90 (broad peak 1H), HPLC-MS (method B): m /z=529(M+1); Rt =8.55min; Mp162.0-164.0°C. Elemental analysis: calculated for C 28 H 27 F 3 N 2 O 3 S: C, 63.62%; H, 5.15% N, 5.30%. Found: C, 63.97%; H, 5.28%; N, 5.26%. Step 3: (R)-3-{4-[1-(4-cyclohexylphenyl)-3- Methyl (4-trifluoromethylthiophenyl)ureidomethyl]benzoylamino}-2-hydroxypropionate

将4-[1-(4-环己基苯基)-3-(4-三氟甲硫基苯基)脲基甲基]苯甲酸(0.32g，0.606mmol)溶解在DMF(7mL)中，并加入HOAt(0.10g，0.727mmol)和EDAC(0.14g，0.727mmol)。将该混合物搅拌30分钟。然后加入(R)-3-氨基-2-羟基丙酸甲酯盐酸盐(0.14g)和二异丙基乙基胺(0.16mL，0.909mmol)。将该反应搅拌过夜。将该反应混合物与乙酸乙酯(30mL)和水(15mL)转移到分液漏斗中，并萃取。用乙酸乙酯(15mL)将水相再萃取一次，将合并的有机相用盐酸(0.2N，3×10mL)和饱和氯化钠水溶液(3×10mL)洗涤，用硫酸镁干燥，过滤并真空浓缩。将残余物在柱(硅胶，30g)上纯化，用乙酸乙酯和正庚烷的混合物(200mL，40∶60和450mL1∶1)洗脱，获得了0.33g(R)-3-{4-[1-(4-环己基苯基)-3-(4-三氟甲硫基苯基)-脲基甲基]苯甲酰基氨基}-2-羟基丙酸甲酯。1H-NMR(DMSO-d6)δ1.16-1.43(m，5H)，1.66-1.81(m，5H)，2.47(m，1H)，3.4(m，1H)，3.51(m，1H)，3.63(s，3H)，4.22(q，1H)，4.97(s，2H)，5.73(d，1H)，7.2(dd，(4H)，7.35(d，2H)，7.60(dd，4H)，7.76(d，2H)，8.50(t，1H)，8.60(s，1H)，HPLC-MS(方法B)：m/z＝630(M+1)；Rt＝8.07min.步骤4：4-[1-(4-Cyclohexylphenyl)-3-(4-trifluoromethylthiophenyl)ureidomethyl]benzoic acid (0.32 g, 0.606 mmol) was dissolved in DMF (7 mL), And HOAt (0.10 g, 0.727 mmol) and EDAC (0.14 g, 0.727 mmol) were added. The mixture was stirred for 30 minutes. Then (R)-methyl 3-amino-2-hydroxypropanoate hydrochloride (0.14 g) and diisopropylethylamine (0.16 mL, 0.909 mmol) were added. The reaction was stirred overnight. The reaction mixture was transferred to a separatory funnel with ethyl acetate (30 mL) and water (15 mL), and extracted. The aqueous phase was extracted once more with ethyl acetate (15 mL), the combined organic phases were washed with hydrochloric acid (0.2 N, 3 x 10 mL) and saturated aqueous sodium chloride (3 x 10 mL), dried over magnesium sulfate, filtered and vacuum concentrate. The residue was purified on a column (silica gel, 30 g) eluting with a mixture of ethyl acetate and n-heptane (200 mL, 40:60 and 450 mL 1:1) to obtain 0.33 g of (R)-3-{4-[ Methyl 1-(4-cyclohexylphenyl)-3-(4-trifluoromethylthiophenyl)-ureidomethyl]benzoylamino}-2-hydroxypropionate. 1 H-NMR (DMSO-d 6 ) δ1.16-1.43 (m, 5H), 1.66-1.81 (m, 5H), 2.47 (m, 1H), 3.4 (m, 1H), 3.51 (m, 1H) , 3.63(s, 3H), 4.22(q, 1H), 4.97(s, 2H), 5.73(d, 1H), 7.2(dd, (4H), 7.35(d, 2H), 7.60(dd, 4H) , 7.76(d, 2H), 8.50(t, 1H), 8.60(s, 1H), HPLC-MS (method B): m/z=630(M+1); Rt =8.07min. Step 4:

将(R)-3-{4-[1-(4-环己基苯基)-3-(4-三氟甲硫基苯基)脲基甲基]苯甲酰基-氨基}-2-羟基丙酸甲酯(0.32g，0.508mmol)溶解在乙醇(15mL)中，并加入氢氧化钠(4N，0.76mL，3.05mmol)。将该反应混合物搅拌1.5小时。将该反应蒸发，加入水(15mL)，用盐酸(4N，0.8mL)酸化。用乙酸乙酯(20mL)萃取该混合物。将水相用乙酸乙酯(15mL)再萃取一次，用水(3×10mL)洗涤合并的有机相，用硫酸镁干燥，过滤并浓缩，获得了本标题化合物(0.3g)。1H-NMR(DMSO-d6)：δ1.12-1.42(m，5H)，1.66-1.82(m，5H)，2.45(m，1H)，3.38(m，1H)，3.54(m，1H)，4.17(q，1H)，4.96(s，2H)，5.45(宽峰，1H)，7.20(dd，4H)，7.34(d，2H)，7.60(dd，4H)，7.78(d，2H)，8.45(t，1H)，8.60(s，1H)，12.53(宽峰，1H)，HPLC-MS(方法B)：m/z＝616(M+1)；Rt＝7.68min.元素分析：C31H32F3N3O5S的计算值：C，60.48％；H，5.24％；N，6.83％.实测值：C，60.25％；H，5.52％；N，6.53％.实施例25(一般方法(A))(R)-3-{4-[1-(4-环己烯-1-基苯基)-3-(3-甲磺酰基-4-三氟甲氧基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸制备在步骤2中使用的异氰酸3-甲基磺酰基-4-三氟甲氧基苯基酯，中间体D-N＝C＝O(R)-3-{4-[1-(4-cyclohexylphenyl)-3-(4-trifluoromethylthiophenyl)ureidomethyl]benzoyl-amino}-2-hydroxy Methyl propionate (0.32 g, 0.508 mmol) was dissolved in ethanol (15 mL), and sodium hydroxide (4N, 0.76 mL, 3.05 mmol) was added. The reaction mixture was stirred for 1.5 hours. The reaction was evaporated, water (15 mL) added and acidified with hydrochloric acid (4N, 0.8 mL). The mixture was extracted with ethyl acetate (20 mL). The aqueous phase was extracted once more with ethyl acetate (15 mL) and the combined organic phases were washed with water (3 x 10 mL), dried over magnesium sulfate, filtered and concentrated to afford the title compound (0.3 g). 1 H-NMR (DMSO-d 6 ): δ1.12-1.42 (m, 5H), 1.66-1.82 (m, 5H), 2.45 (m, 1H), 3.38 (m, 1H), 3.54 (m, 1H) ), 4.17(q, 1H), 4.96(s, 2H), 5.45(broad, 1H), 7.20(dd, 4H), 7.34(d, 2H), 7.60(dd, 4H), 7.78(d, 2H ), 8.45 (t, 1H), 8.60 (s, 1H), 12.53 (broad peak, 1H), HPLC-MS (method B): m/z = 616 (M+1); R t = 7.68min. element Analysis: Calcd . for C31H32F3N3O5S : C, 60.48%; H, 5.24%; N, 6.83 % . Found: C, 60.25%; H, 5.52 % ; N, 6.53%. Example 25 (General Method (A)) (R)-3-{4-[1-(4-cyclohexen-1-ylphenyl)-3-(3-methylsulfonyl-4-trifluoromethane Oxyphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid Preparation of 3-methylsulfonyl-4-trifluoromethoxyphenyl isocyanate used in step 2, intermediate DN=C=O

向甲基碘(59.0g，0.41mol)在DMF(150mL)内的溶液中加入碳酸钾(23.0g，0.16mol)。用30分钟分批加入2-(三氟甲氧基)苯硫酚(16.0g，0.08mol)。将该反应混合物剧烈搅拌过夜。加入水(250mL)。用乙酸乙酯(2×150mL)萃取该反应混合物。将合并的有机相用50％饱和氯化钠水溶液(4×100mL)洗涤，干燥(硫酸镁)，并真空浓缩，获得了15.0g1-甲硫基-2-三氟甲氧基。To a solution of methyl iodide (59.0 g, 0.41 mol) in DMF (150 mL) was added potassium carbonate (23.0 g, 0.16 mol). 2-(Trifluoromethoxy)thiophenol (16.0 g, 0.08 mol) was added in portions over 30 minutes. The reaction mixture was stirred vigorously overnight. Water (250 mL) was added. The reaction mixture was extracted with ethyl acetate (2 x 150 mL). The combined organic phases were washed with 50% saturated aqueous sodium chloride (4 x 100 mL), dried (magnesium sulfate), and concentrated in vacuo to afford 15.0 g of 1-methylthio-2-trifluoromethoxy.

将1-甲硫基-2-三氟甲氧基苯(15.0g，72mmol)溶解在DCM(200mL)中，用30分钟以少量多次的方式加入间氯过苯甲酸(39.0g，216mmol)。然后将该反应混合物静置过夜。加入DCM(200mL)，然后缓慢地加入氢氧化钠(2N，200mL)。分离出有机相，用氢氧化钠(2N，3×150mL)洗涤，干燥(硫酸镁)并真空浓缩，获得了15.8g1-甲基磺酰基-2-三氟甲氧基苯。1H-NMR(400 MHz，CDCl3)：δ8.11(d，1H)，7.71(t，1H)，7.48(m，2H)3.23(s 1H)；M.p.44-46℃.元素分析：C8H7F3O3S的计算值：C，40.00％；H，2.94％. 实测值：C，40.22％；H，2.92％.1-Methylthio-2-trifluoromethoxybenzene (15.0 g, 72 mmol) was dissolved in DCM (200 mL), and m-chloroperbenzoic acid (39.0 g, 216 mmol) was added in small portions over 30 minutes . The reaction mixture was then left overnight. DCM (200 mL) was added followed by sodium hydroxide (2N, 200 mL) slowly. The organic phase was separated, washed with sodium hydroxide (2N, 3 x 150 mL), dried (magnesium sulfate) and concentrated in vacuo to afford 15.8 g of 1-methylsulfonyl-2-trifluoromethoxybenzene. 1 H-NMR (400 MHz, CDCl 3 ): δ8.11(d, 1H), 7.71(t, 1H), 7.48(m, 2H) 3.23(s 1H); Mp44-46℃. Elemental analysis: C 8 Calculated for H 7 F 3 O 3 S: C, 40.00%; H, 2.94%. Found: C, 40.22%; H, 2.92%.

将1-甲基磺酰基-2-三氟甲氧基苯(15.7g，65mmol)溶解在浓硫酸(27mL)中，将该溶液加热至40℃。用45分钟滴加硝酸(100％，27mL)。将该反应混合物在60℃静置过夜，冷却，然后倒入碎冰(300mL)上。通过过滤分离沉淀产物，用水(10×50mL)洗涤，干燥(硫酸镁)，获得了17.5g3-甲基磺酰基-4-三氟甲氧基硝基苯。1-Methylsulfonyl-2-trifluoromethoxybenzene (15.7 g, 65 mmol) was dissolved in concentrated sulfuric acid (27 mL), and the solution was heated to 40°C. Nitric acid (100%, 27 mL) was added dropwise over 45 minutes. The reaction mixture was left at 60° C. overnight, cooled, and poured onto crushed ice (300 mL). The precipitated product was isolated by filtration, washed with water (10 x 50 mL) and dried (magnesium sulfate) to yield 17.5 g of 3-methylsulfonyl-4-trifluoromethoxynitrobenzene.

1H-NMR(400MHz，DMSO-d6)：δ8.69(d，1H)，8.64(d，1H)，7.95(d，1H)3.45(s3H)；M.p. 1 H-NMR (400MHz, DMSO-d 6 ): δ8.69(d, 1H), 8.64(d, 1H), 7.95(d, 1H) 3.45(s3H); Mp

102-104℃.元素分析：C8H6F3NO5S的计算值：C，33.69％；H，2.12％；N，4.91％.实测值：C，33.91％；H，2.08％；N，4.92％.102-104°C. Elemental analysis: Calculated value for C 8 H 6 F 3 NO 5 S: C, 33.69%; H, 2.12%; N, 4.91%. Measured value: C, 33.91%; H, 2.08%; N , 4.92%.

将3-甲基磺酰基-4-三氟甲氧基硝基苯(17.5g)溶解在甲醇(400mL)中，然后加入披钯活性炭(10％，50％水，3.2g)。将该反应混合物在1atm氢气下氢化17小时，过滤并真空浓缩，获得了14.3g3-甲基磺酰基-4-三氟甲氧基苯胺。1H-NMR(400MHz，DMSO-d6)：δ7.26(d，1H)，7.14(d，1H)，6.85(dd，1H)5.89(s，2H)3.21(s，3H)；M.p.106-109℃.元素分析：C8H8F3NO3S的计算值：37.65％C，3.16％H，5.49％N.实测值：37.65％C，3.14％H，5.45％N.3-Methylsulfonyl-4-trifluoromethoxynitrobenzene (17.5 g) was dissolved in methanol (400 mL), then palladium on activated carbon (10%, 50% water, 3.2 g) was added. The reaction mixture was hydrogenated under 1 atm of hydrogen for 17 hours, filtered and concentrated in vacuo to afford 14.3 g of 3-methylsulfonyl-4-trifluoromethoxyaniline. 1 H-NMR (400MHz, DMSO-d 6 ): δ7.26(d, 1H), 7.14(d, 1H), 6.85(dd, 1H) 5.89(s, 2H) 3.21(s, 3H); Mp106- 109°C. Elemental analysis: Calculated for C8H8F3NO3S : 37.65% C , 3.16%H, 5.49% N . Found: 37.65%C, 3.14% H , 5.45%N.

向溶解在乙酸乙酯(6mL)内的3-甲基磺酰基-4-三氟甲氧基苯胺(2.0mmol，500mg)中加入3N氯化氢在乙酸乙酯中的溶液(5mL)，然后真空浓缩。将残余物用甲苯(3×5mL)处理，每次都真空浓缩。在氮气氛下向残余物中加入甲苯(10mL)和双光气(6mmol，0.73mL)，并将该悬浮液轻度回流2小时。再加入双光气(6mmol，0.73mL)，并继续回流过夜。将该反应混合物真空浓缩，获得了异氰酸3-甲基磺酰基-4-三氟甲氧基苯基酯。步骤3：(R)-3-{4-[1-(4-环己烯-1-基苯基)-3-(3-甲磺酰基-4-三氟甲氧基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸甲酯To 3-methylsulfonyl-4-trifluoromethoxyaniline (2.0 mmol, 500 mg) dissolved in ethyl acetate (6 mL) was added 3N hydrogen chloride in ethyl acetate (5 mL), then concentrated in vacuo . The residue was treated with toluene (3 x 5 mL) and concentrated in vacuo each time. To the residue were added toluene (10 mL) and diphosgene (6 mmol, 0.73 mL) under nitrogen atmosphere, and the suspension was refluxed gently for 2 hours. Additional diphosgene (6 mmol, 0.73 mL) was added and reflux was continued overnight. The reaction mixture was concentrated in vacuo to afford 3-methylsulfonyl-4-trifluoromethoxyphenyl isocyanate. Step 3: (R)-3-{4-[1-(4-Cyclohexen-1-ylphenyl)-3-(3-methylsulfonyl-4-trifluoromethoxyphenyl)ureido Methyl]benzoylamino}-2-hydroxypropionate

该中间体是用一般方法(A)(步骤1、2、2a、和3)制得的。1H-NMR(DMSO-d6)：δ1.60(m，2H)，1.72(m，2H)，2.18(m，2H)，2.36(m，2H)，3.27(s，3H)，3.41(m，1H)，3.51(m，1H)，3.61(s，3H)，4.23q，1H)，4.96(s，2H)，5.70(d，1H)，6.18(m，1H)，7.19(d，2H)，7.33(d，2H)，7.39(d，2H)，7.53(d，1H)，7.75(d，2H)，8.00(d，1H)，8.18(s，1H)，8.50(t，1H)，8.85(s，1H)；HPLC-MS(方法B)：m/z＝690(M+1)：Rt＝6.92min.步骤4：This intermediate was prepared using general method (A) (steps 1, 2, 2a, and 3). 1 H-NMR (DMSO-d 6 ): δ1.60 (m, 2H), 1.72 (m, 2H), 2.18 (m, 2H), 2.36 (m, 2H), 3.27 (s, 3H), 3.41 ( m, 1H), 3.51(m, 1H), 3.61(s, 3H), 4.23q, 1H), 4.96(s, 2H), 5.70(d, 1H), 6.18(m, 1H), 7.19(d, 2H), 7.33(d, 2H), 7.39(d, 2H), 7.53(d, 1H), 7.75(d, 2H), 8.00(d, 1H), 8.18(s, 1H), 8.50(t, 1H ), 8.85(s, 1H); HPLC-MS (Method B): m/z=690(M+1): Rt =6.92min. Step 4:

将(R)-3-{4-[1-(4-环己烯-1-基苯基)-3-(3-甲磺酰基-4-三氟甲氧基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸甲酯水解，获得了本标题化合物。1H-NMR(DMSO-d6)：δ1.60(m，2H)，1.72(m，2H)，2.18(m，2H)，2.36(m，2H)，3.27(s，3H)，3.41(m，1H)，3.51(m，1H)，4.17(t，1H)，4.96(s，2H)，5.50(宽峰，1H)，6.18(m，1H)，7.19(d，2H)，7.33(d，2H)，7.39(d，2H)，7.53(d，1H)，7.75(d，2H)，8.00(d，1H)，8.18(s，1H)，8.50(t，1H)，8.85(s，1H)，12.55(宽峰，1H)；HPLC-MS(方法B)：m/z＝676(M+1)；Rt＝6.50min.实施例26(一般方法(A))反式-(R)-3-{4-[-3-(3，5-二(甲基)苯基)-1-(4-叔丁基环己基)脲基甲基]苯甲酰基氨基]-2-羟基丙酸

Figure A0181159100981
步骤1和2：反式-4-[3-(3，5-二(甲基)苯基)-1-(叔丁基环己基)脲基甲基]苯甲酸甲酯1H-NMR(DMSO-d6)：δ0.82(s，9H)，0.93(m，1H)，1.11(m，2H)，1.41(m，2H)，1.71(m，4H)，2.23(s，6H)，3.83(s，3H)，4.09(m，1H)，4.61(s，2H)，6.60(s，1H)，7.08(s，2H)，7.38(d，2H)，7.90(d，2H)，8.20(s，1H)；HPLC-MS(方法B)：m/z＝451(M+1)；Rt＝8.93min.步骤2a：反式-4-[3-(3，5-二(甲基)苯基)-1-(叔丁基环己基)脲基甲基]苯甲酸(R)-3-{4-[1-(4-cyclohexen-1-ylphenyl)-3-(3-methylsulfonyl-4-trifluoromethoxyphenyl)ureidomethyl ]Benzoylamino}-2-hydroxypropionic acid methyl ester was hydrolyzed to obtain the title compound. 1 H-NMR (DMSO-d 6 ): δ1.60 (m, 2H), 1.72 (m, 2H), 2.18 (m, 2H), 2.36 (m, 2H), 3.27 (s, 3H), 3.41 ( m, 1H), 3.51(m, 1H), 4.17(t, 1H), 4.96(s, 2H), 5.50(broad, 1H), 6.18(m, 1H), 7.19(d, 2H), 7.33( d, 2H), 7.39(d, 2H), 7.53(d, 1H), 7.75(d, 2H), 8.00(d, 1H), 8.18(s, 1H), 8.50(t, 1H), 8.85(s , 1H), 12.55 (broad peak, 1H); HPLC-MS (Method B): m/z = 676 (M+1); R t = 6.50min. Example 26 (General Method (A)) trans- (R)-3-{4-[-3-(3,5-di(methyl)phenyl)-1-(4-tert-butylcyclohexyl)ureidomethyl]benzoylamino]-2-hydroxy propionic acid
Figure A0181159100981
Steps 1 and 2: trans-methyl 4-[3-(3,5-bis(methyl)phenyl)-1-(tert-butylcyclohexyl)ureidomethyl]benzoate 1 H-NMR (DMSO- d 6 ): δ0.82(s, 9H), 0.93(m, 1H), 1.11(m, 2H), 1.41(m, 2H), 1.71(m, 4H), 2.23(s, 6H), 3.83( s, 3H), 4.09(m, 1H), 4.61(s, 2H), 6.60(s, 1H), 7.08(s, 2H), 7.38(d, 2H), 7.90(d, 2H), 8.20(s , 1H); HPLC-MS (Method B): m/z = 451 (M+1); Rt = 8.93min. Step 2a: trans-4-[3-(3,5-di(methyl) Phenyl)-1-(tert-butylcyclohexyl)ureidomethyl]benzoic acid

该化合物是通过将反式-4-[3-(3，5-二(甲基)苯基)-1-(叔丁基-环己基)脲基甲基]苯甲酸甲酯水解制得的。1H-NMR(DMSO-d6)：δ0.82(s，9H)，0.93(m，1H)，1.11(m，2H)，1.41(m，2H)，1.71(m，4H)，2.23(s，6H)，4.09(m，1H)，4.61(s，2H)，6.60(s，1H)，7.08(s，2H)，7.38(d，2H)，7.90(d，2H)，8.20(s，1H)，12.82(s，1H)；HPLC-MS(方法B)：m/z＝437(M+1)；Rt＝8.00min.元素分析：C27H36N2O3的计算值：C，74.28％；H，8.31％；N，6.42％.实测值：C，74.31％；H，8.40％；N，6.35％。步骤3：反式-(R)-3-{4-[-3-(3，5-二(甲基)苯基)-1-(4-叔丁基环己基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸甲酯：The compound is prepared by hydrolysis of methyl trans-4-[3-(3,5-bis(methyl)phenyl)-1-(tert-butyl-cyclohexyl)ureidomethyl]benzoate . 1 H-NMR (DMSO-d 6 ): δ0.82(s, 9H), 0.93(m, 1H), 1.11(m, 2H), 1.41(m, 2H), 1.71(m, 4H), 2.23( s, 6H), 4.09(m, 1H), 4.61(s, 2H), 6.60(s, 1H), 7.08(s, 2H), 7.38(d, 2H), 7.90(d, 2H), 8.20(s , 1H), 12.82 (s, 1H); HPLC-MS (Method B): m/z = 437 (M+1); R t = 8.00 min. Elemental analysis: calculated for C 27 H 36 N 2 O 3 : C, 74.28%; H, 8.31%; N, 6.42%. Found values: C, 74.31%; H, 8.40%; N, 6.35%. Step 3: trans-(R)-3-{4-[-3-(3,5-di(methyl)phenyl)-1-(4-tert-butylcyclohexyl)ureidomethyl]benzoyl Amino}-2-hydroxypropionic acid methyl ester:

该化合物是由反式-4-[3-(3，5-二(甲基)苯基)-1-(叔丁基环己基)脲基甲基]苯甲酸制得的。1H-NMR(DMSO-d6)：δ0.82(s，9H)，0.93(m，1H)，1.11(m，2H)，1.43(m，2H)，1.71(m，4H)，2.23(s，6H)，3.42(m，1H)，3.52(m，1H)，3.63(s，3H)，4.05(m，1H)，4.23(q，1H)，4.59(s，2H)，5.70(d，1H)，6.58(s，1H)，7.08(s，2H)，7.30(d，2H)，7.78(d，2H)，8.18(s，1H)，8.47(t，1H)；HPLC-MS(方法B)：m/z＝538(M+1)；Rt＝7.43min；M.p.159-160℃.元素分析：C31H43N3O5的计算值：C，69.25％；H，8.06％；N，7.81％.实测值：C，69.03％；H，8.15％；N，7.79％.步骤4：This compound was prepared from trans-4-[3-(3,5-bis(methyl)phenyl)-1-(tert-butylcyclohexyl)ureidomethyl]benzoic acid. 1 H-NMR (DMSO-d 6 ): δ0.82(s, 9H), 0.93(m, 1H), 1.11(m, 2H), 1.43(m, 2H), 1.71(m, 4H), 2.23( s, 6H), 3.42(m, 1H), 3.52(m, 1H), 3.63(s, 3H), 4.05(m, 1H), 4.23(q, 1H), 4.59(s, 2H), 5.70(d , 1H), 6.58(s, 1H), 7.08(s, 2H), 7.30(d, 2H), 7.78(d, 2H), 8.18(s, 1H), 8.47(t, 1H); HPLC-MS ( Method B): m/z = 538 (M+1); R t = 7.43 min; Mp 159-160°C. Elemental analysis: Calculated for C 31 H 43 N 3 O 5 : C, 69.25%; H, 8.06% ; N, 7.81%. Found: C, 69.03%; H, 8.15%; N, 7.79%. Step 4:

将反式-(R)-3-{4-[-3-(3，5-二(甲基)苯基)-1-(4-叔丁基环己基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸甲酯水解，获得了本标题化合物。1H-NMR(DMSO-d6)：δ0.82(s，9H)，0.93(m，1H)，1.11(m，2H)，1.43(m，2H)，1.71(m，4H)，2.23(s，6H)，3.40(m，1H)，3.55(m，1H)，4.05(m，1H)，4.18(t，1H)，4.59(s，2H)，6.58(s，1H)，7.08(s，2H)，7.30(d，2H)，7.78(d，2H)，8.18(s，1H)，8.47(t，1H)；HPLC-MS(方法B)：m/z＝524(M+1)；Rt＝7.08min.元素分析：C30H41N3O5，1.5H2O的计算值：C，65.43％；H，8.05％；N，7.63％.实测值：C，65.54％；H，7.93％；N，7.44％.实施例27(一般方法(A))(R)-3-{4-[1-(4-环己基苯基)-3-(3，5-二氯苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸 1H-NMR(CDCl3)：δ7.64(d，2H)，7.49(br s，1H)，7.25-7.15(m，6H)，7.03(d，2H)，6.90 (m，1H)，6.40(s，1H)，4.75(s，2H)，4.30(brs，1H)，3.80-3.60(m，2H)，2.49(m，1H)，1.90-1.65(m，5H)，1.45-1.25(m，5H)；HPLC-MS(方法B)：m/z＝584(M+1)；Rt＝5.28min.实施例28(一般方法(A))(R)-(3-{4-[1-(4-环己-1-烯基苯基)-3-(3-氟-5-三氟甲基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸 1H-NMR(DMSO-d6)：δ 8.75(s，1H)，8.42(t，1H)，7.75(d，4H)，7.45-7.30(m，4H)，7.20(d，3H)，6.20(s，1H)，4.96(s，2H)，4.15(dd，1H)，3.55(m，1H)，3.40(m，1H)，2.35(brs，2H)，2.15(brs，2H).1.75-1.55(m，4H)；HPLC-MS(方法B)：m/z＝600(M+1)；Rt＝5.01min.实施例29(一般方法(A))(R)-3-{4-[1-(4-环己基苯基)-3-(3-甲硫基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸

Figure A0181159101012
1H-NMR(DMSO-d6)：δ12.2(brs，1H)，8.44(t，1H)，8.20(s，1H)，7.78(m，2H)，7.40(s，1H)，7.33(m，2H)，7.25-7.10(m，6H)，6.84(d，1H)，4.95(s，1H)，4.15(dd，1H)，3.55(m，1H)，3.38(m，1H).2.42(s，3H)1.85-1.65(m，5H)，1.40-1.15(m，5H)；HPLC-MS(方法B)：m/z＝562(M+1)；Rt＝4.77min.实施例30(一般方法(A))(R)-3-{4-[1-(4-环己-1-烯基苯基)-3-(2，2，4，4-四氟-4H-苯并[1，3]二氧杂环己烯-6-基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸
Figure A0181159101021
1H-NMR(CDCl3)：δ7.70-7.50(m，3H)，7.45-7.30(m，4H)，7.25-6.85(m，6H)，6.12(s，1H)，4.80(s，2H)，4.28(m，1H)，3.70(m，2H)，2.40-2.00(m，4H)，1.70-1.55(m，4H)；HPLC-MS(方法B)：m/z＝644(M+1)；Rt＝5.13min.实施例3 1(一般方法(A))3-{4-[1-(4-环己-1-烯基苯基)-3-(3，5-二氯苯基)脲基甲基]苯甲酰基氨基}-2(R)-甲氧基丙酸：
Figure A0181159101022
步骤3：Trans-(R)-3-{4-[-3-(3,5-di(methyl)phenyl)-1-(4-tert-butylcyclohexyl)ureidomethyl]benzoylamino} -Hydrolysis of methyl 2-hydroxypropionate afforded the title compound. 1 H-NMR (DMSO-d 6 ): δ0.82(s, 9H), 0.93(m, 1H), 1.11(m, 2H), 1.43(m, 2H), 1.71(m, 4H), 2.23( s, 6H), 3.40(m, 1H), 3.55(m, 1H), 4.05(m, 1H), 4.18(t, 1H), 4.59(s, 2H), 6.58(s, 1H), 7.08(s , 2H), 7.30(d, 2H), 7.78(d, 2H), 8.18(s, 1H), 8.47(t, 1H); HPLC-MS (method B): m/z=524(M+1) ; R t = 7.08min. Elemental analysis: C 30 H 41 N 3 O 5 , calculated for 1.5H 2 O: C, 65.43%; H, 8.05%; N, 7.63%. Found: C, 65.54%; H, 7.93%; N, 7.44%. Example 27 (General Procedure (A)) (R)-3-{4-[1-(4-cyclohexylphenyl)-3-(3,5-dichloro phenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid 1 H-NMR (CDCl 3 ): δ7.64 (d, 2H), 7.49 (br s, 1H), 7.25-7.15 (m, 6H), 7.03 (d, 2H), 6.90 (m, 1H), 6.40 (s, 1H), 4.75(s, 2H), 4.30(brs, 1H), 3.80-3.60(m, 2H), 2.49(m, 1H), 1.90-1.65(m, 5H), 1.45-1.25(m , 5H); HPLC-MS (Method B): m/z = 584 (M+1); R t = 5.28 min. Example 28 (General Method (A)) (R)-(3-{4-[ 1-(4-Cyclohex-1-enylphenyl)-3-(3-fluoro-5-trifluoromethylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid 1 H-NMR (DMSO-d 6 ): δ 8.75(s, 1H), 8.42(t, 1H), 7.75(d, 4H), 7.45-7.30(m, 4H), 7.20(d, 3H), 6.20 (s,1H), 4.96(s,2H), 4.15(dd,1H), 3.55(m,1H), 3.40(m,1H), 2.35(brs,2H), 2.15(brs,2H).1.75- 1.55 (m, 4H); HPLC-MS (Method B): m/z = 600 (M+1); R t = 5.01 min. Example 29 (General Method (A)) (R)-3-{4 -[1-(4-cyclohexylphenyl)-3-(3-methylthiophenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid
Figure A0181159101012
1 H-NMR (DMSO-d 6 ): δ12.2 (brs, 1H), 8.44 (t, 1H), 8.20 (s, 1H), 7.78 (m, 2H), 7.40 (s, 1H), 7.33 ( m, 2H), 7.25-7.10(m, 6H), 6.84(d, 1H), 4.95(s, 1H), 4.15(dd, 1H), 3.55(m, 1H), 3.38(m, 1H).2.42 (s, 3H) 1.85-1.65 (m, 5H), 1.40-1.15 (m, 5H); HPLC-MS (method B): m/z = 562 (M+1); Rt = 4.77min. Examples 30 (General procedure (A)) (R)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(2,2,4,4-tetrafluoro-4H- Benzo[1,3]dioxin-6-yl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid
Figure A0181159101021
1 H-NMR (CDCl 3 ): δ7.70-7.50(m, 3H), 7.45-7.30(m, 4H), 7.25-6.85(m, 6H), 6.12(s, 1H), 4.80(s, 2H ), 4.28 (m, 1H), 3.70 (m, 2H), 2.40-2.00 (m, 4H), 1.70-1.55 (m, 4H); HPLC-MS (method B): m/z=644 (M+ 1); R t =5.13min. Example 3 1 (General method (A)) 3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-di Chlorophenyl)ureidomethyl]benzoylamino}-2(R)-methoxypropionic acid:
Figure A0181159101022
Step 3:

将4-[1-(4-环己-1-烯基苯基)-3-(3，5-二氯-苯基)脲基甲基]苯甲酸(500mg，1.0mmol)、HOBt(184mg，1.2mmol)和EDAC(232mg；1.2mrol)溶解在DCM(4.0mL)与DMF(1.0mL)的混合物中。将澄清溶液在室温搅拌1小时。加入3-氨基-2(R)-甲氧基丙酸甲酯盐酸盐(257mg，1.5mmol)在DCM(2.0mL)和DMF(0.2mL)中的溶液，然后加入二异丙基乙基胺(515μL)。将该混合物在室温搅拌过夜，然后用DCM(40mL)稀释，并用饱和氯化钠/水的混合物(1∶2)洗涤一次。用无水硫酸钠干燥有机相，并真空干燥。步骤4：4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichloro-phenyl)ureidomethyl]benzoic acid (500mg, 1.0mmol), HOBt (184mg , 1.2 mmol) and EDAC (232 mg; 1.2 mrol) were dissolved in a mixture of DCM (4.0 mL) and DMF (1.0 mL). The clear solution was stirred at room temperature for 1 hour. A solution of methyl 3-amino-2(R)-methoxypropanoate hydrochloride (257 mg, 1.5 mmol) in DCM (2.0 mL) and DMF (0.2 mL) was added followed by diisopropylethyl Amine (515 μL). The mixture was stirred overnight at room temperature, then diluted with DCM (40 mL) and washed once with a saturated sodium chloride/water mixture (1:2). The organic phase was dried over anhydrous sodium sulfate and dried in vacuo. Step 4:

将该油状物溶解在THF(4.0mL)与甲醇(4.0mL)的混合物中。加入4N氢氧化钠水溶液(625μL，2.5mmol)，并将该混合物在室温搅拌2小时。用1N盐酸将pH调节至3.0，然后除去溶剂。将产物再溶解在乙酸乙酯(20mL)中，并用水(20mL)洗涤。用乙酸乙酯(10mL)回萃取水相，将合并的有机萃取液用氯化钠(2×20mL)洗涤，并用无水硫酸钠干燥。除去溶剂后，获得了230mg(67％)纯的本标题化合物。1H-NMR(DMSO-d6)：δ12.90(bs，1H)，8.55(s，1H)，8.54(t，1H)，7.76(d，2H)，7.63(s，2H)，7.41(d，2H)，7.34(d，2H)，7.20(d，2H)，7.15(s，1H)，6.18(s，1H)，4.95(s，2H)，3.90(dd，1H)，3.57(m，1H)，3.42(m，1H)，3.29(s，3H)，2.34(m，2H)，2.16(m，2H)，170(m，2H)，1.59(m，2H)；HPLC-MS(方法B)：m/z＝596.2(M+1)；Rt＝5.93min.实施例32(一般方法(A))3-(4-{3-(3，5-二氯苯基)-1-[4-(2-甲基环己-1-烯基)苯基]脲基甲基}苯甲酰基氨基)-2-(R)-羟基丙酸和(R，S)-3-(4-{3-(3，5-二氯苯基)-1-[4-(6-甲基环己-1-烯基)苯基]脲基甲基)苯甲酰基氨基)-2-(R)-羟基丙酸

Figure A0181159101031
This oil was dissolved in a mixture of THF (4.0 mL) and methanol (4.0 mL). 4N Aqueous sodium hydroxide solution (625 μL, 2.5 mmol) was added, and the mixture was stirred at room temperature for 2 hr. The pH was adjusted to 3.0 with 1N hydrochloric acid, and then the solvent was removed. The product was redissolved in ethyl acetate (20 mL) and washed with water (20 mL). The aqueous phase was back extracted with ethyl acetate (10 mL), and the combined organic extracts were washed with sodium chloride (2 x 20 mL) and dried over anhydrous sodium sulfate. After removal of the solvent, 230 mg (67%) of pure title compound were obtained. 1 H-NMR (DMSO-d 6 ): δ12.90 (bs, 1H), 8.55 (s, 1H), 8.54 (t, 1H), 7.76 (d, 2H), 7.63 (s, 2H), 7.41 ( d, 2H), 7.34(d, 2H), 7.20(d, 2H), 7.15(s, 1H), 6.18(s, 1H), 4.95(s, 2H), 3.90(dd, 1H), 3.57(m , 1H), 3.42(m, 1H), 3.29(s, 3H), 2.34(m, 2H), 2.16(m, 2H), 170(m, 2H), 1.59(m, 2H); HPLC-MS( Method B): m/z=596.2 (M+1); Rt=5.93min. Example 32 (General method (A)) 3-(4-{3-(3,5-dichlorophenyl)-1 -[4-(2-Methylcyclohex-1-enyl)phenyl]ureidomethyl}benzoylamino)-2-(R)-hydroxypropionic acid and (R,S)-3-( 4-{3-(3,5-dichlorophenyl)-1-[4-(6-methylcyclohex-1-enyl)phenyl]ureidomethyl)benzoylamino)-2- (R)-Hydroxypropionic acid
Figure A0181159101031

使用4-(2-甲基环己-1-烯基)苯胺和(R，S)-4-(6-甲基环己-1-烯基)苯胺(构件11)以及(R)-3-氨基-2-羟基丙酸甲酯(构件5)的混合物，依据一般方法(A)获得了本标题化合物。(R，S)-3-(4-{3-(3，5-二氯苯基)-1-[4-(6-甲基环己-1-烯基)苯基]脲基甲基}苯甲酰基氨基)-2(R)-羟基丙酸：1H-NMR(DMSO-d6)：δ1,55(s，3H)，1,63(bs，4H)，2,03(bs，2H)，2,19(bs，2H)，3,47(dm，2H).4,16(m，1H)，4,96(s，2H)，5,49(bs，1H)，7,15(m，5H)，7,33(d，2H)，7,61(s，2H)，7,78(d，2H)，8,45(t，1H)，8,65(s，1H)，12,53(bs,1H)；M.p.：105-107℃；HPLC-MS(方法B)：m/z＝596(M+)；Rt＝5,34min.3-(4-{3-(3，5-二氯苯基)-1-[4-(6-甲基环己-1-烯基)苯基]脲基甲基}苯甲酰基-氨基)-2(R)-羟基丙酸：1H-NMR(DMSO-d6)：δ0,90(ds，3H)，1,63(bs，4H)，2,03(bs，2H)，2,19(bs，2H)，3,47(dm，2H)，4,16(m，1H)，4,96(s，2H)，5,49(bs，1H)，5,93(t，1H)，7,15(m，5H)，7,33(d，2H)，7,61(s，2H)，7,78(d，2H)，8,45(t，1H)，8,62(s，1H)，12,53(bs，1H).实施例33(一般方法(A))3-{4-[1-[4-(4-叔丁基环己-1-烯基)苯基]-3-(3，5-二氯苯基)脲基甲基]苯甲酰基氨基}-2-(R)-羟基丙酸 Using 4-(2-methylcyclohex-1-enyl)aniline and (R,S)-4-(6-methylcyclohex-1-enyl)aniline (building block 11) and (R)-3 -A mixture of amino-2-hydroxypropionic acid methyl esters (building block 5), the title compound was obtained following general procedure (A). (R, S)-3-(4-{3-(3,5-dichlorophenyl)-1-[4-(6-methylcyclohex-1-enyl)phenyl]ureidomethyl }Benzoylamino)-2(R)-hydroxypropionic acid: 1 H-NMR (DMSO-d 6 ): δ1,55(s, 3H), 1,63(bs, 4H), 2,03(bs , 2H), 2, 19 (bs, 2H), 3, 47 (dm, 2H). 4, 16 (m, 1H), 4, 96 (s, 2H), 5, 49 (bs, 1H), 7 ,15(m,5H), 7,33(d,2H), 7,61(s,2H), 7,78(d,2H), 8,45(t,1H), 8,65(s, 1H), 12,53(bs,1H); Mp: 105-107°C; HPLC-MS (Method B): m/z = 596 (M + ); Rt = 5,34min.3-(4-{ 3-(3,5-dichlorophenyl)-1-[4-(6-methylcyclohex-1-enyl)phenyl]ureidomethyl}benzoyl-amino)-2(R) -Hydroxypropionic acid: 1 H-NMR (DMSO-d 6 ): δ0,90(ds,3H), 1,63(bs,4H), 2,03(bs,2H), 2,19(bs,2H ), 3, 47 (dm, 2H), 4, 16 (m, 1H), 4, 96 (s, 2H), 5, 49 (bs, 1H), 5, 93 (t, 1H), 7, 15 (m, 5H), 7, 33 (d, 2H), 7, 61 (s, 2H), 7, 78 (d, 2H), 8, 45 (t, 1H), 8, 62 (s, 1H) , 12,53 (bs, 1H). Example 33 (General Method (A)) 3-{4-[1-[4-(4-tert-butylcyclohex-1-enyl)phenyl]-3-( 3,5-Dichlorophenyl)ureidomethyl]benzoylamino}-2-(R)-hydroxypropionic acid

使用4-(4-叔丁基环己-1-烯基)苯胺(构件12)和(R)-3-氨基-2-羟基丙酸甲酯(构件5)，依据一般方法(A)获得了本标题化合物。1H-NMR(DMSO-d6)：δ 0,88(s，9H)，1,23(m，2H)，1,93(m，2H)，2,27(m，3H)，3,47(dm，2H)，4,16(dd，1H)，4,95(s，2H)，6,19(m，1H)，7,13(m1H)，7,18(d，2H)，7,33(d，2H)，7,39(d,2H)，7,62(s，2H)，7,77(d，2H)，8,44(t，1H)，8,55(s，1H)，12,53(bs，1H)；M.p.：151-155℃；HPLC-MS(方法B)：m/z＝638(M+)；Rt＝6.04实施例34(一般方法(A))(R，S)-3-(4-(3-(3，5-二氯苯基)-1-(4-(5-甲基环己-1-烯基)苯基)脲基甲基)-苯甲酰基氨基)-2-羟基丙酸和(R，S)-3-(4-(3-(3，5-二氯苯基)-1-(4-(3-甲基环己-1-烯基)苯基)脲基甲基)苯甲酰基氨基)-2-羟基丙酸

Figure A0181159101051
Using 4-(4-tert-butylcyclohex-1-enyl)aniline (Building 12) and (R)-methyl 3-amino-2-hydroxypropionate (Building 5), this was obtained following the general method (A). title compound. 1 H-NMR (DMSO-d 6 ): δ 0,88(s,9H), 1,23(m,2H), 1,93(m,2H), 2,27(m,3H), 3, 47 (dm, 2H), 4, 16 (dd, 1H), 4, 95 (s, 2H), 6, 19 (m, 1H), 7, 13 (m1H), 7, 18 (d, 2H), 7,33(d,2H), 7,39(d,2H), 7,62(s,2H), 7,77(d,2H), 8,44(t,1H), 8,55(s , 1H), 12, 53 (bs, 1H); Mp: 151-155°C; HPLC-MS (Method B): m/z = 638 (M + ); R t = 6.04 Example 34 (General Method (A ))(R, S)-3-(4-(3-(3,5-dichlorophenyl)-1-(4-(5-methylcyclohex-1-enyl)phenyl)ureido Methyl)-benzoylamino)-2-hydroxypropionic acid and (R,S)-3-(4-(3-(3,5-dichlorophenyl)-1-(4-(3-methyl Cyclohex-1-enyl)phenyl)ureidomethyl)benzoylamino)-2-hydroxypropionic acid
Figure A0181159101051

使用(R，S)-4-(5-甲基环己-1-烯基)苯胺与(R，S)-4-(3-甲基环己-1-烯基)苯胺(构件13)的混合物，依据一般方法(A)获得了本标题化合物的混合物(6∶4)。(R，S)-3-(4-(3-(3，5-二氯苯基)-1-(4-(5-甲基环己-1-烯基)苯基)脲基甲基)-苯甲酰基氨基)-2-羟基丙酸：1H-NMR(200 MHz，DMSO-d6)：δ1.02(d，3H)，1.15-1-24(m，1H)，1.61-1.96(m，3H)，2.14-2.44(m，3H)，3.40(t，2H)，3.47-3.62(m，1H)，4.10-4.19(m，1H)，4.95(s，2H)，6.16(t，1H)，7.14(t，1H)，7.17(d，2H)，7.34(d，2H)，7.39(d，2H)，7.61(d，2H)，7.76(d，2H)，8.44(t，1H)，8.56(s，1H)，12.08(sbr，1H).(R，S)-3-(4-(3-(3，5-二氯苯基)-1-(4-(3-甲基环己-1-烯基)苯基)脲基甲基)-苯甲酰基氨基)-2-羟基丙酸：1H-NMR(200MHz，DMSO-d6)：δ1.02(d，3H)，1.15-1-24(m，1H)，1.61-1.96(m，3H)，2.14-2.44(m，3H)，3.40(t，2H)，3.47-3.62(m，1H)，4.10-4.19(m，1H)，4.95(s，2H)，6.04(d，1H)，7.14(t，1H)，7.17(d，2H)，7.34(d，2H)，7.39(d，2H)，7.61(d，2H)，7.76(d，2H)，8.44(t，1H)，8.53(s，1H)，12.08(sbr， 1H).实施例353-{4-[3-[1(S)-(4-氯苯基)乙基]-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2(R)-羟基丙酸4-[(4-环己基苯基氨基)甲基]苯甲酸甲酯Using (R,S)-4-(5-methylcyclohex-1-enyl)aniline with (R,S)-4-(3-methylcyclohex-1-enyl)aniline (Building 13) According to the general method (A), a mixture of the title compound (6:4) was obtained. (R, S)-3-(4-(3-(3,5-dichlorophenyl)-1-(4-(5-methylcyclohex-1-enyl)phenyl)ureidomethyl )-benzoylamino)-2-hydroxypropionic acid: 1 H-NMR (200 MHz, DMSO-d 6 ): δ1.02 (d, 3H), 1.15-1-24 (m, 1H), 1.61- 1.96(m, 3H), 2.14-2.44(m, 3H), 3.40(t, 2H), 3.47-3.62(m, 1H), 4.10-4.19(m, 1H), 4.95(s, 2H), 6.16( t, 1H), 7.14(t, 1H), 7.17(d, 2H), 7.34(d, 2H), 7.39(d, 2H), 7.61(d, 2H), 7.76(d, 2H), 8.44(t , 1H), 8.56(s, 1H), 12.08(sbr, 1H).(R, S)-3-(4-(3-(3,5-dichlorophenyl)-1-(4-(3 -Methylcyclohex-1-enyl)phenyl)ureidomethyl)-benzoylamino)-2-hydroxypropionic acid: 1 H-NMR (200MHz, DMSO-d 6 ): δ1.02(d , 3H), 1.15-1-24(m, 1H), 1.61-1.96(m, 3H), 2.14-2.44(m, 3H), 3.40(t, 2H), 3.47-3.62(m, 1H), 4.10 -4.19(m, 1H), 4.95(s, 2H), 6.04(d, 1H), 7.14(t, 1H), 7.17(d, 2H), 7.34(d, 2H), 7.39(d, 2H), 7.61 (d, 2H), 7.76 (d, 2H), 8.44 (t, 1H), 8.53 (s, 1H), 12.08 (sbr, 1H). Example 353-{4-[3-[1(S) -(4-Chlorophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2(R)-hydroxypropionic acid Methyl 4-[(4-cyclohexylphenylamino)methyl]benzoate

将4-甲酰基苯甲酸甲酯(47g，285mmol)溶解在甲醇(400mL)中，在机械搅拌下缓慢地加入4-环己基苯胺(50g，0.285mmol)在甲醇(200mL)中的溶液。再加入甲醇(1L)，将该悬浮液在室温搅拌3天。过滤，洗涤并真空干燥，获得了90.7g(99％)4-[(4-环己基苯基亚氨基)甲基]苯甲酸甲酯。将其溶解在N-甲基吡咯烷酮(855mL)和甲醇(45mL)中。在机械搅拌下分批加入硼氢化钠小丸(42.4g，1.12mol)，将温度保持在40℃以下。然后将该混合物在室温搅拌2小时，在40℃搅拌16小时。将该混合物冷却至5℃，缓慢地加入水(2L)。然后加入丙酮(350mL)，并将该混合物在5℃搅拌1小时。过滤，用水(2×500mL)洗涤，并真空干燥，获得了78g(86％)4-[(4-环己基苯基氨基)甲基]苯甲酸甲酯，为固体。1H-NMR(CDCl3)：δ1.2-1.4(5H，m)，1.7-1.85(5H，m)，2.39(1H，m)，3.97(3H，s)，4.04(1H，bs)，4.39(2H，s)，6.55(2H，d)，7.01(2H，d)，7.44(2H，d)，8.00(2H，d).N-氯氨基甲酰基-4-[(4-环己基苯基氨基)甲基]苯甲酸甲酯Methyl 4-formylbenzoate (47 g, 285 mmol) was dissolved in methanol (400 mL), and a solution of 4-cyclohexylaniline (50 g, 0.285 mmol) in methanol (200 mL) was added slowly under mechanical stirring. Additional methanol (1 L) was added and the suspension was stirred at room temperature for 3 days. Filtration, washing and vacuum drying afforded 90.7 g (99%) of methyl 4-[(4-cyclohexylphenylimino)methyl]benzoate. This was dissolved in N-methylpyrrolidone (855 mL) and methanol (45 mL). Sodium borohydride pellets (42.4 g, 1.12 mol) were added in portions under mechanical stirring, keeping the temperature below 40°C. The mixture was then stirred at room temperature for 2 hours and at 40°C for 16 hours. The mixture was cooled to 5°C and water (2 L) was added slowly. Acetone (350 mL) was then added, and the mixture was stirred at 5°C for 1 hour. Filtration, washing with water (2 x 500 mL), and drying in vacuo afforded 78 g (86%) of methyl 4-[(4-cyclohexylphenylamino)methyl]benzoate as a solid. 1 H-NMR (CDCl 3 ): δ1.2-1.4 (5H, m), 1.7-1.85 (5H, m), 2.39 (1H, m), 3.97 (3H, s), 4.04 (1H, bs), 4.39(2H, s), 6.55(2H, d), 7.01(2H, d), 7.44(2H, d), 8.00(2H, d).N-chlorocarbamoyl-4-[(4-cyclohexyl Methyl phenylamino)methyl]benzoate

将4-[(4-环己基苯基氨基)甲基]苯甲酸甲酯(75g，0.23mol)溶解在THF(750mL)中。加入二异丙基乙基胺(56.0mL，0.32mmol)和4-二甲基氨基吡啶(1.0g；8.1mmol)。将该溶液冷却至5℃。以少量多次的方式加入碳酸二(三氯甲基)酯(28.0g，0.093mol)，同时将内部反应温度保持在10℃以下。将该混合物在10℃再搅拌2小时，然后转移到分液漏斗中。加入乙酸乙酯(800mL)和水(1000mL)。混合后，分离出有机层，用无水硫酸钠干燥，并通过真空旋转蒸发浓缩至干。以定量产率获得了产物，为稳定、坚硬的结晶物。1H-NMR(CDCl3)：δ7.92(d，2H)；7.40(d，2H)；7.25(d，2H)；7.17(d，2H)；4.98(s，2H)；3.83(s，3H)；2.5(m，1H)；1.65-1.80(m，5H)；1.15-1.40(m，5H).N-氯氨基甲酰基-4-[(4-环己基苯基氨基)甲基]苯甲酸甲酯Methyl 4-[(4-cyclohexylphenylamino)methyl]benzoate (75 g, 0.23 mol) was dissolved in THF (750 mL). Diisopropylethylamine (56.0 mL, 0.32 mmol) and 4-dimethylaminopyridine (1.0 g; 8.1 mmol) were added. The solution was cooled to 5°C. Bis(trichloromethyl)carbonate (28.0 g, 0.093 mol) was added in small portions while maintaining the internal reaction temperature below 10°C. The mixture was stirred for an additional 2 hours at 10°C, then transferred to a separatory funnel. Ethyl acetate (800 mL) and water (1000 mL) were added. After mixing, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness by vacuum rotary evaporation. The product was obtained in quantitative yield as a stable, hard crystalline material. 1 H-NMR (CDCl 3 ): δ7.92(d, 2H); 7.40(d, 2H); 7.25(d, 2H); 7.17(d, 2H); 4.98(s, 2H); 3H); 2.5(m, 1H); 1.65-1.80(m, 5H); 1.15-1.40(m, 5H).N-Chlorocarbamoyl-4-[(4-cyclohexylphenylamino)methyl] methyl benzoate

将4-[(4-环己基苯基氨基)甲基]苯甲酸甲酯(75g，0.23mol)溶解在THF(750mL)中。加入二异丙基乙基胺(56.0mL，0.32mmol)和4-二甲基氨基吡啶(1.0g；8.1mmol)。将该溶液冷却至5℃。以少量多次的方式加入碳酸二(三氯甲基)酯(28.0g，0.093mol)，同时将内部反应温度保持在10℃以下。将该混合物在10℃再搅拌2小时，然后转移到分液漏斗中。加入乙酸乙酯(800mL)和水(1000mL)。混合后，分离出有机层，用无水硫酸钠干燥，并通过真空旋转蒸发浓缩至干。以定量产率获得了产物，为稳定、坚硬的结晶物。1H-NMR(CDCl3)：δ7.92(d，2H)，7.40(d，2H)，7.25(d，2H)，7.17(d，2H)，4.98(s，2H)，3.83(s，3H)，2.5(m，1H)，1.65-1.80(m，5H)，1.15-1.40(m，5H).4-[3-[1(S)-(4-氯苯基)乙基]-1-(4-环己基苯基)脲基甲基]苯甲酸甲酯Methyl 4-[(4-cyclohexylphenylamino)methyl]benzoate (75 g, 0.23 mol) was dissolved in THF (750 mL). Diisopropylethylamine (56.0 mL, 0.32 mmol) and 4-dimethylaminopyridine (1.0 g; 8.1 mmol) were added. The solution was cooled to 5°C. Bis(trichloromethyl)carbonate (28.0 g, 0.093 mol) was added in small portions while maintaining the internal reaction temperature below 10°C. The mixture was stirred for an additional 2 hours at 10°C, then transferred to a separatory funnel. Ethyl acetate (800 mL) and water (1000 mL) were added. After mixing, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness by vacuum rotary evaporation. The product was obtained in quantitative yield as a stable, hard crystalline material. 1 H-NMR (CDCl 3 ): δ7.92(d, 2H), 7.40(d, 2H), 7.25(d, 2H), 7.17(d, 2H), 4.98(s, 2H), 3.83(s, 3H), 2.5(m, 1H), 1.65-1.80(m, 5H), 1.15-1.40(m, 5H).4-[3-[1(S)-(4-chlorophenyl)ethyl]- Methyl 1-(4-cyclohexylphenyl)ureidomethyl]benzoate

向装配有机械搅拌器的2L反应烧瓶中加入N-氯氨基甲酰基-4-[(4-环己基苯基氨基)甲基]苯甲酸甲酯(94g，0.244mol)、N-甲基-2-吡咯烷酮(1.0L)和三乙胺(68mL，0.487mol)。向该澄清溶液中滴加(S)-1-(4-氯苯基)乙基胺(38.0g，0.244mol)，将内部反应温度保持在30℃以下。继续搅拌2小时，然后将该反应混合物在水(1.0L)与乙酸乙酯(1.0L)之间分配。充分混合后，分离出有机层，用5％柠檬酸水溶液(500mL)和饱和氯化铵(500mL)洗涤，然后用无水硫酸钠干燥。除去溶剂，将残余物的油状物从乙腈中蒸发一次。产物的纯度足以进行随后的合成。产量：103g(84％)。1H-NMR(DMSO-d6)：δ7.88(d，2H)，7.32(d，2H)，7.30(d，4H)，7.19(d，2H)，7.08(d，2H)，6.28(d，1H)，4.88(dd，2H)，4.76(m，1H)， 3.81(s，3H)，2.44(m，1H)，1.65-1.80(m，5H)，1.15-Add N-chlorocarbamoyl-4-[(4-cyclohexylphenylamino)methyl]methyl benzoate (94g, 0.244mol), N-methyl- 2-Pyrrolidone (1.0 L) and triethylamine (68 mL, 0.487 mol). To this clear solution was added (S)-1-(4-chlorophenyl)ethylamine (38.0 g, 0.244 mol) dropwise, keeping the internal reaction temperature below 30°C. Stirring was continued for 2 hours, then the reaction mixture was partitioned between water (1.0 L) and ethyl acetate (1.0 L). After mixing well, the organic layer was separated, washed with 5% aqueous citric acid (500 mL) and saturated ammonium chloride (500 mL), and dried over anhydrous sodium sulfate. The solvent was removed and the residual oil was evaporated once from acetonitrile. The purity of the product was sufficient for the subsequent synthesis. Yield: 103 g (84%). 1 H-NMR (DMSO-d 6 ): δ7.88 (d, 2H), 7.32 (d, 2H), 7.30 (d, 4H), 7.19 (d, 2H), 7.08 (d, 2H), 6.28 ( d, 1H), 4.88(dd, 2H), 4.76(m, 1H), 3.81(s, 3H), 2.44(m, 1H), 1.65-1.80(m, 5H), 1.15-

1.40(m，5H)；HPLC-MS(方法B)：m/z＝505(M+1)；Rt＝6.17min.4-[3-[1(S)-(4-氯苯基)乙基]-1-(4-环己基苯基)脲基甲基]苯甲酸1.40 (m, 5H); HPLC-MS (Method B): m/z = 505 (M+1); Rt = 6.17min.4-[3-[1(S)-(4-chlorophenyl) ethyl Base]-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid

将4-[3-[1(S)-(4-氯苯基)乙基]-1-(4-环己基苯基)脲基甲基]苯甲酸甲酯(35.0g，69.3mmol)溶解在乙醇(400mL)中。加入4N氢氧化钠水溶液(100mL)，将该澄清的溶液在室温搅拌3小时。用4N盐酸(100mL)中和该溶液，放置在冰浴上以引起结晶。收集晶体，用水充分洗涤，并真空干燥过夜。产量：34.25g(100％)。1H-NMR(DMSO-d6)：δ12.85(bs，1H)，7.85(d，2H)，7.32(d，2H)，7.30(d，4H)，7.19(d，2H)，7.08(d，2H)，6.27(d，1H)，4.85(m，3H)，2.45(m，1H)，1.65-1.80(m，5H)，1.15-1.40(m，5H)；HPLC-MS(方法B)：m/z＝491(M+1)；Rt＝5.50min.3-{4-[3-[1(S)-(4-氯苯基)乙基]-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2(R)-羟基丙酸甲酯Dissolve methyl 4-[3-[1(S)-(4-chlorophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoate (35.0 g, 69.3 mmol) in ethanol (400 mL). 4N Aqueous sodium hydroxide solution (100 mL) was added, and the clear solution was stirred at room temperature for 3 hours. The solution was neutralized with 4N hydrochloric acid (100 mL) and placed on an ice bath to cause crystallization. The crystals were collected, washed well with water, and dried under vacuum overnight. Yield: 34.25 g (100%). 1 H-NMR (DMSO-d 6 ): δ12.85 (bs, 1H), 7.85 (d, 2H), 7.32 (d, 2H), 7.30 (d, 4H), 7.19 (d, 2H), 7.08 ( d, 2H), 6.27(d, 1H), 4.85(m, 3H), 2.45(m, 1H), 1.65-1.80(m, 5H), 1.15-1.40(m, 5H); HPLC-MS (Method B ): m/z=491(M+1); Rt=5.50min.3-{4-[3-[1(S)-(4-chlorophenyl)ethyl]-1-(4-cyclohexyl Phenyl)ureidomethyl]benzoylamino}-2(R)-hydroxypropionic acid methyl ester

将4-[3-[1(S)-(4-氯苯基)乙基]-1-(4-环己基苯基)脲基甲基]苯甲酸(200mg，0.4mmol)、HOBt(75mg，0.5mmol)、和EDAC(94mg，0.5mmol)溶解在DMF(200μL)和DCM(2mL)的混合物中。将该澄清溶液在室温搅拌90分钟。加入R-异丝氨酸甲酯盐酸盐(95mg，0.6mmol)在DCM(1.0mL)和DMF(0.4mL)的混合物中的溶液，并将该反应混合物在室温搅拌过夜。将该反应混合物在DCM(20mL)与水(20mL)之间分配。分离出有机相，并用盐水和水(1∶2)洗涤，用无水硫酸钠干燥，并蒸发至干。然后将残余物从乙腈中蒸发，以定量产率获得了本标题化合物。1H-NMR(DMSO-d6)：δ 8.48(t，1H)，7.73(d，2H)，7.34(d，2H)，7.30(d，2H)，7.24(d，2H)，7.18(d，2H)，7.08(d，2H)，6.27(d，1H)，5.70(d，1H)，4.34(m，1H)，4.32(d，2H)，4.22(q，1H)，3.62(s，3H)，3.52(m，1H)，3.40(m，1H)，1.65-1.80(m，5H).1.10-1.40(m，9H).3-{4-[3-[1(S)-(4-氯苯基)乙基]-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2(R)-羟基丙酸4-[3-[1(S)-(4-chlorophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid (200mg, 0.4mmol), HOBt (75mg , 0.5 mmol), and EDAC (94 mg, 0.5 mmol) were dissolved in a mixture of DMF (200 μL) and DCM (2 mL). The clear solution was stirred at room temperature for 90 minutes. A solution of R-isoserine methyl ester hydrochloride (95 mg, 0.6 mmol) in a mixture of DCM (1.0 mL) and DMF (0.4 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between DCM (20 mL) and water (20 mL). The organic phase was separated and washed with brine and water (1:2), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was then evaporated from acetonitrile to obtain the title compound in quantitative yield. 1 H-NMR (DMSO-d 6 ): δ 8.48(t, 1H), 7.73(d, 2H), 7.34(d, 2H), 7.30(d, 2H), 7.24(d, 2H), 7.18(d , 2H), 7.08(d, 2H), 6.27(d, 1H), 5.70(d, 1H), 4.34(m, 1H), 4.32(d, 2H), 4.22(q, 1H), 3.62(s, 3H), 3.52(m, 1H), 3.40(m, 1H), 1.65-1.80(m, 5H).1.10-1.40(m, 9H).3-{4-[3-[1(S)-( 4-Chlorophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2(R)-hydroxypropionic acid

将3-{4-[3-[1(S)-(4-氯苯基)乙基]-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2(R)-羟基丙酸甲酯(280mg，0.473mmol)溶解在THF(2.5mL)和甲醇(2.5mL)的混合物中，并加入4N氢氧化钠水溶液(0.355mL)。将该反应混合物在室温搅拌2小时。通过加入1N盐酸将pH调节至3.0。通过真空旋转蒸发除去溶剂，将残余物再溶解在乙酸乙酯(10mL)中。将有机相用水洗涤2次，用盐水洗涤一次，然后真空浓缩至于，获得了本标题化合物，为粉末。产量：168mg(89％)。1H-NMR(DMSO-d6)：δ8.46(t，1H)，7.75(d，2H)，7.35(d，2H)，7.31(d，2H)，7.25(d，2H)，7.19(d，2H)，7.08(d，2H)，6.28(d，2H)，4.85(m，1H)，4.80(d，2H)，4.15(m，1H)，3.55(m，1H)，3.40(m，1H)，1.65-1.80(m，5H)，1.10-1.40(m，9H)；HPLC-MS(方法B)：m/z＝579(M+1)；Rt＝5.27min.实施例363-{4-[3-联苯-2-基甲基-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2(R)-羟基丙酸

Figure A0181159101091
3-{4-[3-[1(S)-(4-chlorophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2(R )-Methyl hydroxypropionate (280 mg, 0.473 mmol) was dissolved in a mixture of THF (2.5 mL) and methanol (2.5 mL), and 4N aqueous sodium hydroxide solution (0.355 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The pH was adjusted to 3.0 by adding 1N hydrochloric acid. The solvent was removed by rotary evaporation in vacuo and the residue was redissolved in ethyl acetate (10 mL). The organic phase was washed twice with water and once with brine, then concentrated in vacuo to give the title compound as a powder. Yield: 168 mg (89%). 1 H-NMR (DMSO-d 6 ): δ8.46(t, 1H), 7.75(d, 2H), 7.35(d, 2H), 7.31(d, 2H), 7.25(d, 2H), 7.19( d, 2H), 7.08(d, 2H), 6.28(d, 2H), 4.85(m, 1H), 4.80(d, 2H), 4.15(m, 1H), 3.55(m, 1H), 3.40(m , 1H), 1.65-1.80 (m, 5H), 1.10-1.40 (m, 9H); HPLC-MS (method B): m/z=579 (M+1); Rt=5.27min. Example 363- {4-[3-Biphenyl-2-ylmethyl-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2(R)-hydroxypropionic acid
Figure A0181159101091

该化合物是这样制得的：按照类似于实施例35的方法，将N-氯氨基甲酰基-4-[(4-环己基苯基氨基)甲基]苯甲酸甲酯和联苯-2-基甲基胺反应，然后将该苯甲酸甲酯水解，与(R)-异丝氨酸乙酯盐酸盐偶联。水解，获得了本标题化合物。1H-NMR(DMSO-d6)：δ12.6(s，1H)，8.45(t，1H)，7.78(d，2H)，7.45-7.20(m，14H)，7.05(d，2H)，6.10(t，1H)，5.50(bs，1H)，4.85(s，2H)，4.2(m，3H)，3.55(m，1H)，2.45(m，1H)，1.85-1.70(m，5H)，1.40-1.20(m，6H)；HPLC-MS(方法B)：m/z＝606(M+1)；Rt＝5.08min.This compound was obtained by mixing methyl N-chlorocarbamoyl-4-[(4-cyclohexylphenylamino)methyl]benzoate and biphenyl-2- methylamine, followed by hydrolysis of the methyl benzoate and coupling with (R)-isoserine ethyl ester hydrochloride. Hydrolysis affords the title compound. 1 H-NMR (DMSO-d 6 ): δ12.6(s, 1H), 8.45(t, 1H), 7.78(d, 2H), 7.45-7.20(m, 14H), 7.05(d, 2H), 6.10(t, 1H), 5.50(bs, 1H), 4.85(s, 2H), 4.2(m, 3H), 3.55(m, 1H), 2.45(m, 1H), 1.85-1.70(m, 5H) , 1.40-1.20 (m, 6H); HPLC-MS (method B): m/z=606 (M+1); Rt=5.08min.

用于液相合成通式(Ia)和(Ib)化合物的一般方法(B)：

Figure A0181159101101
其中R2、R3、R7、R8、A、E和D的定义同式(I)中所述。General method (B) for the liquid phase synthesis of compounds of general formula (Ia) and (Ib):
Figure A0181159101101
The definitions of R 2 , R 3 , R 7 , R 8 , A, E and D are the same as those in formula (I).

当A是-CHOH-时，使用1)BSA和2)D-N＝C＝O进行步骤6。否则仅使用D-N＝C＝O进行步骤6。When A is -CHOH-, proceed to step 6 using 1) BSA and 2) D-N=C=O. Otherwise proceed to step 6 using only D-N=C=O.

在下述实施例中进一步举例说明该方法。实施例37(一般方法(B))(R)-3-{4-[3-(4-氰基-3-三氟甲基苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸

Figure A0181159101111
This method is further illustrated in the following examples. Example 37 (General Procedure (B)) (R)-3-{4-[3-(4-cyano-3-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureido Methyl]benzoylamino}-2-hydroxypropionic acid
Figure A0181159101111

步骤1是用与一般方法(A)相同的方法进行的。步骤2：4-{[叔丁氧基羰基-(4-环己基苯基)氨基]甲基}苯甲酸甲酯Step 1 is carried out by the same method as the general method (A). Step 2: Methyl 4-{[tert-butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}benzoate

将4-((4-环己基苯基氨基)甲基)苯甲酸甲酯(2.0g，6.18mmol)悬浮在氢氧化钠(1N，6.18mL)中，滴加二碳酸二叔丁酯(1.67g，7.42mmol)在THF(10mL)中的溶液。将该反应混合物搅拌过夜，真空浓缩，获得了固体残余物，将其再溶解在乙醚(50mL)中，用水洗涤(25mL)，加入氢氧化钠(1.3mL，1N)。用乙醚(25mL)在pH11-12再次萃取水相。将合并的有机相用硫酸氢钠(30mL，10％)和水(3×20mL)洗涤，用硫酸镁干燥，并真空浓缩。从乙酸乙酯和正庚烷中结晶，获得了1.98g4-{[叔丁氧基羰基-(4-环己基苯基)氨基]甲基}苯甲酸甲酯。1H-NMR(DMSO-d6)：δ1.13-1.44(m，14H)，1.63-1.81(m，5H)，2.46(m，1H)，3.83(s，3H)，4.88(s，2H)，7.12(m，4H)，7.48(d，2H)，7.92(d，2H)；HPLC-MS(方法 B)：m/z＝424(M+1)；Rt＝9.10min；M.p.99.5-101.0℃.元素分析：C26H33NO4的计算值：C，73.73％；H，7.85％；N，3.3 1％.实测值：C，73.30％；H，8.07％；N，3.26％.步骤3：4-{[叔丁氧基羰基-(4-环己基苯基)氨基]甲基}苯甲酸Methyl 4-((4-cyclohexylphenylamino)methyl)benzoate (2.0 g, 6.18 mmol) was suspended in sodium hydroxide (1N, 6.18 mL), and di-tert-butyl dicarbonate (1.67 g, 7.42 mmol) in THF (10 mL). The reaction mixture was stirred overnight and concentrated in vacuo to give a solid residue which was redissolved in diethyl ether (50 mL), washed with water (25 mL), and sodium hydroxide (1.3 mL, IN) was added. The aqueous phase was re-extracted with diethyl ether (25 mL) at pH 11-12. The combined organic phases were washed with sodium bisulfate (30 mL, 10%) and water (3 x 20 mL), dried over magnesium sulfate, and concentrated in vacuo. Crystallization from ethyl acetate and n-heptane gave 1.98 g of methyl 4-{[tert-butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}benzoate. 1 H-NMR (DMSO-d 6 ): δ1.13-1.44 (m, 14H), 1.63-1.81 (m, 5H), 2.46 (m, 1H), 3.83 (s, 3H), 4.88 (s, 2H) ), 7.12(m, 4H), 7.48(d, 2H), 7.92(d, 2H); HPLC-MS (method B): m/z=424(M+1); Rt =9.10min; Mp99. 5-101.0°C. Elemental analysis: Calculated value for C 26 H 33 NO 4 : C, 73.73%; H, 7.85%; N, 3.3 1%. Measured value: C, 73.30%; H, 8.07%; N, 3.26 %. Step 3: 4-{[tert-butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}benzoic acid

将4-{[叔丁氧基羰基-(4-环己基苯基)氨基]甲基}苯甲酸甲酯悬浮在乙醇(30mL)中，并加入氢氧化钠(4N，8.1mL)。将该反应混合物搅拌过夜。将该混合物浓缩至干，悬浮在水(100mL)中，用盐酸(8.5mL，4N)酸化，并用乙酸乙酯(100mL)萃取。用乙酸乙酯(30mL)将水相再萃取一次，将合并的有机相用水(3×50mL)洗涤，用硫酸镁干燥并真空浓缩。将残余物从乙酸乙酯与正庚烷的混合物中结晶，获得了1.75g4-{[叔丁氧基羰基-(4-环己基苯基)氨基]甲基}苯甲酸。1H-NMR(CDCl3-d6)：δ1.18-1.42(m，14H)，1.68-1.87(m，5H)，2.46(m，1H)，4.88(s，2H)，7.10(m，4H)，7.47(d，2H)，8.07(d，2H)；HPLC-MS(方法B)：m/z＝410(M+1)；Rt＝8.15min；M.p.192.5-194.5℃.元素分析：C25H31NO4的计算值：C，73.32％；H，7.63％；N，3.42％.实测值：C，73.03％；H，7.86％；N，3.36％.步骤4：(R)-3-(4-{[叔丁氧基羰基-(4-环己基苯基)氨基]甲基}苯甲酰基氨基)-2-羟基丙酸甲酯Methyl 4-{[tert-butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}benzoate was suspended in ethanol (30 mL), and sodium hydroxide (4N, 8.1 mL) was added. The reaction mixture was stirred overnight. The mixture was concentrated to dryness, suspended in water (100 mL), acidified with hydrochloric acid (8.5 mL, 4N), and extracted with ethyl acetate (100 mL). The aqueous phase was extracted once more with ethyl acetate (30 mL), the combined organic phases were washed with water (3 x 50 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from a mixture of ethyl acetate and n-heptane to obtain 1.75 g of 4-{[tert-butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}benzoic acid. 1 H-NMR (CDCl 3 -d 6 ): δ1.18-1.42 (m, 14H), 1.68-1.87 (m, 5H), 2.46 (m, 1H), 4.88 (s, 2H), 7.10 (m, 4H), 7.47(d, 2H), 8.07(d, 2H); HPLC-MS (Method B): m/z = 410 (M+1); Rt = 8.15min; Mp 192.5-194.5°C. Element Analysis: Calcd for C25H31NO4 : C, 73.32%; H, 7.63% ; N, 3.42%. Found: C, 73.03%; H, 7.86%; N, 3.36%. Step 4: (R )-3-(4-{[tert-butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}benzoylamino)-2-hydroxypropionic acid methyl ester

将4-{[叔丁氧基羰基-(4-环己基苯基)氨基]甲基}苯甲酸溶解在DMF(10mL)中，并加入HOBt(0.40g，2.93mmol)和EDAC(0.52g，2.73mmol)。将该反应混合物搅拌45分钟。然后加入(R)-3-氨基-2-羟基丙酸甲酯在DMF(8mL)中的溶液和二异丙基乙基胺(0.46mL)。将该混合物搅拌过夜。将该反应混合物用水(40mL)稀释，并用乙酸乙酯(75mL)萃取。将水相用乙酸乙酯(30mL)萃取。将合并的有机相用盐酸(0.2N，3×30mL)、水∶饱和氯化钠(3×30mL)洗涤，用硫酸镁干燥并真空浓缩。通过硅胶(100g)柱色谱纯化残余物，使用乙酸乙酯与正庚烷的混合物(1L(1∶1)和0.5L(7∶3))洗脱，获得了0.77g(R)-3-(4-{[叔丁氧基羰基-(4-环己基苯基)氨基]甲基}苯甲酰基氨基)-2-羟基丙酸甲酯。1H-NMR(DMSO-d6)：δ1.16-1.41(m，14H)，1.63-1.81(m，5H)，2.46(m，1H)，3.42(m，1H)，3.54(m，1H)，3.62(s，3H)，4.24(m，1H)，4.84(s，2H)，5.70(d，1H)，7.12(m，4H)，7.28(d，2H)，7.78(d，2H)，8.51(t，1H)；HPLC-MS(方法B)：m/z＝511(M+1)；Rt＝7.63min.步骤5：(R)-3-{4-[(4-环己基苯基氨基)甲基]苯甲酰基氨基}-2-羟基丙酸甲酯4-{[tert-butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}benzoic acid was dissolved in DMF (10 mL), and HOBt (0.40 g, 2.93 mmol) and EDAC (0.52 g, 2.73 mmol). The reaction mixture was stirred for 45 minutes. A solution of (R)-methyl 3-amino-2-hydroxypropanoate in DMF (8 mL) and diisopropylethylamine (0.46 mL) were then added. The mixture was stirred overnight. The reaction mixture was diluted with water (40 mL), and extracted with ethyl acetate (75 mL). The aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were washed with hydrochloric acid (0.2N, 3 x 30 mL), water: saturated sodium chloride (3 x 30 mL), dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel (100 g) eluting with a mixture of ethyl acetate and n-heptane (1 L (1:1) and 0.5 L (7:3)) afforded 0.77 g of (R)-3- Methyl (4-{[tert-butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}benzoylamino)-2-hydroxypropionate. 1 H-NMR (DMSO-d 6 ): δ1.16-1.41 (m, 14H), 1.63-1.81 (m, 5H), 2.46 (m, 1H), 3.42 (m, 1H), 3.54 (m, 1H) ), 3.62(s, 3H), 4.24(m, 1H), 4.84(s, 2H), 5.70(d, 1H), 7.12(m, 4H), 7.28(d, 2H), 7.78(d, 2H) , 8.51(t, 1H); HPLC-MS (Method B): m/z=511(M+1); Rt =7.63min. Step 5: (R)-3-{4-[(4-cyclo Hexylphenylamino)methyl]benzoylamino}-2-hydroxypropionic acid methyl ester

将(R)-3-(4-{[叔丁氧基羰基-(4-环己基苯基)氨基]甲基}苯甲酰基氨基)-2-羟基-丙酸甲酯溶解在乙酸乙酯(10mL)中，加入无水氯化氢在乙酸乙酯中的溶液(3M，10mL)。将该混合物在室温搅拌2小时，并真空浓缩。将残余物悬浮在乙酸乙酯(15mL)中，并浓缩。该操作重复2次。然后将残余物悬浮在乙酸乙酯(10mL)中，并在5℃放置过夜。过滤出沉淀，用冰冷的乙酸乙酯洗涤，并真空干燥，获得了0.62g(R)-3-{4-[(4-环己基苯基氨基)甲基]苯甲酰基氨基}-2-羟基丙酸甲酯。1H-NMR(DMSO-d6)：δ1.12-1.43(m，5H)，1.63-1.82(m，5H)，2.45(m，1H)，3.42(m，1H)，3.53(m，1H),3.60(s，3H)，4.25(t，1H)，4.48(s，2H)，7.18(m，4H)，7.57(d，2H)，7.82(d，2H)，8.58(t，1H)；HPLC-MS(方法B)：m/z＝411(M+1)；Rt＝4.93min.步骤6：(R)-3-{4-[3-(4-氰基-3-三氟甲基苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸甲酯Dissolve (R)-3-(4-{[tert-butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}benzoylamino)-2-hydroxy-propionic acid methyl ester in ethyl acetate (10 mL), a solution of anhydrous hydrogen chloride in ethyl acetate (3M, 10 mL) was added. The mixture was stirred at room temperature for 2 hours, and concentrated in vacuo. The residue was suspended in ethyl acetate (15 mL), and concentrated. This operation was repeated 2 times. The residue was then suspended in ethyl acetate (10 mL) and left at 5°C overnight. The precipitate was filtered off, washed with ice-cold ethyl acetate, and dried in vacuo to obtain 0.62 g of (R)-3-{4-[(4-cyclohexylphenylamino)methyl]benzoylamino}-2- Methyl Hydroxypropionate. 1 H-NMR (DMSO-d 6 ): δ1.12-1.43 (m, 5H), 1.63-1.82 (m, 5H), 2.45 (m, 1H), 3.42 (m, 1H), 3.53 (m, 1H) ), 3.60(s, 3H), 4.25(t, 1H), 4.48(s, 2H), 7.18(m, 4H), 7.57(d, 2H), 7.82(d, 2H), 8.58(t, 1H) ; HPLC-MS (Method B): m/z = 411 (M+1); R t = 4.93 min. Step 6: (R)-3-{4-[3-(4-cyano-3-tri Fluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid methyl ester

将5-氨基-2-氰基三氟甲苯(0.07g，0.36mmol)溶解在乙酸乙酯(2mL)中，并加入无水氯化氢在乙酸乙酯中的溶液(3.5M，5.5mL)。15分钟后，将该溶液浓缩至干，从甲苯(3×5mL)中共蒸发3次。向残余物中加入甲苯(2.5mL)，用氮气吹扫约10分钟，然后加入双光气(0.43mL)。将该混合物在氮气氛下轻度回流1小时。将该混合物冷却，真空浓缩至干，然后从甲苯中共蒸发2次以除去过量双光气，获得了异氰酸4-氰基-3三氟甲基苯基酯。5-Amino-2-cyanobenzotrifluoride (0.07 g, 0.36 mmol) was dissolved in ethyl acetate (2 mL), and a solution of anhydrous hydrogen chloride in ethyl acetate (3.5 M, 5.5 mL) was added. After 15 minutes, the solution was concentrated to dryness and co-evaporated 3 times from toluene (3 x 5 mL). To the residue was added toluene (2.5 mL), purged with nitrogen for about 10 minutes, then diphosgene (0.43 mL) was added. The mixture was gently refluxed for 1 hour under nitrogen atmosphere. The mixture was cooled, concentrated to dryness in vacuo, then co-evaporated twice from toluene to remove excess diphosgene to give 4-cyano-3 trifluoromethylphenyl isocyanate.

将(R)-3-{4-[(4-环己基苯基氨基)甲基]苯甲酰基氨基}-2-羟基丙酸甲酯盐酸盐(0.13g，0.3mmol)溶解在DCM(5mL)中，并加入BSA(0.22mL，0.9mmol)。将该混合物搅拌0.5小时，加入二异丙基乙基胺(0.052mL，0.3mmol)。将该反应混合物加到上述异氰酸酯中，并将该混合物搅拌过夜。将该反应混合物转移到分液漏斗中，并用水(10mL)洗涤2次，用硫酸镁干燥并真空浓缩。通过柱色谱(30g)纯化残余物，依次使用乙酸乙酯/正庚烷(4∶6)(400mL)和乙酸乙酯(200mL)洗脱，获得了0.085g(R)-3-{4-[3-(4-氰基-3-三氟甲基苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸甲酯。  1H-NMR(DMSO-d6)：δ1.12-1.44(m，6H)，1.66-1.82(m，5H)，3.41(m，1H)，3.53(m，1H)，3.60(s，3H)，4.22(m，1H)，4.47(s，2H)，5.69(s，1H)，7.21(m，4H)，7.33(d，2H)，7.76(d，2H)，7.98(s，2H)，8.14(s，1H)，8.48(t，1H)，9.1(s，1H)；HPLC-MS(方法B)：m/z＝623(M+1)；Rt＝6.02min.步骤7：Dissolve (R)-methyl 3-{4-[(4-cyclohexylphenylamino)methyl]benzoylamino}-2-hydroxypropanoate hydrochloride (0.13 g, 0.3 mmol) in DCM ( 5 mL), and BSA (0.22 mL, 0.9 mmol) was added. The mixture was stirred for 0.5 h and diisopropylethylamine (0.052 mL, 0.3 mmol) was added. The reaction mixture was added to the above isocyanate, and the mixture was stirred overnight. The reaction mixture was transferred to a separatory funnel and washed twice with water (10 mL), dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (30 g) eluting sequentially with ethyl acetate/n-heptane (4:6) (400 mL) and ethyl acetate (200 mL) afforded 0.085 g of (R)-3-{4- Methyl [3-(4-cyano-3-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionate. 1 H-NMR (DMSO-d 6 ): δ1.12-1.44 (m, 6H), 1.66-1.82 (m, 5H), 3.41 (m, 1H), 3.53 (m, 1H), 3.60 (s, 3H) ), 4.22(m, 1H), 4.47(s, 2H), 5.69(s, 1H), 7.21(m, 4H), 7.33(d, 2H), 7.76(d, 2H), 7.98(s, 2H) , 8.14(s, 1H), 8.48(t, 1H), 9.1(s, 1H); HPLC-MS (method B): m/z=623(M+1); Rt =6.02min. Step 7:

将(R)-3-{4-[3-(4-氰基-3-三氟甲基苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基-氨基}-2-羟基丙酸甲酯(0.07g，0.124mmol)悬浮在乙醇(3mL)中，并加入氢氧化钠(4N，0.19mL，0.742mmol)。将该反应混合物搅拌1.5小时，浓缩以除去乙醇。将残余物用水(10mL)稀释，并用盐酸(4N，0.21mL)酸化。用乙酸乙酯(2×10mL)萃取该混合物，将合并的有机相用水(3×10mL)洗涤，用硫酸镁干燥并真空浓缩，获得了本标题化合物(0.68g)。1H-NMR(DMSO-d6)：δ.1.16-1.42(m，6H)，1.66-1.82(m，5H)，3.40(m，1H)，3.54(m，1H)，4.16(m，1H)，4.48(s，2H)，7.20(m，4H)，7.34(d，2H)，7.78(d，2H)，7.99(s，2H)，8.16(s，1H)，8.44(t，1H)，9.1(s，1H)；HPLC-MS(方法B)：m/z＝609(M+1)；Rt＝7.27min.实施例38(一般方法(B))(R)-3-{4-[3-(3-叔丁基苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸步骤6：(R)-3-{4-[3-(3-叔丁基苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸甲酯(R)-3-{4-[3-(4-cyano-3-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoyl-amino} - Methyl 2-hydroxypropionate (0.07 g, 0.124 mmol) was suspended in ethanol (3 mL), and sodium hydroxide (4N, 0.19 mL, 0.742 mmol) was added. The reaction mixture was stirred for 1.5 hours, concentrated to remove ethanol. The residue was diluted with water (10 mL) and acidified with hydrochloric acid (4N, 0.21 mL). The mixture was extracted with ethyl acetate (2 x 10 mL), the combined organic phases were washed with water (3 x 10 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound (0.68 g). 1 H-NMR (DMSO-d 6 ): δ.1.16-1.42 (m, 6H), 1.66-1.82 (m, 5H), 3.40 (m, 1H), 3.54 (m, 1H), 4.16 (m, 1H) ), 4.48(s, 2H), 7.20(m, 4H), 7.34(d, 2H), 7.78(d, 2H), 7.99(s, 2H), 8.16(s, 1H), 8.44(t, 1H) , 9.1 (s, 1H); HPLC-MS (Method B): m/z = 609 (M+1); R t = 7.27 min. Example 38 (General Method (B)) (R)-3-{ 4-[3-(3-tert-Butylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid Step 6: (R)-3-{4-[3-(3-tert-Butylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropyl methyl ester

将3-(叔丁基)苯胺(0.054g，0.36mmol)溶解在乙酸乙酯(2mL)中，并加两次无水氯化氢在乙酸乙酯中的溶液(3.5M，3mL+2.5mL)。15分钟后，将该混合物浓缩至干，从甲苯(3×5mL)中共蒸发3次。向残余物中加入甲苯(2.5mL)，用氮气吹扫约10分钟，然后加入双光气(0.43mL)。将该混合物在氮气氛下轻度回流1小时。将该混合物冷却，真空浓缩。该操作重复2次以除去过量双光气。将该混合物浓缩至干，从甲苯中共蒸发3次(每次5mL)。将残余物浓缩至干，并从甲苯中共蒸发两次。然后将其再溶解在甲苯(2.5mL)中，用氮气吹扫约10分钟，然后加入双光气(0.43mL)。将该混合物在氮气氛下轻度回流1小时。冷却后，将该混合物浓缩，从甲苯中共蒸发2次以除去过量双光气，获得了异氰酸3-叔丁基苯基酯。3-(tert-Butyl)aniline (0.054 g, 0.36 mmol) was dissolved in ethyl acetate (2 mL), and a solution of anhydrous hydrogen chloride in ethyl acetate (3.5 M, 3 mL+2.5 mL) was added twice. After 15 minutes, the mixture was concentrated to dryness and co-evaporated 3 times from toluene (3 x 5 mL). To the residue was added toluene (2.5 mL), purged with nitrogen for about 10 minutes, then diphosgene (0.43 mL) was added. The mixture was gently refluxed for 1 hour under nitrogen atmosphere. The mixture was cooled and concentrated in vacuo. This operation was repeated twice to remove excess diphosgene. The mixture was concentrated to dryness and co-evaporated 3 times (5 mL each) from toluene. The residue was concentrated to dryness and co-evaporated twice from toluene. It was then redissolved in toluene (2.5 mL), purged with nitrogen for about 10 minutes, and then diphosgene (0.43 mL) was added. The mixture was gently refluxed for 1 hour under nitrogen atmosphere. After cooling, the mixture was concentrated and co-evaporated twice from toluene to remove excess diphosgene to afford 3-tert-butylphenylisocyanate.

将(R)-3-{4-[(4-环己基苯基氨基)甲基]苯甲酰基氨基}-2-羟基丙酸甲酯盐酸盐(0.13g，0.3mmol)溶解在DCM(5mL)中，加入BSA(0.22mL，0.9mmol)。将该混合物搅拌0.5小时，并加入二异丙基乙基胺(0.052mL，0.3mmol)。将该反应混合物加到上述异氰酸酯中，并搅拌过夜。将该反应混合物转移到分液漏斗中，并用水(10mL)洗涤2次，用硫酸镁干燥并真空浓缩。通过硅胶(30g)柱色谱纯化残余物，依次使用乙酸乙酯和正庚烷(6：4)(400mL)与乙酸乙酯(100mL)洗脱，获得了0.12g(R)-3-{4-[3-(3-叔丁基苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸甲酯。1H-NMR(DMSO-d6)：δ1.23(s，11H)，1.28-1.42(m，3H)，1.65-1.80(m，5H)，2.47(m，1H)，3.40(m，1H)，3.51(m，1H)，4.22(m，1H)，4.94(s，2H)，5.71(d，1H)，6.99(d，1H)，7.12-7-24(m，5H)，7.28(d，1H)，7.36(d，2H)，7.42(s，1H)，7.77(d，2H)，8.08(s，1H)，8.50(t，1H)；HPLC-MS(方法B)：m/z＝(585+1)；Rt＝8.30min步骤7：Dissolve (R)-methyl 3-{4-[(4-cyclohexylphenylamino)methyl]benzoylamino}-2-hydroxypropanoate hydrochloride (0.13 g, 0.3 mmol) in DCM ( 5 mL), BSA (0.22 mL, 0.9 mmol) was added. The mixture was stirred for 0.5 h, and diisopropylethylamine (0.052 mL, 0.3 mmol) was added. The reaction mixture was added to the above isocyanate and stirred overnight. The reaction mixture was transferred to a separatory funnel and washed twice with water (10 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (30 g) eluting with ethyl acetate and n-heptane (6:4) (400 mL) followed by ethyl acetate (100 mL) to obtain 0.12 g of (R)-3-{4- Methyl [3-(3-tert-butylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionate. 1 H-NMR (DMSO-d 6 ): δ1.23(s, 11H), 1.28-1.42(m, 3H), 1.65-1.80(m, 5H), 2.47(m, 1H), 3.40(m, 1H ), 3.51(m, 1H), 4.22(m, 1H), 4.94(s, 2H), 5.71(d, 1H), 6.99(d, 1H), 7.12-7-24(m, 5H), 7.28( d, 1H), 7.36(d, 2H), 7.42(s, 1H), 7.77(d, 2H), 8.08(s, 1H), 8.50(t, 1H); HPLC-MS (Method B): m/ z=(585+1); Rt =8.30min Step 7:

将(R)-3-{4-[3-(3-叔丁基苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸甲酯(0.11g，0.188mmol)溶解在乙醇(4mL)中，并加入氢氧化钠(4N，0.28mL，1.128mmol)。将该反应搅拌1.5小时，并真空浓缩以除去乙醇。将残余物用水(10mL)稀释，用盐酸(4N，0.3mL)酸化，并用乙酸乙酯(2×10mL)萃取。将合并的有机相用水(3×10mL)洗涤，用硫酸镁干燥，并真空浓缩，获得了本标题化合物(0.10g)。1H-NMR(DMSO-d6)：δ1.23(s，9H)，1.28-1.42(m，4H)，1.65-1.81(m，5H)，2.47(m，1H)，3.38(m，1H)，3.55(m，1H)，4.16(m，1H)，4.94(s，2H)，7.00(d，1H)，7.11-7.24(m，6H)，7.28(d，1H)，7.35(d，1H)，7.41(s，1H)，7.80(d，2H)，8.10(s，1H)，8.46(t，1H)；HPLC-MS(方法B)：m/z＝572(M+1)；Rt＝7.78min.实施例39(一般方法(B))(R)-3-{4-[1-(4-环己基苯基)-3-(3-羟基甲基-4-三氟甲氧基苯基)脲基甲基]苯甲酰基氨基]-2-羟基丙酸制备用于步骤6的3-(叔丁基二甲基甲硅烷氧基甲基)-4-三氟甲氧基苯胺：(R)-3-{4-[3-(3-tert-butylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid The ester (0.11 g, 0.188 mmol) was dissolved in ethanol (4 mL), and sodium hydroxide (4N, 0.28 mL, 1.128 mmol) was added. The reaction was stirred for 1.5 hours and concentrated in vacuo to remove ethanol. The residue was diluted with water (10 mL), acidified with hydrochloric acid (4N, 0.3 mL), and extracted with ethyl acetate (2 x 10 mL). The combined organic phases were washed with water (3 x 10 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound (0.10 g). 1 H-NMR (DMSO-d 6 ): δ1.23(s, 9H), 1.28-1.42(m, 4H), 1.65-1.81(m, 5H), 2.47(m, 1H), 3.38(m, 1H ), 3.55(m, 1H), 4.16(m, 1H), 4.94(s, 2H), 7.00(d, 1H), 7.11-7.24(m, 6H), 7.28(d, 1H), 7.35(d, 1H), 7.41(s, 1H), 7.80(d, 2H), 8.10(s, 1H), 8.46(t, 1H); HPLC-MS (method B): m/z=572(M+1); R t =7.78min. Example 39 (General Method (B)) (R)-3-{4-[1-(4-cyclohexylphenyl)-3-(3-hydroxymethyl-4-trifluoro Methoxyphenyl)ureidomethyl]benzoylamino]-2-hydroxypropionic acid Preparation of 3-(tert-butyldimethylsiloxymethyl)-4-trifluoromethoxyaniline for step 6:

将发烟硝酸(5mL)在冰浴上冷却，用30分钟缓慢地加入2-(三氟甲氧基)苯甲酸甲酯(5g，22.7mmol)，同时将温度保持在15℃以下。然后将该反应在60℃搅拌1小时，在室温搅拌2小时。将该混合物倒在冰上，由此分离出了油状物。倾出含水上清液，向油状物中加入水(50mL)。用碳酸氢钠中和后，用乙酸乙酯(25mL)萃取该混合物。用乙酸乙酯(15mL)将水相再萃取一次。将合并的有机相用饱和氯化钠(2×15mL)洗涤，干燥(硫酸镁)，并真空浓缩，获得了5.69g5-硝基-2-三氟甲氧基苯甲酸甲酯。1H NMR(DMSO-d6)：δ3.93(3H，s)，7.82(1H，d)，8.58(1H，d)， 8.67(1H，s)；HPLC-MS(方法B)：m/z：266；Rt＝6.0min.Fuming nitric acid (5 mL) was cooled on an ice bath and methyl 2-(trifluoromethoxy)benzoate (5 g, 22.7 mmol) was added slowly over 30 minutes while keeping the temperature below 15°C. The reaction was then stirred at 60°C for 1 hour and at room temperature for 2 hours. The mixture was poured onto ice, whereupon an oil separated. The aqueous supernatant was decanted and water (50 mL) was added to the oil. After neutralizing with sodium bicarbonate, the mixture was extracted with ethyl acetate (25 mL). The aqueous phase was extracted one more time with ethyl acetate (15 mL). The combined organic phases were washed with saturated sodium chloride (2 x 15 mL), dried (magnesium sulfate), and concentrated in vacuo to afford 5.69 g of methyl 5-nitro-2-trifluoromethoxybenzoate. 1 H NMR (DMSO-d 6 ): δ3.93 (3H, s), 7.82 (1H, d), 8.58 (1H, d), 8.67 (1H, s); HPLC-MS (method B): m/ z: 266; R t = 6.0 min.

将5-硝基-2-三氟甲氧基苯甲酸甲酯(5.69g，21.5mmol)溶解在乙醇99.9％(80mL)中，并加入氯化亚锡(II)二水合物(24.2g，107mmol)。将悬浮液在75℃油浴上搅拌2小时，并真空浓缩。加入乙酸乙酯(100mL)和水(50mL)，用4N氢氧化钠(50mL)将pH调节至8。将沉淀中的液体倾出。用乙酸乙酯将沉淀洗涤2次。用乙酸乙酯(60mL)将水相萃取2次。将合并的有机相用饱和氯化钠溶液(2×100mL)洗涤，干燥(硫酸镁)并真空浓缩。通过柱色谱(120g二氧化硅)纯化，使用乙酸乙酯和庚烷(1∶1)洗脱，获得了3.8g5-氨基-2-三氟甲氧基苯甲酸甲酯。1HNMR(DMSO-d6)：δ3.82(3H，s)，5.63(2H，s)，6.79(1H，d)，7.07(1H，s)，7.11(1H，d)；HPLC-MS(方法B)：m/z：236，Rt＝4.6min.Methyl 5-nitro-2-trifluoromethoxybenzoate (5.69 g, 21.5 mmol) was dissolved in ethanol 99.9% (80 mL), and stannous (II) chloride dihydrate (24.2 g, 107 mmol). The suspension was stirred on a 75°C oil bath for 2 hours and concentrated in vacuo. Ethyl acetate (100 mL) and water (50 mL) were added, and the pH was adjusted to 8 with 4N sodium hydroxide (50 mL). The liquid in the precipitate was decanted. The precipitate was washed twice with ethyl acetate. The aqueous phase was extracted twice with ethyl acetate (60 mL). The combined organic phases were washed with saturated sodium chloride solution (2 x 100 mL), dried (magnesium sulfate) and concentrated in vacuo. Purification by column chromatography (120 g silica) eluting with ethyl acetate and heptane (1:1) afforded 3.8 g of methyl 5-amino-2-trifluoromethoxybenzoate. 1 HNMR (DMSO-d 6 ): δ3.82 (3H, s), 5.63 (2H, s), 6.79 (1H, d), 7.07 (1H, s), 7.11 (1H, d); HPLC-MS ( Method B): m/z: 236, R t = 4.6 min.

在装配有温度计和加液漏斗的三颈烧瓶内，于氮气氛下将5-氨基-2-三氟甲氧基苯甲酸甲酯(3.0g，12.8mmol)溶解在THF(20mL)中。在搅拌下用10分钟滴加冰冷的氢化锂铝(1MTHF溶液，15mL)。继续在室温搅拌1小时，将该反应真空浓缩。将残余物悬浮在DCM(150mL)和水(50mL)中，然后经由硅藻土过滤，用DCM和水洗涤。分离出滤液，用DCM(30mL)将水相再萃取一次。将合并的有机相用水(2×20mL)洗涤，干燥(硫酸镁)并真空浓缩，获得了2.47g(5-氨基-2-三氟甲氧基苯基)甲醇。1HNMR(DMSO-d6)：δ3.92(2H.d)，5.18(1H，t)，5.28(2H，s)，6.45(1H，d)，6.91(1H，d)；HPLC-MS(方法B)：m/z：208，Rt＝7.2min.In a three-necked flask equipped with a thermometer and addition funnel, methyl 5-amino-2-trifluoromethoxybenzoate (3.0 g, 12.8 mmol) was dissolved in THF (20 mL) under nitrogen atmosphere. Ice-cold lithium aluminum hydride (1M THF solution, 15 mL) was added dropwise with stirring over 10 minutes. Stirring was continued at room temperature for 1 hour, and the reaction was concentrated in vacuo. The residue was suspended in DCM (150 mL) and water (50 mL), then filtered through Celite, washing with DCM and water. The filtrate was separated and the aqueous phase was extracted once more with DCM (30 mL). The combined organic phases were washed with water (2 x 20 mL), dried (magnesium sulfate) and concentrated in vacuo to afford 2.47 g of (5-amino-2-trifluoromethoxyphenyl)methanol. 1 HNMR (DMSO-d 6 ): δ3.92 (2H.d), 5.18 (1H, t), 5.28 (2H, s), 6.45 (1H, d), 6.91 (1H, d); HPLC-MS ( Method B): m/z: 208, Rt=7.2min.

将5-氨基-2-三氟甲氧基苯基)甲醇(1.2g，5.8mmol)溶解在DMF(5mL)中，加入咪唑(0.48g，7.1mmol)和叔丁基二甲基甲硅烷基氯(0.99g，6.6mmol)。将该反应混合物搅拌16小时，加入水(20mL)。用乙酸乙酯(2×50mL)萃取该混合物，将合并的有机相用水(10mL)、柠檬酸(10mL，10％)和水(2×10mL)洗涤，干燥(硫酸镁)并真空浓缩。通过柱色谱(110g，二氧化硅)纯化残余物，使用乙酸乙酯和庚烷(1∶3)洗脱，获得了1.2g3-(叔丁基二甲基甲硅烷氧基甲基)-4-三氟甲氧基苯胺。1HNMR(DMSO-d6)：δ0.82(9H，s)，3.25(6H，s)，4.52(2H，s)，5.23(2H，s)，6.41(1H，d)，6.61(1H，s)，6.86(1H，d)；HPLC-MS(方法B)：m/z：322；Rt＝7.17min.步骤6：(R)-3-{4-[3-[3-(叔丁基二甲基甲硅烷氧基甲基)-4-三氟甲氧基苯基]-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸甲酯Dissolve 5-amino-2-trifluoromethoxyphenyl)methanol (1.2g, 5.8mmol) in DMF (5mL), add imidazole (0.48g, 7.1mmol) and tert-butyldimethylsilyl Chlorine (0.99 g, 6.6 mmol). The reaction mixture was stirred for 16 hours and water (20 mL) was added. The mixture was extracted with ethyl acetate (2 x 50 mL), the combined organic phases were washed with water (10 mL), citric acid (10 mL, 10%) and water (2 x 10 mL), dried (magnesium sulfate) and concentrated in vacuo. Purification of the residue by column chromatography (110 g, silica) eluting with ethyl acetate and heptane (1:3) afforded 1.2 g of 3-(tert-butyldimethylsilyloxymethyl)-4 -trifluoromethoxyaniline. 1 H NMR (DMSO-d 6 ): δ0.82 (9H, s), 3.25 (6H, s), 4.52 (2H, s), 5.23 (2H, s), 6.41 (1H, d), 6.61 (1H, s), 6.86(1H,d); HPLC-MS (Method B): m/z: 322; Rt = 7.17min. Step 6: (R)-3-{4-[3-[3-(tert Butyldimethylsilyloxymethyl)-4-trifluoromethoxyphenyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid methyl ester

将碳酸二(三氯甲基)酯(三光气)(0.09g，0.31mmol)溶解在DCM(2mL)中，并在冰浴中于氮气氛下冷却。将3-(叔丁基二甲基甲硅烷氧基甲基)-4-三氟甲氧基苯胺(0.3g，0.93mmol)从甲苯中蒸发2次以除去所有水分，然后溶解在DCM(2mL)中，并加入二异丙基乙基胺(0.32mL)。将该溶液加到冷却的三光气溶液中，并将该混合物在20℃搅拌2.5小时。将(R)-3-{4-[(4-环己基苯基氨基)甲基]苯甲酰基氨基}-2-羟基-丙酸甲酯盐酸盐(0.37g，0.83mmol)从甲苯中蒸发2次，溶解在DMF(3mL)中，并加入二异丙基乙基胺(0.141mL，0.83mmol)。在搅拌下将该溶液加到上述异氰酸酯中，在氮气氛下于80℃加热2小时。将该反应混合物真空蒸发，用DCM(80mL)、柠檬酸水溶液(10％，25mL)萃取残余物。用DCM(30mL)萃取水相。将合并的有机相用柠檬酸水溶液(10％，3×25mL)洗涤，用硫酸镁干燥并真空蒸发。通过硅胶(58g)柱色谱纯化残余物，使用乙酸乙酯和正庚烷(940mL，1∶1和300mL乙酸乙酯)洗脱，获得了0.03g(R)-3-{4-[3-[3-(叔丁基二甲基甲硅烷氧基甲基)-4-三氟甲氧基苯基]-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸甲酯。HPLC-MS(方法B)：m/z＝758(M+1)；Rt＝9.57分钟。步骤7：Bis(trichloromethyl)carbonate (triphosgene) (0.09 g, 0.31 mmol) was dissolved in DCM (2 mL) and cooled in an ice bath under a nitrogen atmosphere. 3-(tert-Butyldimethylsiloxymethyl)-4-trifluoromethoxyaniline (0.3 g, 0.93 mmol) was evaporated twice from toluene to remove all water, then dissolved in DCM (2 mL ), and diisopropylethylamine (0.32 mL) was added. This solution was added to the cooled triphosgene solution, and the mixture was stirred at 20°C for 2.5 hours. (R)-3-{4-[(4-Cyclohexylphenylamino)methyl]benzoylamino}-2-hydroxy-propionic acid methyl ester hydrochloride (0.37g, 0.83mmol) was dissolved in toluene Evaporated twice, dissolved in DMF (3 mL), and added diisopropylethylamine (0.141 mL, 0.83 mmol). This solution was added to the above isocyanate with stirring and heated at 80° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was evaporated in vacuo and the residue was extracted with DCM (80 mL), aqueous citric acid (10%, 25 mL). The aqueous phase was extracted with DCM (30 mL). The combined organic phases were washed with aqueous citric acid (10%, 3 x 25 mL), dried over magnesium sulfate and evaporated in vacuo. Purification of the residue by column chromatography on silica gel (58 g) eluting with ethyl acetate and n-heptane (940 mL, 1:1 and 300 mL ethyl acetate) afforded 0.03 g of (R)-3-{4-[3-[ 3-(tert-butyldimethylsilyloxymethyl)-4-trifluoromethoxyphenyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2 - Methyl hydroxypropionate. HPLC-MS (Method B): m/z = 758 (M+1); Rt = 9.57 min. Step 7:

将(R)-3-{4-[3-[3-(叔丁基二甲基甲硅烷氧基甲基)-4-三氟甲氧基苯基]-1-(4-环己基-苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸甲酯(24mg，0.032mmol)溶解在乙醇(1mL)中，并加入氢氧化钠(0.05mL，019mmol)。将该反应混合物搅拌2小时，浓缩以除去乙醇。将残余物用水(10mL)稀释，用盐酸(4N，0.3mL)酸化，并用乙酸乙酯(2×10mL)萃取。将合并的有机相用水(3×10mL)洗涤，用硫酸镁干燥并真空浓缩，获得了17mg(R)-3-{4-[3-[3-(叔丁基二甲基甲硅烷氧基甲基)-4-三氟甲氧基苯基]-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸。HPLC-MS(方法B)：m/z＝744(M+1)；Rt＝9.35分钟。(R)-3-{4-[3-[3-(tert-butyldimethylsilyloxymethyl)-4-trifluoromethoxyphenyl]-1-(4-cyclohexyl- Phenyl)ureidomethyl]benzoylamino}-2-hydroxypropanoic acid methyl ester (24 mg, 0.032 mmol) was dissolved in ethanol (1 mL), and sodium hydroxide (0.05 mL, 019 mmol) was added. The reaction mixture was stirred for 2 hours, concentrated to remove ethanol. The residue was diluted with water (10 mL), acidified with hydrochloric acid (4N, 0.3 mL), and extracted with ethyl acetate (2 x 10 mL). The combined organic phases were washed with water (3 x 10 mL), dried over magnesium sulfate and concentrated in vacuo to afford 17 mg of (R)-3-{4-[3-[3-(tert-butyldimethylsilyloxy Methyl)-4-trifluoromethoxyphenyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropanoic acid. HPLC-MS (Method B): m/z = 744 (M+1); Rt = 9.35 min.

将(R)-3-{4-[3-[3-(叔丁基二甲基甲硅烷氧基甲基)-4-三氟甲氧基苯基]-1-(4-环己基-苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸(17mg，0.023mmol)溶解在乙腈∶水(9∶1)(2mL)中，并加入氟化铯(35mg，0.35mmol)。将该反应混合物在80℃搅拌6小时，再加入氟化铯(35mg)。将该混合物在60℃搅拌过夜，真空浓缩，用乙酸乙酯(10mL)和水(5mL)稀释。将有机相用水(3×5mL)洗涤，用硫酸镁干燥并真空浓缩。通过制备HPLC纯化残余物，获得了本标题化合物。1H-NMR(DMSO-d6)：δ1.35(m，5H)，1.79(m，5H)，4.49(s，2H)，4.95(s，2H)，5.29(s，1H)，7.12-7.26(m，6H)，7.34(d，2H)，7.49(dd，1H)，7.63(d，1H)，7.77(d，2H)，8.42(t，1H)；HPLC-Ms(方法B)：m/z＝630(M+1)；Rt＝6.62min.(R)-3-{4-[3-[3-(tert-butyldimethylsilyloxymethyl)-4-trifluoromethoxyphenyl]-1-(4-cyclohexyl- Phenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid (17 mg, 0.023 mmol) was dissolved in acetonitrile:water (9:1) (2 mL), and cesium fluoride (35 mg, 0.35 mmol ). The reaction mixture was stirred at 80°C for 6 hours, and cesium fluoride (35 mg) was added. The mixture was stirred at 60 °C overnight, concentrated in vacuo, diluted with ethyl acetate (10 mL) and water (5 mL). The organic phase was washed with water (3 x 5 mL), dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by preparative HPLC afforded the title compound. 1 H-NMR (DMSO-d 6 ): δ1.35 (m, 5H), 1.79 (m, 5H), 4.49 (s, 2H), 4.95 (s, 2H), 5.29 (s, 1H), 7.12- 7.26 (m, 6H), 7.34 (d, 2H), 7.49 (dd, 1H), 7.63 (d, 1H), 7.77 (d, 2H), 8.42 (t, 1H); HPLC-Ms (Method B): m/z=630(M+1); Rt =6.62min.

用于固相合成通式(Ic)化合物的一般方法(C)：

Figure A0181159101191
Figure A0181159101201
其中R2、R3、R4、R5、A、Z、D和E的定义同(I)中所述，X是-C(O)NH-或-C(O)NHCR12R13-其中R12和R13的定义同式(I)中所述，且树脂是用2-氯三苯甲基连接基团负载的聚苯乙烯树脂。当A是-CHOH-时，使用1)BSA和2)D-N＝C＝O或D-CHR13-N＝C＝O进行步骤4。否则，仅使用D-N＝C＝O或D-CHR13-N＝C＝O进行步骤4。General method (C) for solid-phase synthesis of compounds of general formula (Ic):
Figure A0181159101191
Figure A0181159101201
Wherein R 2 , R 3 , R 4 , R 5 , A, Z, D and E are as defined in (I), X is -C(O)NH- or -C(O)NHCR 12 R 13 - Wherein R 12 and R 13 are defined as described in formula (I), and the resin is a polystyrene resin supported by a 2-chlorotrityl linking group. When A is -CHOH-, proceed to step 4 using 1) BSA and 2) DN=C=O or D- CHR13 -N=C=O. Otherwise, proceed to step 4 using only DN=C=O or D-CHR 13 -N=C=O.

在下述实施例中举例说明该方法。实施例40(一般方法(C))(R)-3-{4-[1-(4-叔丁基苯基)-3-(3，4-二氯苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸步骤1：结合在树脂上的(R)-Fmoc-异丝氨酸This method is illustrated in the following examples. Example 40 (General method (C)) (R)-3-{4-[1-(4-tert-butylphenyl)-3-(3,4-dichlorophenyl)ureidomethyl]benzene Formylamino}-2-hydroxypropionic acid Step 1: (R)-Fmoc-Isoserine bound to the resin

将用2-氯三苯甲基氯连接团官能化的50mg聚苯乙烯树脂与N-甲基-2-吡咯烷酮(500μL)和1，2-二氯丙烷(500μL)涡旋1小时。将树脂过滤，并用N-甲基-2-吡咯烷酮：1，2-二氯丙烷(1∶1，2×1mL)洗涤。加入N-甲基-2-吡咯烷酮(500μL)和1，2-二氯丙烷(500μL)，然后加入150μmol(R)-Fmoc-异丝氨酸和100μL二异丙基乙基胺。将该悬浮液在25℃振摇4小时后，通过过滤分离出树脂，并用DCM∶甲醇∶二异丙基乙基胺17∶2∶1(2×1mL)和N-甲基-2-吡咯烷酮(2×1mL)洗涤。步骤2：结合在树脂上的(R)-3-(4-甲酰基苯甲酰基氨基)-2-羟基丙酸50 mg of polystyrene resin functionalized with 2-chlorotrityl chloride linker was vortexed with N-methyl-2-pyrrolidone (500 μL) and 1,2-dichloropropane (500 μL) for 1 hour. The resin was filtered and washed with N-methyl-2-pyrrolidone:1,2-dichloropropane (1:1, 2 x 1 mL). N-methyl-2-pyrrolidone (500 μL) and 1,2-dichloropropane (500 μL) were added, followed by 150 μmol (R)-Fmoc-isoserine and 100 μL diisopropylethylamine. After shaking the suspension at 25 °C for 4 h, the resin was isolated by filtration and washed with DCM:methanol:diisopropylethylamine 17:2:1 (2 x 1 mL) and N-methyl-2-pyrrolidone (2 x 1 mL) washes. Step 2: (R)-3-(4-formylbenzoylamino)-2-hydroxypropionic acid bound to the resin

向上述结合在树脂上的(R)-Fmoc-异丝氨酸中加入500μL20％吡啶在DMF中的溶液。振摇30分钟后，排放出树脂，并用N-甲基-2-吡咯烷酮(6×1mL)洗涤。然后将200μmol 4-甲酰基苯甲酸(30mg)和200μmolHOBt(31mg)溶解在N-甲基-2-吡咯烷酮(500μL)中，并加到树脂中，然后加入溶解在乙腈(500μL)中的200μmol二异丙基碳二亚胺(25.2mg)。将该混合物在25℃振摇4小时，然后过滤，并用N-甲基-2-吡咯烷酮(3×1mL)洗涤树脂。步骤3：结合在树脂上的(R)-3-{4-[(4-叔丁基苯基氨基)甲基]苯甲酰基氨基}-2-羟基丙酸To the above resin-bound (R)-Fmoc-isoserine was added 500 μL of 20% pyridine in DMF. After shaking for 30 minutes, the resin was drained and washed with N-methyl-2-pyrrolidone (6 x 1 mL). Then 200 μmol of 4-formylbenzoic acid (30 mg) and 200 μmol of HOBt (31 mg) were dissolved in N-methyl-2-pyrrolidone (500 μL) and added to the resin, followed by the addition of 200 μmol of dimethicone dissolved in acetonitrile (500 μL). Isopropylcarbodiimide (25.2 mg). The mixture was shaken at 25°C for 4 hours, then filtered and the resin was washed with N-methyl-2-pyrrolidone (3 x 1 mL). Step 3: (R)-3-{4-[(4-tert-butylphenylamino)methyl]benzoylamino}-2-hydroxypropionic acid bound to resin

将上述结合在树脂上的(R)-3-(4-甲酰基苯甲酰基氨基)-2-羟基丙酸用0.5M4-叔丁基苯胺(0.25mmol)在N-甲基-2-吡咯烷酮与原甲酸三甲酯的混合物(1∶1，0.5mL)中的溶液和冰醋酸(50μL)于25℃处理1小时。加入溶解在N-甲基-2-吡咯烷酮和甲醇(1∶1，0.25mL)中的氰基硼氢化钠(250μmol，16mg)，将该混合物在25℃涡旋4小时，然后过滤，并用N-甲基-2-吡咯烷酮与甲醇的混合物(1∶1，2×1mL)3×1mL N-甲基-2-吡咯烷酮(3×1mL)和1，2-二氯丙烷与二异丙基乙基胺的混合物(7∶1，2×0.75mL)洗涤。步骤4：结合在树脂上的(R)-3-{4-[1-(4-叔丁基苯基)-3-(3，4-二氯苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸The above (R)-3-(4-formylbenzoylamino)-2-hydroxypropionic acid bound to the resin was mixed with 0.5M 4-tert-butylaniline (0.25mmol) in N-methyl-2-pyrrolidone The solution in a mixture with trimethyl orthoformate (1:1, 0.5 mL) and glacial acetic acid (50 μL) was treated at 25° C. for 1 hour. Sodium cyanoborohydride (250 μmol, 16 mg) dissolved in N-methyl-2-pyrrolidone and methanol (1:1, 0.25 mL) was added, and the mixture was vortexed at 25 °C for 4 h, then filtered, and washed with N -A mixture of methyl-2-pyrrolidone and methanol (1:1, 2×1mL) 3×1mL N-methyl-2-pyrrolidone (3×1mL) and 1,2-dichloropropane and diisopropylethyl A mixture of amines (7:1, 2 x 0.75 mL) was washed. Step 4: (R)-3-{4-[1-(4-tert-butylphenyl)-3-(3,4-dichlorophenyl)ureidomethyl]benzoyl bound to the resin Amino}-2-hydroxypropionic acid

向上述结合在树脂上的(R)-3-{4-[(4-叔丁基苯基氨基)甲基]苯甲酰基氨基}-2-羟基丙酸中加入1，2-二氯丙烷(500μL)和BSA(100μL)，并将该混合物在25℃涡旋1小时。加入200μmol异氰酸3，4-二氯苯酯，在25℃振摇5小时，然后过滤，将树脂用2×1mLDCM、4×1mL N-甲基-2-吡咯烷酮、2×1mL H2O、3×1mL THF和5×1mLDCM洗涤，获得了结合在树脂上的本标题化合物。步骤5：(R)-3-{4-[1-(4-叔丁基苯基)-3-(3，4-二氯苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸Add 1,2-dichloropropane to the above resin-bound (R)-3-{4-[(4-tert-butylphenylamino)methyl]benzoylamino}-2-hydroxypropionic acid (500 μL) and BSA (100 μL), and the mixture was vortexed at 25° C. for 1 hour. Add 200 μmol 3,4-dichlorophenyl isocyanate, shake at 25°C for 5 hours, then filter, wash the resin with 2×1 mL DCM, 4×1 mL N-methyl-2-pyrrolidone, 2×1 mL H 2 O , 3 x 1 mL THF and 5 x 1 mL DCM washes afforded the title compound bound to the resin. Step 5: (R)-3-{4-[1-(4-tert-butylphenyl)-3-(3,4-dichlorophenyl)ureidomethyl]benzoylamino}-2- Hydroxypropionic acid

将上述结合在树脂上的(R)-3-{4-[1-(4-叔丁基苯基)-3-(3，4-二氯苯基)脲基甲基]-苯甲酰基氨基}-2-羟基丙酸用1mL 20％TFA在DCM中的溶液于25℃处理1小时。过滤出产物，将树脂用1mL DCM洗涤。将合并的萃取液真空浓缩，获得了本标题化合物。1H-NMR(CDCl3)：δ7.65(d，2H)，7.45-7.40(m，4H)，7.35-7.20(m，3H)，7.10-7.00(m，3H)，6.30(s，1H)，4.90(s，2H)，4.40(m，1H)，3.83(m，2H)，1.32(s，9H)；HPLC-MS(方法B)：m/z＝558(M+1)；Rt＝4.71min.The above (R)-3-{4-[1-(4-tert-butylphenyl)-3-(3,4-dichlorophenyl)ureidomethyl]-benzoyl group bound to the resin Amino}-2-hydroxypropionic acid was treated with 1 mL of 20% TFA in DCM for 1 hour at 25°C. The product was filtered off and the resin was washed with 1 mL of DCM. The combined extracts were concentrated in vacuo to afford the title compound. 1 H-NMR (CDCl 3 ): δ7.65(d, 2H), 7.45-7.40(m, 4H), 7.35-7.20(m, 3H), 7.10-7.00(m, 3H), 6.30(s, 1H ), 4.90(s, 2H), 4.40(m, 1H), 3.83(m, 2H), 1.32(s, 9H); HPLC-MS (method B): m/z=558(M+1); R t = 4.71min.

下述实施例是如上所述进行的。实施例41(一般方法(C))(R)-3-{4-[1-(4-叔丁基环己基)-3-(3，4-二氯苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸HPLC-MS(方法B)：m/z＝564(M+1)；Rt＝4.92分钟/5.02分钟。实施例42(一般方法(C))(R)-3-{4-[1-(4-环己基苯基)-3-(3，4-二氯苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸HPLC-MS(方法B)：m/z＝584(M+1)；Rt＝5.12分钟。实施例43(一般方法(C))(R)-3-{4-[1-(4-环己基苯基)-3-(2，2，4，4-四氟-4H-苯并[1，3]二氧杂环己烯-6-基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸

Figure A0181159101231
HPLC-MS(方法B)：m/z＝646(M+1)；Rt＝5.24分钟。实施例44(一般方法(C))(R)-3-{4-[1-(4-叔丁基苯基)-3-(2，2，4，4-四氟-4H-苯并[1，3]二氧杂环己烯-6-基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸HPLC-MS(方法B)：m/z＝620(M+1)；Rt＝4.88分钟。实施例45(一般方法(C))(R)-3-{4-[1-(4-叔丁基环己基)-3-(2，2，4，4-四氟-4H-苯并[1，3]二氧杂环己烯-6-基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸HPLC-MS(方法B)：m/z＝606(M+1)；Rt＝5.11分钟/5.20分钟。实施例46(-般方法(C))(R)-3-{4-[1-(4-叔丁基苯基)-3-(3，4-二氟苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸
Figure A0181159101242
HPLC-MS(方法B)：m/z＝526(M+1)；Rt＝4.24分钟。实施例47(一般方法(C))(R)-3-{4-[1-(4-环己基苯基)-3-(3，4-二氟苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸
Figure A0181159101243
HPLC-MS(方法B)：m/z＝552(M+1)；Rt＝4.65分钟。实施例48(一般方法(C))(R)-3-{4-[1-(4-环己-1-烯基苯基)-3-(3，4-二氟苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸
Figure A0181159101251
HPLC-MS(方法A)：m/z＝550(M+1)；Rt＝6.77分钟。实施例49(一般方法(C))(R)-3-{4-[3-(4-氯-3-三氟甲基苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸HPLC-MS(方法A)：m/z＝618(M+1)；Rt＝7.58分钟。实施例50(一般方法(C))(R)-3-{4-[1-(4-环己基苯基)-3-(4-氟-3-硝基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸HPLC-MS(方法A)：m/z＝579(M+1)；Rt＝6.85分钟。实施例51(一般方法(C))(R)-3-{4-[1-(4-环己基苯基)-3-(4-异丙基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸HPLC-MS(方法A)：m/z＝558(M+1)；Rt＝7.73分钟。实施例52(一般方法(C))(R)-3-{4-[1-(4-环己-1-烯基苯基)-3-(3，4-二氯苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸HPLC-MS(方法B)：m/z＝582(M+1)；Rt＝4.99分钟。实施例53(一般方法(C))(R)-3-{4-[3-(4-乙酰基苯基)-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸HPLC-MS(方法A)：m/z＝558(M+1)；Rt＝6.42分钟。实施例54(一般方法(C))3-{4-[3-[1(RS)-(4-溴苯基)乙基]-1-(4-环己基苯基)脲基甲基]苯甲酰基氨基}-2(R)-羟基丙酸
Figure A0181159101271
HPLC-MS(方法A)：m/z＝624(M+1)；Rt＝7.45分钟。实施例55(一般方法(C))(R)-3-{4-[1-(4-环己基苯基)-3-(3，5-二氟苯基)脲基甲基]苯甲酰基氨基}-2-羟基丙酸
Figure A0181159101272
HPLC-MS(方法B)：m/z＝552(M+1)；Rt＝4.76分钟。The following examples were carried out as described above. Example 41 (General Procedure (C)) (R)-3-{4-[1-(4-tert-butylcyclohexyl)-3-(3,4-dichlorophenyl)ureidomethyl]benzoyl Amino}-2-hydroxypropionic acid HPLC-MS (Method B): m/z = 564 (M+1); Rt = 4.92 min/5.02 min. Example 42 (General Procedure (C)) (R)-3-{4-[1-(4-cyclohexylphenyl)-3-(3,4-dichlorophenyl)ureidomethyl]benzene Acylamino}-2-hydroxypropionic acid HPLC-MS (Method B): m/z = 584 (M+1); Rt = 5.12 min. Example 43 (General Procedure (C)) (R)-3-{4-[1-(4-cyclohexylphenyl)-3-(2,2,4,4-tetrafluoro-4H-benzo[ 1,3]dioxin-6-yl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid
Figure A0181159101231
HPLC-MS (Method B): m/z = 646 (M+1); Rt = 5.24 min. Example 44 (General Procedure (C)) (R)-3-{4-[1-(4-tert-butylphenyl)-3-(2,2,4,4-tetrafluoro-4H-benzo [1,3]Dioxin-6-yl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid HPLC-MS (Method B): m/z = 620 (M+1); Rt = 4.88 min. Example 45 (General Procedure (C)) (R)-3-{4-[1-(4-tert-butylcyclohexyl)-3-(2,2,4,4-tetrafluoro-4H-benzo[1 ,3] dioxin-6-yl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid HPLC-MS (Method B): m/z = 606 (M+1); Rt = 5.11 min/5.20 min. Example 46 (General method (C)) (R)-3-{4-[1-(4-tert-butylphenyl)-3-(3,4-difluorophenyl)ureidomethyl] Benzoylamino}-2-hydroxypropionic acid
Figure A0181159101242
HPLC-MS (Method B): m/z = 526 (M+1); Rt = 4.24 min. Example 47 (General Procedure (C)) (R)-3-{4-[1-(4-cyclohexylphenyl)-3-(3,4-difluorophenyl)ureidomethyl]benzene Acylamino}-2-hydroxypropionic acid
Figure A0181159101243
HPLC-MS (Method B): m/z = 552 (M+1); Rt = 4.65 min. Example 48 (General Procedure (C)) (R)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,4-difluorophenyl)ureido Methyl]benzoylamino}-2-hydroxypropionic acid
Figure A0181159101251
HPLC-MS (Method A): m/z = 550 (M+1); Rt = 6.77 min. Example 49 (General Procedure (C)) (R)-3-{4-[3-(4-Chloro-3-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)carbamide base]benzoylamino}-2-hydroxypropionic acid HPLC-MS (Method A): m/z = 618 (M+1); Rt = 7.58 min. Example 50 (General Procedure (C)) (R)-3-{4-[1-(4-cyclohexylphenyl)-3-(4-fluoro-3-nitrophenyl)ureidomethyl] Benzoylamino}-2-hydroxypropionic acid HPLC-MS (Method A): m/z = 579 (M+1); Rt = 6.85 min. Example 51 (General Procedure (C)) (R)-3-{4-[1-(4-cyclohexylphenyl)-3-(4-isopropylphenyl)ureidomethyl]benzoyl Amino}-2-hydroxypropionic acid HPLC-MS (Method A): m/z = 558 (M+1); Rt = 7.73 min. Example 52 (General Procedure (C)) (R)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,4-dichlorophenyl)ureido Methyl]benzoylamino}-2-hydroxypropionic acid HPLC-MS (Method B): m/z = 582 (M+1); Rt = 4.99 min. Example 53 (General Procedure (C)) (R)-3-{4-[3-(4-acetylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino }-2-Hydroxypropionic acid HPLC-MS (Method A): m/z = 558 (M+1); Rt = 6.42 min. Example 54 (General Procedure (C)) 3-{4-[3-[1(RS)-(4-bromophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl] Benzoylamino}-2(R)-hydroxypropionic acid
Figure A0181159101271
HPLC-MS (Method A): m/z = 624 (M+1); Rt = 7.45 min. Example 55 (General Procedure (C)) (R)-3-{4-[1-(4-cyclohexylphenyl)-3-(3,5-difluorophenyl)ureidomethyl]benzidine Acylamino}-2-hydroxypropionic acid
Figure A0181159101272
HPLC-MS (Method B): m/z = 552 (M+1); Rt = 4.76 min.

用于固相合成通式(Id)化合物的一般方法(D)：

Figure A0181159101273
Figure A0181159101281
其中R2、R3、R4、R5、A、Z、D和E的定义同式(I)中所述，X是-C(O)-(CR12R13)r-(CH2)s-其中r、s、R12和R13的定义同式(I)中所述，且树脂是用2-氯三苯甲基连接基团负载的聚苯乙烯树脂。当A是-CHOH-时，用1)BSA和2)D-C(O)OH或D-CHR13-C(O)OH进行步骤4。否则，仅用D-C(O)OH或D-CHR13-C(O)OH进行步骤4。实施例56(一般方法(D))(R)-3-[4-({(4-叔丁基环己基)-[2-(4-三氟甲氧基苯基)乙酰基]氨基}甲基)苯甲酰基氨基]-2-羟基丙酸
Figure A0181159101282
步骤1：结合在树脂上的(R)-Fmoc-异丝氨酸General method (D) for solid-phase synthesis of compounds of general formula (Id):
Figure A0181159101273
Figure A0181159101281
Wherein R 2 , R 3 , R 4 , R 5 , A, Z, D and E are as defined in formula (I), X is -C(O)-(CR 12 R 13 ) r -(CH 2 ) s - wherein r, s, R 12 and R 13 are as defined in formula (I), and the resin is a polystyrene resin loaded with a 2-chlorotrityl linking group. When A is -CHOH-, proceed to step 4 with 1) BSA and 2) DC(O)OH or D- CHR13 -C(O)OH. Otherwise, proceed to step 4 with only DC(O)OH or D- CHR13 -C(O)OH. Example 56 (General Procedure (D)) (R)-3-[4-({(4-tert-butylcyclohexyl)-[2-(4-trifluoromethoxyphenyl)acetyl]amino}methyl ) benzoylamino] -2-hydroxypropionic acid
Figure A0181159101282
Step 1: (R)-Fmoc-Isoserine bound to the resin

将用2-氯三苯甲基氯连接团官能化的50mg聚苯乙烯树脂与N-甲基-2-吡咯烷酮(500μL)和1，2-二氯丙烷(500μL)涡旋1小时。将树脂过滤，并用N-甲基-2-吡咯烷酮：1，2-二氯丙烷(1∶1，2×1mL)洗涤。加入N-甲基-2-吡咯烷酮(500μL)和1，2-二氯丙烷(500μL)，然后加入150μmol(R)-Fmoc-异丝氨酸和100μL二异丙基乙基胺。将该悬浮液在25℃振摇4小时后，通过过滤分离出树脂，并用DCM∶甲醇∶二异丙基乙基胺17∶2∶1(2×1mL)和N-甲基-2-吡咯烷酮(2×1mL)洗涤。步骤2：结合在树脂上的(R)-3-(4-甲酰基苯甲酰基氨基)-2-羟基丙酸50 mg of polystyrene resin functionalized with 2-chlorotrityl chloride linker was vortexed with N-methyl-2-pyrrolidone (500 μL) and 1,2-dichloropropane (500 μL) for 1 hour. The resin was filtered and washed with N-methyl-2-pyrrolidone:1,2-dichloropropane (1:1, 2 x 1 mL). N-methyl-2-pyrrolidone (500 μL) and 1,2-dichloropropane (500 μL) were added, followed by 150 μmol (R)-Fmoc-isoserine and 100 μL diisopropylethylamine. After shaking the suspension at 25 °C for 4 h, the resin was isolated by filtration and washed with DCM:methanol:diisopropylethylamine 17:2:1 (2 x 1 mL) and N-methyl-2-pyrrolidone (2 x 1 mL) washes. Step 2: (R)-3-(4-formylbenzoylamino)-2-hydroxypropionic acid bound to the resin

向上述结合在树脂上的(R)-Fmoc-异丝氨酸中加入500μL20％吡啶在DMF中的溶液。振摇30分钟后，排放出树脂，并用N-甲基-2-吡咯烷酮(6×1mL)洗涤。然后将200μmol4-甲酰基苯甲酸(30mg)和200μmolHOBt(31mg)溶解在N-甲基-2-吡咯烷酮(500μL)中，并加到树脂中，然后加入溶解在乙腈(500μL)中的200μmol二异丙基碳二亚胺(25.2mg)。将该混合物在25℃振摇4小时，然后过滤，并用N-甲基-2-吡咯烷酮(3×1mL)洗涤树脂。步骤3：结合在树脂上的(R)-3-{4-[(4-叔丁基环己基氨基)甲基]苯甲酰基氨基}-2-羟基丙酸To the above resin-bound (R)-Fmoc-isoserine was added 500 μL of 20% pyridine in DMF. After shaking for 30 minutes, the resin was drained and washed with N-methyl-2-pyrrolidone (6 x 1 mL). Then 200 μmol 4-formylbenzoic acid (30 mg) and 200 μmol HOBt (31 mg) were dissolved in N-methyl-2-pyrrolidone (500 μL) and added to the resin, followed by the addition of 200 μmol diisocyanate dissolved in acetonitrile (500 μL) Propylcarbodiimide (25.2mg). The mixture was shaken at 25°C for 4 hours, then filtered and the resin was washed with N-methyl-2-pyrrolidone (3 x 1 mL). Step 3: (R)-3-{4-[(4-tert-butylcyclohexylamino)methyl]benzoylamino}-2-hydroxypropionic acid bound to resin

将上述结合在树脂上的(R)-3-(4-甲酰基苯甲酰基氨基)-2-羟基丙酸用0.5M4-叔丁基环己基胺(0.25mmol)在N-甲基-2-吡咯烷酮与原甲酸三甲酯的混合物(1∶1，0.5mL)中的溶液和冰醋酸(50μL)于25℃处理1小时。加入溶解在N-甲基-2-吡咯烷酮和甲醇(1∶1，0.25mL)中的氰基硼氢化钠(250μmol，16mg)，将该混合物在25℃涡旋4小时，然后过滤，并用N-甲基-2-吡咯烷酮与甲醇的混合物(1∶1，2×1mL)3×1mL N-甲基-2-吡咯烷酮(3×1mL)和1，2-二氯丙烷与二异丙基乙基胺的混合物(7∶1，2×0.75mL)洗涤。步骤4：结合在树脂上的(R)-3-[4-({(4-叔丁基环己基)-2-(4-三氟甲氧基苯基)乙酰基]氨基}甲基)苯甲酰基氨基]-2-羟基丙酸The above-mentioned (R)-3-(4-formylbenzoylamino)-2-hydroxypropionic acid bound to the resin was mixed with 0.5M 4-tert-butylcyclohexylamine (0.25mmol) in N-methyl-2-pyrrolidone The solution in a mixture with trimethyl orthoformate (1:1, 0.5 mL) and glacial acetic acid (50 μL) was treated at 25° C. for 1 hour. Sodium cyanoborohydride (250 μmol, 16 mg) dissolved in N-methyl-2-pyrrolidone and methanol (1:1, 0.25 mL) was added, and the mixture was vortexed at 25 °C for 4 h, then filtered, and washed with N -A mixture of methyl-2-pyrrolidone and methanol (1:1, 2×1mL) 3×1mL N-methyl-2-pyrrolidone (3×1mL) and 1,2-dichloropropane and diisopropylethyl A mixture of amines (7:1, 2 x 0.75 mL) was washed. Step 4: (R)-3-[4-({(4-tert-butylcyclohexyl)-2-(4-trifluoromethoxyphenyl)acetyl]amino}methyl)benzidine bound to resin Acylamino]-2-hydroxypropionic acid

向上述结合在树脂上的(R)-3-{4-[(4-叔丁基环己基氨基)甲基]苯甲酰基氨基}-2-羟基丙酸中加入1，2-二氯丙烷(500μL)和BSA(100μL)，将该混合物在25℃涡旋1小时，然后过滤。向该树脂中加入4-(三氟甲氧基)苯基乙酸(400μmol)在N-甲基-2-吡咯烷酮、1，2-二氯丙烷和二异丙基乙基胺(4.5∶4.5∶1，1mL)中的溶液，然后加入溴三(吡咯烷基)鏻六氟磷酸盐(400μmol)在1，2-二氯丙烷(500μL)中的溶液。将该混合物在50℃反应3小时，将树脂冷却至25℃，同时用N-甲基-2-吡咯烷酮(4×1mL)、和DCM(10×1mL)洗涤，获得了结合在树脂上的本标题化合物。步骤5：(R)-3-[4-({(4-叔丁基环己基)-[2-(4-三氟甲氧基苯基)乙酰基]氨基}甲基)苯甲酰基氨基]-2-羟基丙酸Add 1,2-dichloropropane (500 μL ) and BSA (100 μL), the mixture was vortexed at 25° C. for 1 hour, then filtered. To this resin was added 4-(trifluoromethoxy)phenylacetic acid (400 μmol) in N-methyl-2-pyrrolidone, 1,2-dichloropropane and diisopropylethylamine (4.5:4.5: 1, 1 mL), followed by a solution of bromotris(pyrrolidinyl)phosphonium hexafluorophosphate (400 μmol) in 1,2-dichloropropane (500 μL). The mixture was reacted at 50°C for 3 hours, and the resin was cooled to 25°C while washing with N-methyl-2-pyrrolidone (4×1mL) and DCM (10×1mL) to obtain the present compound bound to the resin. title compound. Step 5: (R)-3-[4-({(4-tert-butylcyclohexyl)-[2-(4-trifluoromethoxyphenyl)acetyl]amino}methyl)benzoylamino]- 2-Hydroxypropionic acid

将上述结合在树脂上的(R)-3-{4-[1-(4-叔丁基环己基)-3-(4-三氟甲氧基苯基)-脲基甲基]苯甲酰基氨基}-2-羟基丙酸用1mL 20％TFA在DCM中的溶液于25℃处理1小时。过滤出产物，并用1mL DCM洗涤树脂。将合并的萃取液真空浓缩，获得了本标题化合物。HPLC-MS(方法A)：m/z＝579(M+1)；Rt＝7.20分钟。The above (R)-3-{4-[1-(4-tert-butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)-ureidomethyl]benzoylamino group bound to the resin }-2-Hydroxypropionic acid was treated with 1 mL of 20% TFA in DCM for 1 hour at 25°C. The product was filtered off and the resin was washed with 1 mL of DCM. The combined extracts were concentrated in vacuo to afford the title compound. HPLC-MS (Method A): m/z = 579 (M+1); Rt = 7.20 min.

下述实施例是如上所述进行的。实施例57(一般方法(D))(R)-3-[4-({(4-叔丁基环己基)-[2-(3-氟-5-三氟甲基苯基)乙酰基]氨基}甲基)苯甲酰基氨基]-2-羟基丙酸

Figure A0181159101301
HPLC-MS(方法A)：m/z＝581(M+1)；Rt＝7.22分钟。实施例58(一般方法(D))(R)-3-[4-({(2，2-二苯基乙基)-[2-(3-氟-5-三氟甲基苯基)乙酰基]氨基}甲基)苯甲酰基氨基]-2-羟基丙酸HPLC-MS(方法A)：m/z＝623(M+1)；Rt＝6.87分钟。实施例59(一般方法(D))(R)-3-(4-{[5-氯苯并[b]噻吩-3-羰基)-(2，2-二苯基乙基)氨基]甲基}苯甲酰基氨基)-2-羟基丙酸
Figure A0181159101311
HPLC-MS(方法A)：m/z＝613(M+1)；Rt＝6.50分钟。实施例60(一般方法(D))(R)-3-[4-({(2，2-二苯基乙基)-[2-(4-三氟甲氧基苯基)乙酰基]氨基}甲基)苯甲酰基氨基]-2-羟基丙酸HPLC-MS(方法A)：m/z＝621(M+1)；Rt＝6.90分钟。实施例61(-般方法(D))(R)-3-(4-{[(4-叔丁基环己基)-(5-氯苯并[b]噻吩-3-羰基)氨基]甲基}苯甲酰基氨基)-2-羟基丙酸HPLC-MS(方法A)：m/z＝571(M+1)；Rt＝7.15分钟。实施例62(一般方法(D))(R)-3-(4-{[(2，2-二苯基乙基)-(5-三氟甲氧基-1H-吲哚-2-羰基)氨基]甲基}苯甲酰基氨基)-2-羟基丙酸HPLC-MS(方法A)：m/z＝646(M+1)；Rt＝6.93分钟。实施例63(一般方法(D))(R)-3-[4-({(4-环己基苯基)-[(4-三氟甲氧基苯基)乙酰基]氨基}甲基)苯甲酰基氨基]-2-羟基丙酸
Figure A0181159101322
HPLC-MS(方法B)：m/z＝599(M+1)；Rt＝5.19分钟。实施例64(一般方法(D))(R)-3-[4-({(4-环己基苯基)-[(3-三氟甲氧基苯基)乙酰基]氨基}甲基)苯甲酰基氨基]-2-羟基丙酸
Figure A0181159101323
HPLC-MS(方法B)：m/z＝599(M+1)；Rt＝5.1 7分钟。实施例65(一般方法(D))(R)-3-[4-({(4-环己基苯基)-[(3-氟-5-三氟甲基苯基)乙酰基]氨基}甲基)苯甲酰基氨基]-2-羟基丙酸HPLC-MS(方法B)：m/z＝601(M+1)；Rt＝5.19分钟。实施例66(一般方法(D))(R)-3-(4-{([(3，5-二(三氟甲基)苯基)乙酰基]-(4-环己基苯基)氨基)甲基}苯甲酰基氨基)-2-羟基丙酸HPLC-MS(方法B)：m/z＝651(M+1)；Rt＝5.50分钟。实施例67(一般方法(D))(R)-3-[4-({(4-环己基苯基)-[(3-三氟甲基苯基)乙酰基]氨基}甲基)苯甲酰基氨基]-2-羟基丙酸HPLC-MS(方法B)：m/z＝583(M+1)；Rt＝5.08分钟。实施例68(一般方法(D))(R)-3-[4-({(4-环己基苯基)-[(3，4-二氯苯基)乙酰基]氨基}甲基)苯甲酰基氨基]-2-羟基丙酸
Figure A0181159101341
HPLC-MS(方法B)：m/z＝583(M+1)；Rt＝5.26分钟。实施例69(一般方法(D))(R)-3-(4-{[[(3-溴苯基)乙酰基]-(4-环己基苯基)氨基]甲基}苯甲酰基氨基)-2-羟基丙酸
Figure A0181159101342
HPLC-MS(方法B)：m/z＝595(M+1)；Rt＝5.01分钟。实施例70(一般方法(D))(R)-3-(4-{[(联苯-4-基乙酰基)-(4-环己基苯基)氨基]甲基}苯甲酰基氨基)-2-羟基-丙酸
Figure A0181159101343
HPLC-MS(方法B)：m/z＝591(M+1)；Rt＝5.38分钟。实施例71(一般方法(D))(R)-3-(4-{[(4-环己基苯基)-(2-萘基乙酰基)氨基]甲基}苯甲酰基氨基)-2-羟基丙酸HPLC-MS(方法B)：m/z＝565(M+1)；Rt＝5.10分钟。实施例72(一般方法(D))(R)-3-(4-{[(3-(3，5-二(三氟甲基)苯基)丙酰基)-(4-环己基苯基)氨基]甲基}苯甲酰基氨基)-2-羟基丙酸HPLC-MS(方法B)：m/z＝665(M+1)；Rt＝5.51分钟。实施例73(一般方法(D))(R)-3-[4-({(4-环己基苯基)-[3-(3-硝基苯基)丙酰基]氨基}甲基)苯甲酰基氨基]-2-羟基丙酸HPLC-MS(方法B)：m/z＝665(M+1)；Rt＝5.51分钟。The following examples were carried out as described above. Example 57 (General Procedure (D)) (R)-3-[4-({(4-tert-butylcyclohexyl)-[2-(3-fluoro-5-trifluoromethylphenyl)acetyl]amino }methyl)benzoylamino]-2-hydroxypropionic acid
Figure A0181159101301
HPLC-MS (Method A): m/z = 581 (M+1); Rt = 7.22 min. Example 58 (General Procedure (D)) (R)-3-[4-({(2,2-diphenylethyl)-[2-(3-fluoro-5-trifluoromethylphenyl) Acetyl]amino}methyl)benzoylamino]-2-hydroxypropionic acid HPLC-MS (Method A): m/z = 623 (M+1); Rt = 6.87 min. Example 59 (General Procedure (D)) (R)-3-(4-{[5-chlorobenzo[b]thiophene-3-carbonyl)-(2,2-diphenylethyl)amino]methanol phenyl)benzoylamino)-2-hydroxypropionic acid
Figure A0181159101311
HPLC-MS (Method A): m/z = 613 (M+1); Rt = 6.50 min. Example 60 (General Procedure (D)) (R)-3-[4-({(2,2-diphenylethyl)-[2-(4-trifluoromethoxyphenyl)acetyl] Amino}methyl)benzoylamino]-2-hydroxypropionic acid HPLC-MS (Method A): m/z = 621 (M+1); Rt = 6.90 min. Example 61 (General method (D)) (R)-3-(4-{[(4-tert-butylcyclohexyl)-(5-chlorobenzo[b]thiophene-3-carbonyl)amino]methyl} Benzoylamino)-2-hydroxypropionic acid HPLC-MS (Method A): m/z = 571 (M+1); Rt = 7.15 min. Example 62 (General Procedure (D)) (R)-3-(4-{[(2,2-diphenylethyl)-(5-trifluoromethoxy-1H-indole-2-carbonyl )amino]methyl}benzoylamino)-2-hydroxypropionic acid HPLC-MS (Method A): m/z = 646 (M+1); Rt = 6.93 min. Example 63 (General Procedure (D)) (R)-3-[4-({(4-cyclohexylphenyl)-[(4-trifluoromethoxyphenyl)acetyl]amino}methyl) Benzoylamino]-2-hydroxypropionic acid
Figure A0181159101322
HPLC-MS (Method B): m/z = 599 (M+1); Rt = 5.19 min. Example 64 (General Procedure (D)) (R)-3-[4-({(4-cyclohexylphenyl)-[(3-trifluoromethoxyphenyl)acetyl]amino}methyl) Benzoylamino]-2-hydroxypropionic acid
Figure A0181159101323
HPLC-MS (method B): m/z = 599 (M+1); Rt = 5.1 7 min. Example 65 (General Procedure (D)) (R)-3-[4-({(4-cyclohexylphenyl)-[(3-fluoro-5-trifluoromethylphenyl)acetyl]amino} Methyl)benzoylamino]-2-hydroxypropionic acid HPLC-MS (Method B): m/z = 601 (M+1); Rt = 5.19 min. Example 66 (General Procedure (D)) (R)-3-(4-{([(3,5-bis(trifluoromethyl)phenyl)acetyl]-(4-cyclohexylphenyl)amino )methyl}benzoylamino)-2-hydroxypropionic acid HPLC-MS (Method B): m/z = 651 (M+1); Rt = 5.50 min. Example 67 (General Procedure (D)) (R)-3-[4-({(4-cyclohexylphenyl)-[(3-trifluoromethylphenyl)acetyl]amino}methyl)benzene Formylamino]-2-hydroxypropionic acid HPLC-MS (Method B): m/z = 583 (M+1); Rt = 5.08 min. Example 68 (General Procedure (D)) (R)-3-[4-({(4-cyclohexylphenyl)-[(3,4-dichlorophenyl)acetyl]amino}methyl)benzene Formylamino]-2-hydroxypropionic acid
Figure A0181159101341
HPLC-MS (Method B): m/z = 583 (M+1); Rt = 5.26 min. Example 69 (General Procedure (D)) (R)-3-(4-{[[(3-bromophenyl)acetyl]-(4-cyclohexylphenyl)amino]methyl}benzoylamino )-2-hydroxypropionic acid
Figure A0181159101342
HPLC-MS (Method B): m/z = 595 (M+1); Rt = 5.01 min. Example 70 (General Procedure (D)) (R)-3-(4-{[(biphenyl-4-ylacetyl)-(4-cyclohexylphenyl)amino]methyl}benzoylamino) -2-Hydroxy-propionic acid
Figure A0181159101343
HPLC-MS (Method B): m/z = 591 (M+1); Rt = 5.38 min. Example 71 (General Procedure (D)) (R)-3-(4-{[(4-cyclohexylphenyl)-(2-naphthylacetyl)amino]methyl}benzoylamino)-2 -Hydroxypropionic acid HPLC-MS (Method B): m/z = 565 (M+1); Rt = 5.10 min. Example 72 (General Procedure (D)) (R)-3-(4-{[(3-(3,5-bis(trifluoromethyl)phenyl)propanoyl)-(4-cyclohexylphenyl )amino]methyl}benzoylamino)-2-hydroxypropionic acid HPLC-MS (Method B): m/z = 665 (M+1); Rt = 5.51 min. Example 73 (General Procedure (D)) (R)-3-[4-({(4-cyclohexylphenyl)-[3-(3-nitrophenyl)propionyl]amino}methyl)benzene Formylamino]-2-hydroxypropionic acid HPLC-MS (Method B): m/z = 665 (M+1); Rt = 5.51 min.

下列优选的化合物在本发明范围内，并且可依据本文所公开的方法制得。其它优选的化合物是

Figure A0181159101354
其中
Figure A0181159101371
Figure A0181159101391
Figure A0181159101411
The following preferred compounds are within the scope of this invention and can be prepared according to the methods disclosed herein. Other preferred compounds are
Figure A0181159101354
in
Figure A0181159101371
Figure A0181159101391
Figure A0181159101411

此外，下列化合物在本发明范围内，并且可依据本文所公开的方法制得：

Figure A0181159101431
Figure A0181159101451
Figure A0181159101461
Figure A0181159101471
Figure A0181159101501
Figure A0181159101511
Figure A0181159101521
Figure A0181159101541
Figure A0181159101571
Figure A0181159101581
Figure A0181159101591
Figure A0181159101611
Figure A0181159101631
Figure A0181159101651
Additionally, the following compounds are within the scope of the invention and can be prepared according to the methods disclosed herein:
Figure A0181159101431
Figure A0181159101451
Figure A0181159101461
Figure A0181159101471
Figure A0181159101501
Figure A0181159101511
Figure A0181159101521
Figure A0181159101541
Figure A0181159101571
Figure A0181159101581
Figure A0181159101591
Figure A0181159101611
Figure A0181159101631
Figure A0181159101651

此外，下列优选的化合物(纯的(R)或(S)构型的对映体，或其混合物，包括外消旋体)在本发明范围内，并且可依据上述方法制得：

Figure A0181159101671
Figure A0181159101691
Figure A0181159101701
Figure A0181159101721
Figure A0181159101741
Figure A0181159101751
Figure A0181159101761
Figure A0181159101781
药理方法In addition, the following preferred compounds (pure (R) or (S) configuration enantiomers, or mixtures thereof, including racemates) are within the scope of the present invention and can be prepared according to the methods described above:
Figure A0181159101671
Figure A0181159101691
Figure A0181159101701
Figure A0181159101721
Figure A0181159101741
Figure A0181159101751
Figure A0181159101761
Figure A0181159101781
Pharmacological method

下面描述用于评价本发明化合物效力的结合测定以及功能测定。Binding assays as well as functional assays for evaluating the potency of the compounds of the invention are described below.

可在使用克隆人胰高血糖素受体的竞争性结合测定中测定化合物与胰高血糖素受体的结合。Binding of compounds to the glucagon receptor can be determined in a competitive binding assay using cloned human glucagon receptor.

拮抗作用可作为在5nM胰高血糖素存在下化合物抑制形成的cAMP的量来确定。胰高血糖素结合测定(I)Antagonism can be determined as the amount of cAMP that compounds inhibit the formation of in the presence of 5 nM glucagon. Glucagon Binding Assay (I)

使用克隆人受体测定受体结合(Lok等人，Gene140，203-209(1994))。在幼仓鼠肾细胞系(A3 BHK570-25)中表达插到使用EcoRI/SSt1限制性位点的pLJ6’表达载体(Lok等人)中的受体。在0.5mg/mL G-418存在下选择克隆，并且显示在40代以上是稳定的。经表明Kd是0.1nM。Receptor binding was assayed using cloned human receptors (Lok et al., Gene 140, 203-209 (1994)). The receptor inserted into the pLJ6' expression vector (Lok et al.) using EcoRI/SSt1 restriction sites was expressed in a baby hamster kidney cell line (A3 BHK570-25). Clones were selected in the presence of 0.5 mg/mL G-418 and were shown to be stable over passage 40. K d was shown to be 0.1 nM.

质膜是这样制备的：将细胞生长至融合，将其从表面分离下来，将细胞重悬在冷的缓冲液(10mM tris/HCl，pH7.4，含有30mM NaCl，1mM二硫苏糖醇，5mg/L亮抑蛋白酶肽(Sigma)，5mg/L胃蛋白酶抑制剂(Sigma)，100mg/L杆菌肽(Sigma)和15 mg/L重组的抑肽酶(NovoNordisk A/S))，使用Poltron PT10-35匀浆器(Kinematica)匀浆两次，每次10秒，并在一层41 w/v％蔗糖上以95.000×g离心75分钟。将位于两层之间的白色带在缓冲剂中稀释，以40.000×g离心45分钟。将含有质膜的沉淀悬浮在缓冲液中，并在-80℃贮藏直至使用。Plasma membranes were prepared by growing cells to confluence, detaching them from the surface, and resuspending cells in cold buffer (10 mM tris/HCl, pH 7.4, containing 30 mM NaCl, 1 mM dithiothreitol, 5 mg/L leupeptin (Sigma), 5 mg/L pepstatin (Sigma), 100 mg/L bacitracin (Sigma) and 15 mg/L recombinant aprotinin (NovoNordisk A/S)) using Poltron Homogenize twice for 10 sec each with a PT10-35 homogenizer (Kinematica) and centrifuge at 95.000 x g for 75 min over a layer of 41 w/v % sucrose. The white band located between the two layers was diluted in buffer and centrifuged at 40.000 x g for 45 minutes. Plasma membrane-containing pellets were suspended in buffer and stored at -80°C until use.

依据氯胺T法(Hunter和Greenwood，Nature194，495(1962))将胰高血糖素碘化，并用阴离子交换色谱法(Jrgensen等人，Hormoneand Metab.Res.4，223-224(1972)纯化。在碘化当天，比活性是460μCi/μg。将示踪剂以等分试样的方式在-18℃贮藏，融化后立即使用。Glucagon was iodinated according to the Chloramine T method (Hunter and Greenwood, Nature 194, 495 (1962)) and purified by anion exchange chromatography (Jergensen et al., Hormone and Metab. Res. 4, 223-224 (1972)). On the day of iodination, the specific activity was 460 [mu]Ci/[mu]g.The tracer was stored in aliquots at -18[deg.] C. and used immediately after thawing.

在滤器微量滴定板(MADVN65，Millipore)中以一式三份进行结合测定。缓冲液是50mM HEPES，5mM EGTA，5mM MgCl2，0.005％吐温20，pH7.4。将胰高血糖素溶解在0.05MHCl中，加入等量(w/w)人血清白蛋白，并冷冻干燥。在使用的当天，将其溶解在水中，并在缓冲液中稀释至所需浓度。Binding assays were performed in triplicate in filter microtiter plates (MADVN65, Millipore). The buffer was 50 mM HEPES, 5 mM EGTA, 5 mM MgCl 2 , 0.005% Tween 20, pH 7.4. Glucagon was dissolved in 0.05M HCl, an equal amount (w/w) of human serum albumin was added, and lyophilized. On the day of use, dissolve it in water and dilute to the desired concentration in buffer.

将测试化合物溶解并在DMSO中稀释。向各个孔中加入140μL缓冲液、25μL胰高血糖素或缓冲液、和10μLDMSO或测试化合物。将示踪剂(50.000cpm)在缓冲剂中稀释，并向各孔中加入25μL。然后向各孔中加入25μL等分试样的在缓冲液中稀释的1-4μg新融化的质膜蛋白。将平板在30℃培养2小时。用10-6M胰高血糖素测定非特异性结合。然后通过真空过滤(Millipore真空歧管)将结合的示踪剂与未结合的示踪剂分离。用2×100μL缓冲液/孔洗涤平板。将平板风干2小时，之后使用Millipore Puncher将滤器从平板上取下来。将滤器在γ计数器中计数。功能测定(I)Test compounds were dissolved and diluted in DMSO. 140 μL of buffer, 25 μL of glucagon or buffer, and 10 μL of DMSO or test compound were added to each well. Tracer (50.000 cpm) was diluted in buffer and 25 [mu]L was added to each well. A 25 μL aliquot of 1-4 μg of freshly thawed plasma membrane protein diluted in buffer was then added to each well. Plates were incubated at 30°C for 2 hours. Non-specific binding was measured with 10 -6 M glucagon. Bound tracer was then separated from unbound tracer by vacuum filtration (Millipore vacuum manifold). Plates were washed with 2 x 100 [mu]L buffer/well. The plates were air dried for 2 hours, after which the filters were removed from the plates using a Millipore Puncher. The filters are counted in a gamma counter. Functional Assay (I)

在96孔微量滴定板(组织培养板，Nunc)中进行功能测定。在测定中使用的缓冲液是50mM tris/HCl，1mM EGTA，1.5mM MgSO4，1.7mM ATP，20μMGTP，2mM IBMX，0.02％吐温-20和0.1％人血清白蛋白。pH是7.4。加入35μL等分试样的在50 mM tris/HCl，1mMEGTA，1.8mM MgSO4，0.0222％吐温-20和0.111％人血清白蛋白，pH7.4中稀释的胰高血糖素和所测试的拮抗剂。加入20μL50mM tris/HCl，1mM EGTA，1.5mM MgSO4，11.8mM ATP，0.14mM GTP，14mM IBMX和0.1％人血清白蛋白，pH7.4。在临测定前将GTP溶解。Functional assays were performed in 96-well microtiter plates (tissue culture plates, Nunc). The buffer used in the assay was 50 mM tris/HCl, 1 mM EGTA, 1.5 mM MgSO 4 , 1.7 mM ATP, 20 μM GTP, 2 mM IBMX, 0.02% Tween-20 and 0.1% human serum albumin. The pH is 7.4. Add 35 μL aliquots of glucagon diluted in 50 mM tris/HCl, 1 mM GTA, 1.8 mM MgSO 4 , 0.0222% Tween-20 and 0.111% human serum albumin, pH 7.4 and the tested antagonist agent. Add 20 μL of 50 mM tris/HCl, 1 mM EGTA, 1.5 mM MgSO 4 , 11.8 mM ATP, 0.14 mM GTP, 14 mM IBMX and 0.1% human serum albumin, pH 7.4. GTP was dissolved immediately before the assay.

加入在tris/HCl，EGTA，MgSO4，人血清白蛋白缓冲液(实际浓度取决于贮藏的质膜中的蛋白浓度)中的含有5μg质膜蛋白的50μL。50 μL containing 5 μg of plasma membrane protein in tris/HCl, EGTA, MgSO 4 , human serum albumin buffer (actual concentration depends on protein concentration in stored plasma membrane) was added.

总测定体积为140μL。将平板在连续振摇下于37℃培养2小时。通过加入25μL0.5NHCl来终止反应。使用闪烁近似工具(Amersham)测定cAMP。胰高血糖素结合测定(II)The total assay volume was 140 μL. Plates were incubated for 2 hours at 37°C with continuous shaking. The reaction was terminated by adding 25 μL of 0.5N HCl. cAMP was determined using the scintillation approximation tool (Amersham). Glucagon Binding Assay (II)

用人胰高血糖素受体转染BHK(幼仓鼠肾细胞系)细胞，并制备细胞的膜制备物。让含有闪烁剂的小麦胚芽凝集素(Wheat GermAgglutinin)衍生化的SPA珠子(WGA珠子)(Amersham)与膜结合。125I-胰高血糖素与膜中的人胰高血糖素受体结合，并将在WGA珠子中的闪烁剂激发至轻度发射。与受体结合的胰高血糖素或样本与125I-胰高血糖素竞争。BHK (baby hamster kidney cell line) cells were transfected with the human glucagon receptor and membrane preparations of the cells were prepared. Wheat Germ Agglutinin derivatized SPA beads (WGA beads) (Amersham) containing scintillator were bound to the membrane. 125 I-Glucagon binds to the human glucagon receptor in the membrane and excites the scintillator in the WGA beads to a slight emission. Glucagon or sample bound to the receptor competes with125I - glucagon.

膜制备的所有步骤都是在冰上或在4℃进行的。收获BHK细胞并离心。将离心团重悬在匀浆缓冲液(25mM HEPES，pH＝7.4，2.5mMCaCl2，1.0mM MgCl2，250mg/L杆菌肽，0.1mM Pefabloc)中，使用Poltron 10-35匀浆器(Kinematica)匀浆2×10秒，并加入相同量的用于重悬的匀浆缓冲液。离心(以2000×g离心15分钟)后，将上清液转移到冷的离心管中，并以40.000×g离心45分钟。将离心团重悬在匀浆缓冲液中，匀浆2×10秒(Polytron)，再加入匀浆缓冲液。将该悬浮液以40.000×g离心45分钟，将离心团重悬在重悬缓冲液(25mMHEPES，pH＝7.4，2.5mM CaCl2，1.0mM MgCl2)中，并匀浆2×10秒(Polytron)。蛋白浓度一般为约1.75 mg/mL。加入闪烁缓冲液(25mMHEPES，pH＝7.4，2.5mM CaCl2，1.0mM MgCl2，1％牛血清白蛋白，500mg/L杆菌肽，2.5 M蔗糖)，并将膜制备物在-80℃贮藏。All steps of membrane preparation were performed on ice or at 4 °C. BHK cells were harvested and centrifuged. The pellet was resuspended in homogenization buffer (25 mM HEPES, pH=7.4, 2.5 mM CaCl 2 , 1.0 mM MgCl 2 , 250 mg/L bacitracin, 0.1 mM Pefabloc) using a Poltron 10-35 homogenizer (Kinematica) Homogenize 2 x 10 sec and add the same amount of homogenization buffer used for resuspension. After centrifugation (15 min at 2000 x g), the supernatant was transferred to a cold centrifuge tube and centrifuged at 40.000 x g for 45 min. The pellet was resuspended in homogenization buffer, homogenized 2 x 10 sec (Polytron), and homogenization buffer was added. The suspension was centrifuged at 40.000×g for 45 minutes, the pellet was resuspended in resuspension buffer (25 mM HEPES, pH=7.4, 2.5 mM CaCl 2 , 1.0 mM MgCl 2 ), and homogenized 2×10 seconds (Polytron ). The protein concentration is typically about 1.75 mg/mL. Scintillation buffer (25 mM HEPES, pH = 7.4, 2.5 mM CaCl 2 , 1.0 mM MgCl 2 , 1% bovine serum albumin, 500 mg/L bacitracin, 2.5 M sucrose) was added and membrane preparations were stored at -80°C.

在opti板(聚苯乙烯微板，Packard)中进行胰高血糖素结合测定。向每个孔中加入50μL测定缓冲液(25 mM HEPES，pH＝7.5，2.5mM CaCl2，1.0mM MgCl2，0.003％吐温-20，0.005％杆菌肽，0.05％叠氮化钠)和5μL胰高血糖素或测试化合物(在DMSO中)。然后向孔中加入50μL示踪剂(125I-猪胰高血糖素，50.000cpm)和含有人胰高血糖素受体的50μL膜(7.5μg)。最后将含有1 mg珠子的50μLWGA珠子转移到孔中。将opti板在摇动器上培养4小时，然后静置8-48小时。将opti板在Topcounter中计数。用500nM胰高血糖素测定非特异性结合。Glucagon binding assays were performed in opti plates (polystyrene microplates, Packard). To each well, add 50 μL of assay buffer (25 mM HEPES, pH=7.5, 2.5 mM CaCl 2 , 1.0 mM MgCl 2 , 0.003% Tween-20, 0.005% bacitracin, 0.05% sodium azide) and 5 μL Glucagon or test compound (in DMSO). Then 50 μL of tracer ( 125 I-porcine glucagon, 50.000 cpm) and 50 μL of membrane containing human glucagon receptor (7.5 μg) were added to the wells. Finally transfer 50 μL of WGA beads containing 1 mg of beads to the wells. Opti plates were incubated on a shaker for 4 hours and then left to rest for 8-48 hours. The opti plates were counted in Topcounter. Non-specific binding was determined with 500 nM glucagon.

实施例的化合物表现出的IC50值低于1500nM，并且当在胰高血糖素结合测定(II)中测试时，它们当中有很多低于250nM。GIP结合测定The compounds of the examples exhibited IC50 values below 1500 nM and many of them were below 250 nM when tested in the glucagon binding assay (II). GIP binding assay

用人GIP受体转染BHK(幼仓鼠肾细胞系)细胞，并制备细胞的膜制备物。让含有闪烁剂的小麦胚芽凝集素衍生化的SPA珠子(WGA珠子)(Amersham)与膜结合。让125I-GIP与膜中的人GIP受体结合，将在WGA珠子中的闪烁剂激发至轻度发射。与受体结合的GIP或样本与125I-GIP竞争。BHK (baby hamster kidney cell line) cells were transfected with the human GIP receptor and membrane preparations of the cells were prepared. Wheat germ agglutinin derivatized SPA beads containing scintillant (WGA beads) (Amersham) were bound to the membrane. Allowing125I -GIP to bind to the human GIP receptor in the membrane excites the scintillator in the WGA beads to a slight emission. GIP or sample bound to the receptor competes with125I -GIP.

膜制备的所有步骤都是在冰上或在4℃进行的。收获BHK细胞并离心。将离心团重悬在匀浆缓冲液(25mM HEPES，pH＝7.4，2.5mMCaCl2，1.0mM MgCl2，250mg/L杆菌肽，0.1mM Pefabloc)中，使用Poltron 10-35匀浆器(Kinematica)匀浆2×10秒，并加入相同量的用于重悬的匀浆缓冲液。离心(以2000×g离心15分钟)后，将上清液转移到冷的离心管中，并以40.000×g离心45分钟。将离心团重悬在匀浆缓冲液中，匀浆2×10秒(Polytron)，再加入匀浆缓冲液。将该悬浮液以40.000×g离心45分钟，将离心团重悬在重悬缓冲液(25mMHEPES，pH＝7.4，2.5mM CaCl2，1.0mM MgCl2)中，并匀浆2×10秒(Polytron)。蛋白浓度一般为约1.75mg/mL。加入稳定化缓冲液(25mMHEPES，pH＝7.4，2.5mM CaCl2，1.0mM MgCl2，1％牛血清白蛋白，500mg/L杆菌肽，2.5M蔗糖)，并将膜制备物在-80℃贮藏。All steps of membrane preparation were performed on ice or at 4°C. BHK cells were harvested and centrifuged. The pellet was resuspended in homogenization buffer (25 mM HEPES, pH=7.4, 2.5 mM CaCl 2 , 1.0 mM MgCl 2 , 250 mg/L bacitracin, 0.1 mM Pefabloc) using a Poltron 10-35 homogenizer (Kinematica) Homogenize 2 x 10 sec and add the same amount of homogenization buffer used for resuspension. After centrifugation (15 min at 2000 x g), the supernatant was transferred to a cold centrifuge tube and centrifuged at 40.000 x g for 45 min. The pellet was resuspended in homogenization buffer, homogenized 2 x 10 sec (Polytron), and homogenization buffer was added. The suspension was centrifuged at 40.000×g for 45 minutes, the pellet was resuspended in resuspension buffer (25 mM HEPES, pH=7.4, 2.5 mM CaCl 2 , 1.0 mM MgCl 2 ), and homogenized 2×10 seconds (Polytron ). The protein concentration is typically about 1.75 mg/mL. Stabilization buffer (25 mM HEPES, pH=7.4, 2.5 mM CaCl 2 , 1.0 mM MgCl 2 , 1% bovine serum albumin, 500 mg/L bacitracin, 2.5 M sucrose) was added and the membrane preparation was stored at -80°C .

在opti板(聚苯乙烯微板，Packard)中进行GIP结合测定。向每个孔中加入50测定缓冲液(25 mM HEPES，pH＝7.5，2.5mM CaCl2，1.0mM MgCl2，0.003％吐温-20，0.005％杆菌肽，0.05％叠氮化钠)和5μLGIP或测试化合物(在DMSO中)。然后向孔中加入50μL示踪剂(125I-猪GIP，50.000cpm)和含有人GIP受体的50μL膜(20μg)。最后将含有1mg珠子的50μLWGA珠子转移到孔中。将opti板在摇动器上培养3.5小时，然后静置8-48小时。将opti板在Topcounter中计数。用500nM GIP测定非特异性结合。GIP binding assays were performed in opti plates (polystyrene microplates, Packard). Add 50 μL of assay buffer (25 mM HEPES, pH=7.5, 2.5 mM CaCl 2 , 1.0 mM MgCl 2 , 0.003% Tween-20, 0.005% bacitracin, 0.05% sodium azide) and 5 μL of GIP or test compound (in DMSO). Then 50 μL of tracer ( 125 I-porcine GIP, 50.000 cpm) and 50 μL of membrane containing human GIP receptor (20 μg) were added to the wells. Finally transfer 50 μL of WGA beads containing 1 mg of beads to the wells. Opti plates were incubated on a shaker for 3.5 hrs and then left to rest for 8-48 hrs. The opti plates were counted in Topcounter. Non-specific binding was determined with 500 nM GIP.

Claims (71)

1.通式(I)化合物： 1. Compounds of general formula (I): 其中R1、R2、R3、R4和R5独立地为氢或C1-6-烷基，wherein R 1 , R 2 , R 3 , R 4 and R 5 are independently hydrogen or C 1-6 -alkyl, A是-C(O)-、-CH(OR6)-或-CHF-，A is -C(O)-, -CH(OR 6 )- or -CHF-, 其中R6是氢或C1-6-烷基，wherein R 6 is hydrogen or C 1-6 -alkyl, Z是亚芳基或衍生自含有1或2个选自氮、氧和硫的杂原子的5或6元杂芳环的二价基团，其可任选被1或2个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR9、-NR9R10和C1-6-烷基的R7和R8取代，Z is an arylene group or a divalent group derived from a 5- or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, optionally replaced by 1 or 2 heteroatoms selected from halogen, R 7 and R 8 substitution of -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 9 , -NR 9 R 10 and C 1-6 -alkyl, 其中R9和R10独立地为氢或C1-6-烷基，wherein R 9 and R 10 are independently hydrogen or C 1-6 -alkyl, X是-(CH2)q-(CR12R13)r-(CH2)s-  ，
Figure A0181159100022
Figure A0181159100023
Figure A0181159100025
或
Figure A0181159100026
其中r是0或1，q和s独立地为0、1、2或3，R11、R12、R13和R14独立地为氢、C1-6-烷基或C3-8环烷基，D是 或其中R15、R16、R17和R18独立地为·氢、卤素、-CN，-CHF2，-CF3，-OCF3，-OCHF2，-OCH2CF3，-OCF2CHF2，-S(O)2CF3，-SCF3，-NO2，-OR21，-NR21R22，-SR21，-NR21S(O)2R22，-S(O)2NR21R22，-S(O)NR21R22，-S(O)R21，-S(O)2R21，-C(O)NR21R22，-OC(O)NR21R22，-NR21C(O)R22，-CH2C(O)NR21R22，-OCH2C(O)NR21R22-OC(O)R21，-C(O)R21或-C(O)OR21，或-C(O)OR21，X is -(CH 2 ) q -(CR 12 R 13 ) r -(CH 2 ) s -,
Figure A0181159100022
Figure A0181159100023
Figure A0181159100025
or
Figure A0181159100026
wherein r is 0 or 1, q and s are independently 0, 1, 2 or 3, R 11 , R 12 , R 13 and R 14 are independently hydrogen, C 1-6 -alkyl or C 3-8 ring Alkyl, D is or wherein R 15 , R 16 , R 17 and R 18 are independently hydrogen, halogen, -CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3 , -SCF 3 , -NO 2 , -OR 21 , -NR 21 R 22 , -SR 21 , -NR 21 S(O) 2 R 22 , -S(O) 2 NR 21 R 22 , -S(O)NR 21 R 22 , -S(O)R 21 , -S(O) 2 R 21 , -C(O)NR 21 R 22 , -OC(O)NR 21 R 22 , -NR 21 C(O)R 22 , -CH 2 C(O)NR 21 R 22 , -OCH 2 C(O)NR 21 R 22 -OC(O)R 21 , -C(O)R 21 or -C(O)OR 21 , or -C(O)OR 21 , ·C1-6-烷基、C2-6-链烯基或C2-6炔基，所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR21、-NR21R22和C1-6-烷基的取代基取代，· C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 alkynyl, which may optionally be replaced by one or more selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 21 , -NR 21 R 22 and C 1-6 -alkyl substituents, ·C3-8环烷基、C4-8-环烯基、杂环基、C3-8环烷基-C1-6-烷基、C3-8-环烷基-C1-6-烷氧基、C3-8环烷氧基、C3-8环烷基-C1-6-烷硫基、C3-8-环烷硫基、C3-8-环烷基-C2-6链烯基、C3-8环烷基-C2-6-炔基、C4-8-环烯基-C1-6-烷基、C4-8-环烯基-C2-6-链烯基、C4-8-环烯基-C2-6炔基、杂环基-C1-6-烷基、杂环基-C2-6-链烯基、杂环基-C2-6-炔基、芳基、芳氧基、芳氧基羰基、芳酰基、芳基-C1-6-烷氧基、芳基-C1-6-烷基、芳基-C2-6-链烯基、芳基-C2-6炔基、杂芳基、杂芳基-C1-6烷基、杂芳基-C2-6-链烯基或杂芳基-C2-6-炔基，· C 3-8 cycloalkyl, C 4-8 -cycloalkenyl, heterocyclyl, C 3-8 cycloalkyl-C 1-6 -alkyl, C 3-8 -cycloalkyl-C 1- 6 -Alkoxy, C 3-8 cycloalkoxy, C 3-8 cycloalkyl-C 1-6 -alkylthio, C 3-8 -cycloalkylthio, C 3-8 -cycloalkyl -C 2-6 alkenyl, C 3-8 cycloalkyl-C 2-6 -alkynyl, C 4-8 -cycloalkenyl-C 1-6 -alkyl, C 4-8 -cycloalkenyl -C 2-6 -alkenyl, C 4-8 -cycloalkenyl-C 2-6 alkynyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl , heterocyclyl-C 2-6 -alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C 1-6 -alkoxy, aryl-C 1-6 -alkyl , aryl-C 2-6 -alkenyl, aryl-C 2-6 alkynyl, heteroaryl, heteroaryl-C 1-6 alkyl, heteroaryl-C 2-6 -alkenyl or heteroaryl-C 2-6 -alkynyl, 其中所述环部分可任选被一个或多个选自卤素、-C(O)OR21、-CN、-CF3、-OCF3、-NO2、-OR21、-NR21R22和C1-6-烷基的取代基取代，Wherein the ring moiety can be optionally replaced by one or more selected from halogen, -C(O)OR 21 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 21 , -NR 21 R 22 and Substitution of C 1-6 -alkyl substituents, 其中R21和R22独立地为氢、C1-6-烷基、芳基-C1-6-烷基或芳基，wherein R 21 and R 22 are independently hydrogen, C 1-6 -alkyl, aryl-C 1-6 -alkyl or aryl, 或者当连接在同一氮原子上时，R21和R22与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环，Or when attached to the same nitrogen atom, R 21 and R 22 and said nitrogen atom may together form an additional heteroatom optionally containing 1 or 2 selected from nitrogen, oxygen and sulfur, and optionally containing 1 or 2 A 3-8 membered heterocycle with a double bond, 或者当处于相邻位置时，R15-R18中的两个基团可一起形成桥基团-(CR23R24)a-O-(CR25R26)c-O-，Or when they are in adjacent positions, two groups in R 15 -R 18 can form together a bridging group -(CR 23 R 24 ) a -O-(CR 25 R 26 ) c -O-, 其中in a是0、1或2，a is 0, 1 or 2, c是1或2，c is 1 or 2, R23、R24、R25和R26独立地为氢、C1-6-烷基或氟，R 23 , R 24 , R 25 and R 26 are independently hydrogen, C 1-6 -alkyl or fluoro, R19和R20独立地为氢、C1-6-烷基、C3-8-环烷基或C3-8-环烷基-C1-6-烷基，R 19 and R 20 are independently hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or C 3-8 -cycloalkyl-C 1-6 -alkyl, E是
Figure A0181159100042
或 E is
Figure A0181159100042
or 其中R27和R28独立地为氢、卤素、-CN、-CF3、-OR32、-NR32R33、C1-6-烷基、C3-8-环烷基、C4-8-环烯基或芳基，wherein R 27 and R 28 are independently hydrogen, halogen, -CN, -CF 3 , -OR 32 , -NR 32 R 33 , C 1-6 -alkyl, C 3-8 -cycloalkyl, C 4- 8 -cycloalkenyl or aryl, 其中所述芳基可任选被一个或多个选自卤素、-CN、-CF3、-NO2、-OR32、-NR32R33和C1-6-烷基的取代基取代，wherein said aryl group can be optionally substituted by one or more substituents selected from halogen, -CN, -CF 3 , -NO 2 , -OR 32 , -NR 32 R 33 and C 1-6 -alkyl, 其中R32和R33独立地为氢或C1-6-烷基，wherein R 32 and R 33 are independently hydrogen or C 1-6 -alkyl, 或者当连接在同一氮原子上时，R32和R33与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环，Or when attached to the same nitrogen atom, R 32 and R 33 and said nitrogen atom may together form an additional heteroatom optionally containing 1 or 2 selected from nitrogen, oxygen and sulfur, and optionally containing 1 or 2 A 3-8 membered heterocycle with a double bond, R29、R30和R31独立地为R 29 , R 30 and R 31 are independently ■氢、卤素、-CHF2，-CF3，-OCF3，-OCHF2，-OCH2CF3，-OCF2CHF2，-SCF3，-OR34，-NR34R35，-SR34，-S(O)R34，-S(O)2R34 ，-C(O)NR34R35，-OC(O)NR34R35，-NR34C(O)R35，-OCH2C(O)NR34R35，-C(O)R34或-C(O)OR34，■Hydrogen, Halogen, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -SCF 3 , -OR 34 , -NR 34 R 35 , -SR 34 , -S(O)R 34 , -S(O) 2 R34 , -C(O)NR 34 R 35 , -OC(O)NR 34 R 35 , -NR 34 C(O)R 35 , -OCH 2 C(O)NR 34 R 35 , -C(O)R 34 or -C(O)OR 34 , ■C1-6-烷基、C2-6-链烯基或C2-6-炔基，C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl, 所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，Said groups may be optionally substituted with one or more selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl base substitution, ■C3-8-环烷基、C4-8-环烯基、杂环基、C3-8环烷基-C1-6-烷基、C3-8-环烷基-C2-6-链烯基、C3-8-环烷基-C2-6-炔基、C4-8-环烯基-C1-6-烷基、C4-8-环烯基-C2-6-链烯基、C4-8-环烯基-C2-6-炔基、杂环基-C1-6-烷基、杂环基-C2-6-链烯基、杂环基-C2-6-炔基、芳基、芳氧基、芳酰基、芳基-C1-6-烷氧基、芳基-C1-6-烷基、芳基-C2-6-链烯基、芳基-C2-6-炔基、杂芳基、杂芳基-C1-6-烷基、杂芳基-C2-6-链烯基或杂芳基-C2-6-炔基，■C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl, heterocyclyl, C 3-8 cycloalkyl-C 1-6 -alkyl, C 3-8 -cycloalkyl-C 2 -6 -alkenyl, C 3-8 -cycloalkyl-C 2-6 -alkynyl, C 4-8 -cycloalkenyl-C 1-6 -alkyl, C 4-8 -cycloalkenyl- C 2-6 -alkenyl, C 4-8 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl , heterocyclyl-C 2-6 -alkynyl, aryl, aryloxy, aroyl, aryl-C 1-6 -alkoxy, aryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, aryl- C2-6 -alkynyl, heteroaryl, heteroaryl- C1-6 -alkyl, heteroaryl- C2-6 -alkenyl or heteroaryl Base-C 2-6 -alkynyl, 其中所述环部分可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，Wherein said ring moiety can be optionally replaced by one or more selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl substituent substitution, 其中R34和R35独立地为氢、C1-6-烷基或芳基，wherein R 34 and R 35 are independently hydrogen, C 1-6 -alkyl or aryl, 或者当连接在同一氮原子上时，R34和R35与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环，Or when attached to the same nitrogen atom, R34 and R35 and said nitrogen atom may together form optionally containing 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing 1 or 2 A 3-8 membered heterocycle with a double bond, 或者当连接在同一环碳原子或不同的环碳原子上时，R29、R30和R31当中的两个基团可一起形成基团-O-(CH2)t-CR36R37-(CH2)l-O-、-(CH2)t-CR36R37-(CH2)l-或-S-(CH2)t-CR36R37-(CH2)l-S-，Or when connected to the same ring carbon atom or different ring carbon atoms, two groups among R 29 , R 30 and R 31 may together form the group -O-(CH 2 ) t -CR 36 R 37 - (CH 2 ) l -O-, -(CH 2 ) t -CR 36 R 37 -(CH 2 ) l -or -S-(CH 2 ) t -CR 36 R 37 -(CH 2 ) l -S- , 其中t和l独立地为0、1、2、3、4或5，wherein t and l are independently 0, 1, 2, 3, 4 or 5, R36和R37独立地为氢或C1-6-烷基，R 36 and R 37 are independently hydrogen or C 1-6 -alkyl, 以及通式(I)化合物的旋光或几何异构体或互变异构形式，包括这些异构体或互变异构形式的混合物，或它们的可药用盐。And optical or geometric isomers or tautomeric forms of the compound of general formula (I), including mixtures of these isomers or tautomeric forms, or their pharmaceutically acceptable salts. 2.权利要求1的化合物，其中R1、R2、R3、R4和R5是氢。2. The compound of claim 1, wherein R1 , R2 , R3 , R4 and R5 are hydrogen. 3.权利要求1或2的化合物，其中A是-CHF-。3. The compound of claim 1 or 2, wherein A is -CHF-. 4.权利要求1或2的化合物，其中A是-CH(OR6)-，其中R6如权利要求1中所定义。4. The compound of claim 1 or 2, wherein A is -CH( OR6 )-, wherein R6 is as defined in claim 1 . 5.权利要求4的化合物，其中A是-CH(OH)-。5. The compound of claim 4, wherein A is -CH(OH)-. 6.前述权利要求任一项的化合物，其中Z是
Figure A0181159100061
其中R7和R8如权利要求1中所定义。6. The compound of any one of the preceding claims, wherein Z is
Figure A0181159100061
wherein R7 and R8 are as defined in claim 1. 7.权利要求6的化合物，其中Z是 7. The compound of claim 6, wherein Z is 8.前述权利要求任一项的化合物，其中X是 -(CH2)s-，
Figure A0181159100073
Figure A0181159100074
或 8. The compound of any one of the preceding claims, wherein X is -( CH2 ) s- ,
Figure A0181159100073
Figure A0181159100074
or 其中q是0或1，r是0或1，s是0、1或2，且R12和R13独立地为氢或C1-6-烷基。wherein q is 0 or 1, r is 0 or 1, s is 0, 1 or 2, and R 12 and R 13 are independently hydrogen or C 1-6 -alkyl. 9.权利要求8的化合物，其中X是-C(O)NH-、-C(O)NHCH2-、-C(O)NHCH(CH3)-、-C(O)NHC(CH3)2-、-C(O)NHCH2CH2-、-C(O)CH2-、-C(O)CH2CH2-、-C(O)CH＝CH-、-(CH2)s-、-C(O)-、-C(O)O-或-NHC(O)-，其中s是0或1。9. The compound of claim 8, wherein X is -C(O)NH-, -C(O) NHCH2- , -C(O)NHCH( CH3 )-, -C(O)NHC( CH3 ) 2 -, -C(O)NHCH 2 CH 2 -, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -C(O)CH=CH-, -(CH 2 ) s -, -C(O)-, -C(O)O- or -NHC(O)-, wherein s is 0 or 1 . 10.权利要求9的化合物，其中X是-C(O)NH-、-C(O)NHCH2-、-C(O)NHCH(CH3)-、-C(O)NHCH2CH2-、-C(O)CH2-、-C(O)CH＝CH-、-(CH2)s-、-C(O)-、-C(O)O-或-NHC(O)-，其中s是0或1。10. The compound of claim 9, wherein X is -C(O)NH-, -C(O) NHCH2- , -C(O)NHCH( CH3 )-, -C( O ) NHCH2CH2- , -C(O)CH 2 -, -C(O)CH=CH-, -(CH 2 ) s -, -C(O)-, -C(O)O- or -NHC(O)-, where s is 0 or 1. 11.权利要求1 0的化合物，其中X是-C(O)NH-、-C(O)NHCH2-、-C(O)NHCH(CH3)-、-C(O)NHCH2CH2-、-C(O)CH2-、-CH2-、-C(O)-或-NHC(O)-。11. The compound of claim 10, wherein X is -C(O)NH-, -C(O) NHCH2- , -C(O)NHCH( CH3 )-, -C( O ) NHCH2CH2 -, -C(O) CH2- , -CH2- , -C(O)- or -NHC(O)-. 12.权利要求11的化合物，其中X是-C(O)NH-、-C(O)NHCH2-、-C(O)NHCH(CH3)-、-C(O)CH2-或-C(O)-。12. The compound of claim 11, wherein X is -C(O)NH-, -C(O) NHCH2- , -C(O)NHCH( CH3 )-, -C(O) CH2- or - C(O)-. 13.权利要求12的化合物，其中X是-C(O)NH-。13. The compound of claim 12, wherein X is -C(O)NH-. 14.前述权利要求任一项的化合物，其中D是
Figure A0181159100081
或 其中R15、R16、R17、R18、R19和R29如权利要求1中所定义。14. The compound of any one of the preceding claims, wherein D is
Figure A0181159100081
or wherein R 15 , R 16 , R 17 , R 18 , R 19 and R 29 are as defined in claim 1. 15.权利要求14的化合物，其中D是其中R15、R16和R17如权利要求1中所定义。15. The compound of claim 14, wherein D is wherein R 15 , R 16 and R 17 are as defined in claim 1 . 16.权利要求14或15的化合物，其中R15、R16和R17独立地为氢、卤素、-CN、-NO2、-CF3、-OCF3-、-SCF3、C1-6-烷基、C1-6-烷氧基、-S-C1-6-烷基、-C(O)OR21、-C(O)R21、-CH2OR21、-C(O)NR21R22、-S(O)R21、-S(O)2R21、-S(O)2CF3、-S(O)2NR21R22、C3-8-环烷基、C3-8-环烷基-C1-6-烷氧基或C3-8-环烷基-C1-6-烷硫基，或16. The compound of claim 14 or 15, wherein R 15 , R 16 and R 17 are independently hydrogen, halogen, -CN, -NO 2 , -CF 3 , -OCF 3 -, -SCF 3 , C 1-6 -Alkyl, C 1-6 -Alkoxy, -SC 1-6 -Alkyl, -C(O)OR 21 , -C(O)R 21 , -CH 2 OR 21 , -C(O)NR 21 R 22 , -S(O)R 21 , -S(O) 2 R 21 , -S(O) 2 CF 3 , -S(O) 2 NR 21 R 22 , C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkoxy or C 3-8 -cycloalkyl-C 1-6 -alkylthio, or 芳基、杂芳基或芳氧基，其中所述基团可任选被-CF3、-OCF3、C1-6-烷基、卤素或-C(O)OR21取代，Aryl, heteroaryl or aryloxy, wherein said groups may optionally be substituted by -CF 3 , -OCF 3 , C 1-6 -alkyl, halogen or -C(O)OR 21 , 或者当处于相邻位置时，R15、R16和R17当中的两个基团可一起形成桥基团-(CR23R24)a-O-(CR25R26)c-O-，Or when in adjacent positions, two groups among R 15 , R 16 and R 17 can together form a bridging group -(CR 23 R 24 ) a -O-(CR 25 R 26 ) c -O-, 其中R21和R22独立地为氢或C1-6-烷基，且a、c、R23、R24、R25和R26如权利要求1中所定义。wherein R 21 and R 22 are independently hydrogen or C 1-6 -alkyl, and a, c, R 23 , R 24 , R 25 and R 26 are as defined in claim 1 . 17.权利要求16的化合物，其中R15、R16和R17独立地为氢、卤素、-CN、-CF3、-OCF3或C1-6-烷氧基，或者R15和R16一起形成桥基团-CF2-O-CF2-O-，且R17是氢。17. The compound of claim 16, wherein R 15 , R 16 and R 17 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3 or C 1-6 -alkoxy, or R 15 and R 16 together form a bridging group -CF2 -O- CF2 -O-, and R17 is hydrogen. 18.权利要求17的化合物，其中R15、R16和R17独立地为氢、卤素、-CN、-CF3、-OCF3或C1-6-烷氧基。18. The compound of claim 17, wherein R15 , R16 and R17 are independently hydrogen, halogen, -CN, -CF3 , -OCF3 or C1-6 -alkoxy. 19.权利要求14的化合物，其中D是
Figure A0181159100091
或 其中R15、R16、R19和R20如权利要求1中所定义。19. The compound of claim 14, wherein D is
Figure A0181159100091
or wherein R 15 , R 16 , R 19 and R 20 are as defined in claim 1 . 20.权利要求19的化合物，其中D是 20. The compound of claim 19, wherein D is 其中R15和R16都是氢，且R19是C1-6-烷基、C3-8-环烷基或C3-8-环烷基-C1-6-烷基。wherein R 15 and R 16 are both hydrogen and R 19 is C 1-6 -alkyl, C 3-8 -cycloalkyl or C 3-8 -cycloalkyl-C 1-6 -alkyl. 21.权利要求19的化合物，其中D是其中R15和R16都是氢，且R19和R20都是C1-6-烷基。21. The compound of claim 19, wherein D is wherein R 15 and R 16 are both hydrogen, and R 19 and R 20 are both C 1-6 -alkyl. 22.前述权利要求任一项的化合物，其中E
Figure A0181159100101
或
Figure A0181159100103
其中R27、R28、R29、R30和R31如权利要求1中所定义。22. The compound of any one of the preceding claims, wherein E
Figure A0181159100101
or
Figure A0181159100103
wherein R 27 , R 28 , R 29 , R 30 and R 31 are as defined in claim 1. 23.权利要求22的化合物，其中E是其中R27和R28如权利要求1中所定义。23. The compound of claim 22, wherein E is wherein R27 and R28 are as defined in claim 1. 24.权利要求23的化合物，其中E是其中R27和R28如权利要求1中所定义。24. The compound of claim 23, wherein E is wherein R27 and R28 are as defined in claim 1. 25.权利要求23或24的化合物，其中R27和R28独立地为氢、C1-6-烷基、C3-8-环烷基、C4-8-环烯基或苯基，其中苯基任选如权利要求1所述被取代。25. The compound of claim 23 or 24, wherein R 27 and R 28 are independently hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl or phenyl, wherein the phenyl group is optionally substituted as described in claim 1. 26.权利要求25的化合物，其中R27和R28独立地为氢、C1-6-烷基、C3-8-环烷基或C4-8-环烯基。26. The compound of claim 25, wherein R 27 and R 28 are independently hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl. 27.权利要求26的化合物，其中R27是氢，且R28是C1-6-烷基、C3-8-环烷基或C4-8-环烯基。27. The compound of claim 26, wherein R 27 is hydrogen and R 28 is C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl. 28.权利要求27的化合物，其中R27是氢，且R28是C1-6-烷基或C3-8-环烷基。28. The compound of claim 27, wherein R 27 is hydrogen and R 28 is C 1-6 -alkyl or C 3-8 -cycloalkyl. 29.权利要求22的化合物，其中E是其中R29、R30和R31如权利要求1中所定义。29. The compound of claim 22, wherein E is wherein R 29 , R 30 and R 31 are as defined in claim 1. 30.权利要求29的化合物，其中E是其中R29、R30和R31如权利要求1中所定义。30. The compound of claim 29, wherein E is wherein R 29 , R 30 and R 31 are as defined in claim 1. 31.权利要求29或30的化合物，其中R29、R30和R31独立地为31. The compound of claim 29 or 30, wherein R 29 , R 30 and R 31 are independently ■氢、-CHF2，-CF3，-OCF3，-OCHF2，-OCH2CF3，-OCF2CHF2，-SCF3，-OR34，-NR34R35，-SR34，-S(O)R34，-S(O)2R34，-C(O)NR34R35，-OC(O)NR34R35，-NR34C(O)R35，-OCH2C(O)NR34R35，-C(O)R34或-C(O)OR34，Hydrogen, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -SCF 3 , -OR 34 , -NR 34 R 35 , -SR 34 , - S(O)R 34 , -S(O) 2 R 34 , -C(O)NR 34 R 35 , -OC(O)NR 34 R 35 , -NR 34 C(O)R 35 , -OCH 2 C (O)NR 34 R 35 , -C(O)R 34 or -C(O)OR 34 , ■C1-6-烷基、C2-6-链烯基或C2-6-炔基，其中所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，■C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl, wherein said group can optionally be selected by one or more selected from halogen, -CN, -CF 3 , Substituents of -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl, ■C3-8环烷基或C4-8-环烯基，其中所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的基团取代，■ C 3-8 cycloalkyl or C 4-8 -cycloalkenyl, wherein said group can be optionally replaced by one or more selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl group substitution, 其中R34和R35独立地为氢、C1-6-烷基或芳基，wherein R 34 and R 35 are independently hydrogen, C 1-6 -alkyl or aryl, 或者当连接在同一氮原子上时，R34和R35与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环。Or when attached to the same nitrogen atom, R34 and R35 and said nitrogen atom may together form optionally containing 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing 1 or 2 A 3-8 membered heterocycle with a double bond. 32.权利要求31的化合物，其中R29、R30和R31独立地为氢、C1-6-烷氧基、卤素、-CF3、-OCF3或-NR34R35，其中R34和R35如权利要求1中所定义，或32. The compound of claim 31, wherein R 29 , R 30 and R 31 are independently hydrogen, C 1-6 -alkoxy, halogen, -CF 3 , -OCF 3 or -NR 34 R 35 , wherein R 34 and R 35 as defined in claim 1, or C1-6-烷基、C3-8-环烷基或C4-8-环烯基，所述基团任选如权利要求1所述被取代。C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl, optionally substituted as claimed in claim 1 . 33.权利要求32的化合物，其中R29、R30和R31独立地为33. The compound of claim 32, wherein R 29 , R 30 and R 31 are independently 氢或hydrogen or C1-6-烷基、C3-8-环烷基或C4-8-环烯基，所述基团任选如权利要求1所述被取代。C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl, optionally substituted as claimed in claim 1 . 34.权利要求32的化合物，其中R29、R30和R31独立地为34. The compound of claim 32, wherein R 29 , R 30 and R 31 are independently 氢或hydrogen or C1-6-烷基、C3-8-环烷基或C4-8环烯基，C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 cycloalkenyl, ■所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，■The group can optionally be replaced by one or more selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl substituent substitution, ■其中R34和R35独立地为氢、C1-6烷基或芳基，■wherein R 34 and R 35 are independently hydrogen, C 1-6 alkyl or aryl, ■或者当连接在同一氮原子上时，R34和R35与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环。or when attached to the same nitrogen atom, R34 and R35 and said nitrogen atom may together form optionally containing 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing 1 or 3-8 membered heterocyclic ring with 2 double bonds. 35.权利要求34的化合物，其中R29和R31都是氢，且R30不是氢。35. The compound of claim 34, wherein R 29 and R 31 are both hydrogen, and R 30 is not hydrogen. 36.权利要求34的化合物，其中R29和R31都是氢，且R30是C3-8-环烷基或C4-8-环烯基，36. The compound of claim 34, wherein R 29 and R 31 are both hydrogen, and R 30 is C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl, ■所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，■The group can optionally be replaced by one or more selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl substituent substitution, ■其中R34和R35独立地为氢、C1-6-烷基或芳基，■ wherein R 34 and R 35 are independently hydrogen, C 1-6 -alkyl or aryl, ■或者当连接在同一氮原子上时，R34和R35与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环。or when attached to the same nitrogen atom, R34 and R35 and said nitrogen atom may together form optionally containing 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing 1 or 3-8 membered heterocyclic ring with 2 double bonds. 37.权利要求36的化合物，其中R29和R31都是氢，且R30是C4-8-环烯基，37. The compound of claim 36, wherein R 29 and R 31 are hydrogen, and R 30 is C 4-8 -cycloalkenyl, ■所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，■The group can optionally be replaced by one or more selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl substituent substitution, ■其中R34和R35独立地为氢、C1-6-烷基或芳基，■ wherein R 34 and R 35 are independently hydrogen, C 1-6 -alkyl or aryl, ■或者当连接在同一氮原子上时，R34和R35与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环。or when attached to the same nitrogen atom, R34 and R35 and said nitrogen atom may together form optionally containing 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing 1 or 3-8 membered heterocyclic ring with 2 double bonds. 38.权利要求37的化合物，其中R29和R31都是氢，且R30是环己烯基，38. The compound of claim 37, wherein R 29 and R 31 are both hydrogen, and R 30 is cyclohexenyl, ■所述基团可任选被一个或多个选自卤素、-CN、-CF3、-OCF3、-NO2、-OR34、-NR34R35和C1-6-烷基的取代基取代，■The group can optionally be replaced by one or more selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl substituent substitution, ■其中R34和R35独立地为氢、C1-6-烷基或芳基，■ wherein R 34 and R 35 are independently hydrogen, C 1-6 -alkyl or aryl, ■或者当连接在同一氮原子上时，R34和R35与所述氮原子可一起形成任选含有1或2个选自氮、氧和硫的另外的杂原子、并任选含有1或2个双键的3-8元杂环。or when attached to the same nitrogen atom, R34 and R35 and said nitrogen atom may together form optionally containing 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing 1 or 3-8 membered heterocyclic ring with 2 double bonds. 39.权利要求37或38的化合物，其中R30被一个C1-6-烷基取代基取代。39. The compound according to claim 37 or 38, wherein R30 is substituted by a C1-6 -alkyl substituent. 40.权利要求33的化合物，其中R29、R30和R31独立地为氢、C1-6-烷基、C3-8-环烷基或C4-8-环烯基。40. The compound of claim 33, wherein R 29 , R 30 and R 31 are independently hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl. 41.权利要求40的化合物，其中R29和R31都是氢，且R30是C1-6-烷基、C3-8-环烷基或C4-8-环烯基。41. The compound of claim 40, wherein R 29 and R 31 are both hydrogen, and R 30 is C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl. 42.权利要求1的化合物，其具有通式(I1)： 42. The compound of claim 1 having the general formula (I 1 ): 其中R1、R2、R3、R4、R5、R6、R7、R8、X、D和E如权利要求1或任一前述权利要求中所定义。wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, D and E are as defined in claim 1 or any preceding claim. 43.权利要求1的通式(I2)化合物： 43. The compound of general formula ( I2 ) according to claim 1: 其中R1、R2、R3、R4、R5、R6、R7、R8、D和E如权利要求1或任一前述权利要求中所定义。wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , D and E are as defined in claim 1 or any preceding claim. 44.权利要求1的化合物，其具有通式(I3)： 44. The compound of claim 1 having the general formula ( I3 ): 其中R1、R2、R3、R4、R5、R6、R7、R8、R15、R16、R17、R29、R30、和R31如权利要求1或任一前述权利要求中所定义。Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 15 , R 16 , R 17 , R 29 , R 30 , and R 31 are as claimed in claim 1 or any defined in the preceding claims. 45.权利要求42、43或44的化合物，其中R1、R2、R3、R4、R5、R6、R7和R8是氢。45. The compound of claim 42, 43 or 44, wherein R1 , R2 , R3 , R4 , R5 , R6 , R7 and R8 are hydrogen. 46.权利要求1的化合物，其具有通式(I4)： 46. The compound of claim 1 having the general formula ( I4 ): 其中R1、R2、R3、R4、R5、R7、R8、X、D和E如权利要求1或任一前述权利要求中所定义。wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , X, D and E are as defined in claim 1 or any preceding claim. 47.权利要求1的通式(I5)化合物： 47. The compound of general formula ( I5 ) according to claim 1: 其中R1、R2、R3、R4、R5、R7、R8、D和E如权利要求1或任一前述权利要求中所定义。wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , D and E are as defined in claim 1 or any preceding claim. 48.权利要求46或47的化合物，其中R1、R2、R3、R4、R5、R7和R8是氢。48. The compound of claim 46 or 47, wherein R1 , R2 , R3 , R4 , R5 , R7 and R8 are hydrogen. 49.前述权利要求任一项的化合物，其中所述化合物的IC50值不高于5μM，所述值是通过本文所公开的胰高血糖素结合测定(I)或胰高血糖素结合测定(II)测定的。49. The compound of any one of the preceding claims, wherein said compound has an IC50 value of no higher than 5 μM as determined by the Glucagon Binding Assay (I) or the Glucagon Binding Assay (I) disclosed herein ( II) Measured. 50.权利要求49的化合物，其中所述化合物的IC50值低于1μM、优选低于500nM、更优选低于100nM，所述值是通过本文所公开的胰高血糖素结合测定(I)或胰高血糖素结合测定(II)测定的。50. The compound of claim 49, wherein said compound has an IC50 value of less than 1 μM, preferably less than 500 nM, more preferably less than 100 nM, as determined by the glucagon binding assay (I) or As determined by glucagon binding assay (II). 51.前述权利要求任一项的化合物，其中所述化合物是可用于治疗和/或预防选自高血糖、IGT、2型糖尿病、1型糖尿病、异常脂血症和肥胖症的适应征的物质。51. The compound of any one of the preceding claims, wherein said compound is a substance useful for the treatment and/or prevention of indications selected from the group consisting of hyperglycemia, IGT, type 2 diabetes, type 1 diabetes, dyslipidemia and obesity . 52.用作药物的权利要求1-51任一项的化合物。52. A compound according to any one of claims 1-51 for use as a medicament. 53.药物组合物，其中包含至少一种权利要求1-51任一项的化合物作为活性组分和一种或多种可药用载体或赋形剂。53. A pharmaceutical composition comprising at least one compound according to any one of claims 1-51 as active ingredient together with one or more pharmaceutically acceptable carriers or excipients. 54.单位剂型形式的权利要求53的组合物，其中包含约0.05mg-约1000mg、优选约0.1mg-约500mg、特别优选约0.5mg-约200mg权利要求1-51任一项的化合物。54. The composition of claim 53 in unit dosage form comprising about 0.05 mg to about 1000 mg, preferably about 0.1 mg to about 500 mg, particularly preferably about 0.5 mg to about 200 mg of a compound according to any one of claims 1-51. 55.权利要求1-51任一项的化合物在制备用于治疗和/或预防能受益于胰高血糖素拮抗作用的病症或疾病的药物中的应用。55. Use of a compound according to any one of claims 1-51 for the manufacture of a medicament for the treatment and/or prophylaxis of conditions or diseases which can benefit from glucagon antagonism. 56.权利要求1-51任一项的化合物在制备用于治疗和/或预防胰高血糖素介导的病症和疾病的药物中的应用。56. Use of a compound according to any one of claims 1-51 for the preparation of a medicament for the treatment and/or prophylaxis of glucagon-mediated disorders and diseases. 57.权利要求1-51任一项的化合物在制备用于治疗和/或预防高血糖的药物中的应用。57. Use of a compound according to any one of claims 1-51 for the preparation of a medicament for the treatment and/or prevention of hyperglycemia. 58.权利要求1-51任一项的化合物在制备用于降低哺乳动物血糖的药物中的应用。58. Use of a compound according to any one of claims 1-51 for the manufacture of a medicament for lowering blood sugar in a mammal. 59.权利要求1-51任一项的化合物在制备用于治疗和/或预防IGT的药物中的应用。59. Use of a compound according to any one of claims 1-51 for the preparation of a medicament for the treatment and/or prevention of IGT. 60.权利要求1-51任一项的化合物在制备用于治疗和/或预防2型糖尿病的药物中的应用。60. Use of a compound according to any one of claims 1-51 for the preparation of a medicament for the treatment and/or prevention of type 2 diabetes. 61.权利要求60的应用，其中所述应用是在制备用于延迟或预防从IGT向2型糖尿病转化的进程的药物中的应用。61. The use according to claim 60, wherein said use is for the preparation of a medicament for delaying or preventing the progression from IGT to type 2 diabetes. 62.权利要求60的应用，其中所述应用是在制备用于延迟或预防从非胰岛素需要性2型糖尿病向胰岛素需要性2型糖尿病转化的进程的药物中的应用。62. The use according to claim 60, wherein said use is for the preparation of a medicament for delaying or preventing the transition from non-insulin-requiring type 2 diabetes to insulin-requiring type 2 diabetes. 63.权利要求1-51任一项的化合物在制备用于治疗和/或预防1型糖尿病的药物中的应用。63. Use of a compound according to any one of claims 1-51 for the preparation of a medicament for the treatment and/or prevention of type 1 diabetes. 64.权利要求1-51任一项的化合物在制备用于治疗和/或预防肥胖症的药物中的应用。64. Use of a compound according to any one of claims 1-51 for the preparation of a medicament for the treatment and/or prevention of obesity. 65.权利要求1-51任一项的化合物在制备用于治疗和/或预防异常脂血症的药物中的应用。65. Use of the compound according to any one of claims 1-51 in the preparation of a medicament for the treatment and/or prevention of dyslipidemia. 66.权利要求55-65任一项的应用，其中所述药物与另外的抗糖尿病剂联合用于治疗。66. The use of any one of claims 55-65, wherein the medicament is used in combination therapy with an additional antidiabetic agent. 67.权利要求55-66任一项的应用，其中所述药物与另外的抗肥胖剂联合用于治疗。67. The use according to any one of claims 55-66, wherein the medicament is used in combination therapy with an additional anti-obesity agent. 68.权利要求55-67任一项的应用，其中所述药物与另外的抗高脂血症剂联合用于治疗。68. The use of any one of claims 55-67, wherein the medicament is used in combination therapy with an additional antihyperlipidemic agent. 69.权利要求55-68任一项的应用，其中所述药物与另外的抗高血压剂联合用于治疗。69. The use of any one of claims 55-68, wherein the medicament is used in combination therapy with an additional antihypertensive agent. 70.治疗和/或预防能受益于胰高血糖素拮抗作用的病症或疾病的方法，所述方法包括给有此需要的个体施用有效量的权利要求1-51任一项的化合物或权利要求53或54的药物组合物。70. A method of treating and/or preventing a condition or disease which would benefit from glucagon antagonism, said method comprising administering to an individual in need thereof an effective amount of a compound according to any one of claims 1-51 or claim 53 or 54 pharmaceutical compositions. 71.权利要求70的方法，其中化合物的有效量为约0.05mg-约2000mg/天、优选约0.1mg-约1000mg/天、特别优选约0.5mg-约500mg/天。71. The method of claim 70, wherein the effective amount of the compound is about 0.05 mg to about 2000 mg/day, preferably about 0.1 mg to about 1000 mg/day, particularly preferably about 0.5 mg to about 500 mg/day.
CN01811591A 2000-06-23 2001-06-21 Glucagon antagonists/inverse agonists Pending CN1437581A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DKPA200000984 2000-06-23
DKPA200000984 2000-06-23
DKPA200001734 2000-11-17
DKPA200001734 2000-11-17

Publications (1)

Publication Number Publication Date
CN1437581A true CN1437581A (en) 2003-08-20

Family

ID=26068842

Family Applications (1)

Application Number Title Priority Date Filing Date
CN01811591A Pending CN1437581A (en) 2000-06-23 2001-06-21 Glucagon antagonists/inverse agonists

Country Status (14)

Country Link
EP (1) EP1296942A1 (en)
JP (1) JP2004501897A (en)
KR (1) KR20030029061A (en)
CN (1) CN1437581A (en)
AU (1) AU2001265834A1 (en)
BR (1) BR0111908A (en)
CA (1) CA2411552A1 (en)
CZ (1) CZ20024105A3 (en)
HU (1) HUP0301501A2 (en)
IL (1) IL153181A0 (en)
MX (1) MXPA02012273A (en)
NO (1) NO20026149L (en)
PL (1) PL359619A1 (en)
WO (1) WO2002000612A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101312963B (en) * 2005-11-23 2012-03-14 伊莱利利公司 Glucagon receptor antagonists, preparation and therapeutic uses

Families Citing this family (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030203946A1 (en) * 2000-11-17 2003-10-30 Carsten Behrens Glucagon antagonists/inverse agonists
US6762318B2 (en) 2001-12-03 2004-07-13 Novo Nordisk A/S Glucagon antagonists
US6881746B2 (en) 2001-12-03 2005-04-19 Novo Nordick A/S Glucagon antagonists/inverse agonists
EP1463715A1 (en) * 2001-12-03 2004-10-06 Novo Nordisk A/S Novel glucagon antagonists
US7081473B2 (en) 2002-05-22 2006-07-25 Sanwa Kagaku Kenkyusho Co., Ltd. Agent for preventing/ameliorating obesity comprising methylidene hydrizide compound as active ingredient
EP1519723A1 (en) * 2002-06-27 2005-04-06 Novo Nordisk A/S Novel glucagon antagonists/inverse agonists
WO2004056763A2 (en) * 2002-12-20 2004-07-08 Novo Nordisk A/S Novel glucagon antagonists
WO2004063147A1 (en) * 2003-01-10 2004-07-29 Novo Nordisk A/S Salts and solvates of glucagon antagonists
US7572922B2 (en) 2003-01-27 2009-08-11 Merck & Co., Inc. Substituted pyrazoles, compositions containing such compounds and methods of use
WO2004101505A1 (en) * 2003-05-14 2004-11-25 Novo Nordisk A/S Novel compounds for treatment of obesity
CA2529662A1 (en) * 2003-07-21 2005-02-10 Applied Research Systems Ars Holding N.V. Aryl dicarboxamides
EP1689707A1 (en) * 2003-11-25 2006-08-16 Novo Nordisk A/S Novel compounds for the treatment of obesity
WO2005058845A2 (en) * 2003-12-19 2005-06-30 Novo Nordisk A/S Novel glucagon antagonists/inverse agonists
PL1758853T3 (en) * 2004-06-14 2010-06-30 Lilly Co Eli Glucagon receptor antagonists, preparation and therapeutic uses
EP1863755A1 (en) 2005-03-21 2007-12-12 Merck & Co., Inc. Substituted aryl and heteroaryl derivatives
WO2006104826A2 (en) 2005-03-30 2006-10-05 Merck & Co., Inc. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
CA2614537A1 (en) 2005-07-26 2007-02-08 Merck & Co., Inc. Process for synthesizing a substituted pyrazole
TW200745031A (en) 2005-10-13 2007-12-16 Merck & Co Inc Acyl indoles, compositions containing such compounds and methods of use
CA2645639A1 (en) 2006-03-23 2007-10-04 Merck & Co. Inc. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
CA2650619A1 (en) 2006-05-16 2007-11-29 Merck And Co., Inc. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
TW200821284A (en) 2006-10-03 2008-05-16 Merck & Co Inc Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
KR20200123866A (en) * 2007-02-09 2020-10-30 메타베이시스 테라퓨틱스, 인크. Novel antagonists of the glucagon receptor
JP2011520897A (en) 2008-05-16 2011-07-21 シェーリング コーポレイション Glucagon receptor antagonists, compositions and methods of their use
ES2527670T3 (en) 2008-08-13 2015-01-28 Metabasis Therapeutics, Inc. Glucagon antagonists
RU2013127611A (en) 2010-12-23 2015-01-27 Пфайзер Инк. Glucagon receptor modulators
JP5562495B2 (en) 2011-02-08 2014-07-30 ファイザー・インク Glucagon receptor modulator
WO2013014569A1 (en) 2011-07-22 2013-01-31 Pfizer Inc. Quinolinyl glucagon receptor modulators
US9725427B2 (en) 2012-03-16 2017-08-08 Biohaven Pharmaceutical Holding Company Limited Prodrugs of riluzole and their method of use
EP3065736B1 (en) 2013-11-04 2018-11-14 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions thereof, and methods of use
US10076504B2 (en) 2014-06-12 2018-09-18 Ligand Pharmaceuticals, Inc. Glucagon antagonists
WO2019160940A1 (en) 2018-02-13 2019-08-22 Ligand Pharmaceuticals Incorporated Glucagon receptor antagonists
US11976052B2 (en) 2019-01-11 2024-05-07 Naegis Pharmaceuticals Inc. Leukotriene synthesis inhibitors
MX2024000313A (en) 2021-07-09 2024-03-06 Plexium Inc Aryl compounds and pharmaceutical compositions that modulate ikzf2.

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6174905B1 (en) * 1996-09-30 2001-01-16 Mitsui Chemicals, Inc. Cell differentiation inducer
JP2003514508A (en) * 1997-07-01 2003-04-15 ノボ ノルディスク アクティーゼルスカブ Glucagon antagonist / adverse agent
US6613942B1 (en) * 1997-07-01 2003-09-02 Novo Nordisk A/S Glucagon antagonists/inverse agonists
CZ20013767A3 (en) * 1999-05-17 2002-04-17 Novo Nordisk A/S Compound, pharmaceutical preparation, use of the compound and treatment method

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101312963B (en) * 2005-11-23 2012-03-14 伊莱利利公司 Glucagon receptor antagonists, preparation and therapeutic uses

Also Published As

Publication number Publication date
IL153181A0 (en) 2003-06-24
EP1296942A1 (en) 2003-04-02
AU2001265834A1 (en) 2002-01-08
CA2411552A1 (en) 2002-01-03
WO2002000612A1 (en) 2002-01-03
CZ20024105A3 (en) 2003-05-14
KR20030029061A (en) 2003-04-11
BR0111908A (en) 2003-04-01
PL359619A1 (en) 2004-08-23
NO20026149D0 (en) 2002-12-20
NO20026149L (en) 2003-02-21
HUP0301501A2 (en) 2003-08-28
MXPA02012273A (en) 2003-04-25
JP2004501897A (en) 2004-01-22

Similar Documents

Publication Publication Date Title
CN1437581A (en) Glucagon antagonists/inverse agonists
US6562807B2 (en) Glucagon antagonists/inverse agonists
CN1066436C (en) Compounds
CN1274670C (en) Diaminopropionic acid derivatives
CN1226294C (en) Fused heteroaromatic glucokinase activators
CN1356977A (en) Glucagon antagonists/inverse agonists
CN1177821C (en) Matrix Metalloproteinase Inhibitors
CN1107061C (en) Cyclic amine derivatives-CCR-3 receptor antagonists
CN1176915C (en) Inulin Kinase Activator of Alkynylphenyl Aromatic Heterocycle
CN1243723C (en) N-phenylpropylcyclopentyl substituted glutaramide derivatives as NEP inhibitors of FSAD
CN1090612C (en) Amine derivatives of oxo- and hydroxy-substituted hydrocarbons
CN1267281A (en) Glucagon antagonists/inverse agonists
CN1658871A (en) Amide derivatives as GK activators
US20030203946A1 (en) Glucagon antagonists/inverse agonists
CN1092768A (en) Pyrazoles and pyrazolopyrimidine
CN1628111A (en) 2-furancarboxylic acid hydrazides and pharmaceutical compositions containing the same
CN1261877A (en) 4-bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as MEK inhibitors
CN1411453A (en) Trans olefinic glucokinase activators
US6649641B2 (en) Glucagon antagonists/inverse agonists
CN1522244A (en) Anthranilic acid amides, method for the production thereof, their use as antiarrhythmia agents, and pharmaceutical preparations thereof
CN1630517A (en) CXCR4-antagonistic drugs composed of nitrogen-containing compound
CN1331674A (en) Sulfonamide hydroxamates
CN1440385A (en) Pyrrole derivatives for treating AIDS
CN1167670C (en) Aryl carboxylic acid and tetrazole derivatives
CN101031541A (en) 4-aminomethyl benzamidine derivatives and their use as factor viia inhibitors

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication