TW200418454A - Bicyclic-substituted amines as histamine-3 receptor ligands - Google Patents

Bicyclic-substituted amines as histamine-3 receptor ligands Download PDF

Info

Publication number
TW200418454A
TW200418454A TW092131661A TW92131661A TW200418454A TW 200418454 A TW200418454 A TW 200418454A TW 092131661 A TW092131661 A TW 092131661A TW 92131661 A TW92131661 A TW 92131661A TW 200418454 A TW200418454 A TW 200418454A
Authority
TW
Taiwan
Prior art keywords
ethyl
methyl
group
pyrrolidinyl
pyrrolidin
Prior art date
Application number
TW092131661A
Other languages
Chinese (zh)
Other versions
TWI359658B (en
Inventor
Robert J Altenbach
Lawrence A Black
Sou-Jen Chang
Marlon D Cowart
Ramin Faghih
A Gfesser Gregory
Ku Yi-Yin
Liu Huaqing
A Lukin Kirill
L Nersesian Diana
Pu Yu-Ming
N Sharma Padam
L Bennani Youssef
P Curtis Michael
Original Assignee
Abbott Lab
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
Priority claimed from US10/292,422 external-priority patent/US20040092521A1/en
Priority claimed from US10/689,735 external-priority patent/US7153889B2/en
Application filed by Abbott Lab filed Critical Abbott Lab
Publication of TW200418454A publication Critical patent/TW200418454A/en
Application granted granted Critical
Publication of TWI359658B publication Critical patent/TWI359658B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—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
    • C07D213/61—Halogen atoms or nitro 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
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • 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
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/12—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/28—Cinnolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Diabetes (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pulmonology (AREA)
  • Cardiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Addiction (AREA)
  • Rheumatology (AREA)
  • Psychology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Compounds of formula (I), are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Also disclosed are pharmaceutical compositions comprising the histamine-3 receptor ligands, methods for using such compounds and compositions, and a process for preparing compounds within the scope of formula (I).

Description

200418454 玖、發明說明： 【發明所屬之技術領域】 本發明係有關經雙環取代之胺化合物’包含此等化合物 <組合物，製備該等化合物之方法及使用此等化合物與組 合物治療病症與病變之方法。 【先前技術】 組織胺係一種習知之神經元活性調節劑。文獻上已提出 至少四種組織胺受體，典型地稱為組織胺4、組織胺4、組 織胺-3與，組織胺_4。咸信已知為組織胺_3受體之組織胺受體 在中樞神經系統之神經傳遞上扮演重要角色。 組織胺-3 (HD受體首先在組織胺激導性神經末端中鍵定 出其藥理學（Nature，302:832-837 (1983))，其係在中樞神經 系統及周邊為官（特定言之肺部、心血管系統與胃腸道）中調 節神經遞質之釋出。咸信Hs受體位於組織胺激導性神經末 端及處理其他活性（如：腎上腺素激導性、膽鹼激導性、血 凊素激導性與多巴胺激導性活性）之神經元之突觸前。Η;受 體之存在可由選擇性Η;受體促效劑與擷抗劑來證實 ((Nature，327:1 17-123 (1987) ; Lenrs與 Timmerman編輯，”h3 文體之歷史·新藥物之目標（The History of H3 Receptor·: a Target for New Drugs)” Elsevier (1998))。 對Η;受體之活性可藉由投與Ha受體配位體來修飾或調節 。配位體可證實擷抗劑、促效劑或部份促效劑活性。例如 ·· %受體在其他全身活性中特別涉及與記憶及認知過程、 神經病變過程、心血管功能、及調節血糖等有關之病症與 89248.doc 病變。雖然已有多種化合物證實具有Η3受體調節活性，但 仍需提供其他在Η3受體上具有活性且可加至適用於醫療之 醫藥組合物中之化合物。 【發明内容】 本發明係有關經取代之胺類，更特定言之緩雙環取代之 胺類。因此本發明一方面係有關式（1)化合物：200418454 (ii) Description of the invention: [Technical field to which the invention belongs] The present invention relates to bicyclic substituted amine compounds' comprising these compounds < compositions, methods of preparing these compounds, and using these compounds and compositions to treat disorders and diseases Pathological methods. [Prior art] Histamine is a known neuronal activity modulator. At least four histamine receptors have been proposed in the literature, typically referred to as histamine 4, histamine 4, histamine-3 and histamine-4. The histamine receptors known by Xianxin as histamine-3 receptors play an important role in the neurotransmission of the central nervous system. Histamine-3 (HD receptors first bind their pharmacology to histamine-induced nerve endings (Nature, 302: 832-837 (1983)), which is the official agent in the central nervous system and its periphery (specifically, Of the lung, cardiovascular system, and gastrointestinal tract) to regulate the release of neurotransmitters. The Hs receptor is located at the end of histamine-induced nerves and processes other activities (such as epinephrine-induced, choline-induced) Presynaptic neurons of the sex, heparin-inducing and dopamine-inducing activity); the presence of receptors can be confirmed by selective Η; receptor agonists and antagonists ((Nature, 327 : 1 17-123 (1987); Edited by Lenrs and Timmerman, "The History of H3 Receptor: a Target for New Drugs" Elsevier (1998)). Confrontation; Receptor The activity can be modified or adjusted by administering a Ha receptor ligand. The ligand can confirm the activity of the antagonist, agonist, or part of the agonist. For example, the% receptor is particularly useful in other systemic activities. Involves disorders related to memory and cognitive processes, neuropathy processes, cardiovascular function, and regulation of blood glucose And 89248.doc lesions. Although a variety of compounds have been confirmed to have 受体 3 receptor-modulating activity, there is still a need to provide other compounds which are active on Η3 receptors and can be added to medical compositions suitable for medical use. [Summary of the Invention] The present invention relates to substituted amines, and more specifically to slow bicyclic substituted amines. Therefore, one aspect of the present invention relates to compounds of formula (1):

R3b (1) 或其醫藥上可接受之鹽類、酯類、醯胺類或前藥，其中： Υ與Υ分別獨立選自下列組成之群中：CH、CF與Ν ; X、X’、Ζ與Ζ’分別獨立為C或Ν ;R3b (1) or a pharmaceutically acceptable salt, ester, amidine or prodrug thereof, wherein: Υ and Υ are independently selected from the group consisting of: CH, CF and Ν; X, X ', Z and Z 'are independently C or N;

Ri與R2中之一係選自下列組成之群中：鹵素、氰基、與 L2R6 ; 心與R2中另一個係選自下列組成之群中：氫、烷基、烷 氧基、芳基、環烷基、鹵素、氰基與硫烷氧基，但其限制 條件為當Z’為N時，則1不存在； 當X ’為N時，則r3不存在或r3係選自下列組成之群中： 氫、烷基、烷氧基、南素、氰基與硫垸氧基； — 當Z為N時，則R3a不存在或R3a係選自下列組成之群中： 氯、基、烷氧基、南素與氰基； 89248.doc 200418454 當X為N時，則R3b不存在或R3b係選自下列組成之群中： 氫、烷基、烷氧基、函素、羥基、氰基與硫烷氧基； R4與I分別獨立選自下列組成之群中：烷基、鹵烷基、羥 垸基、烷氧烷基、環烷基、環烷基烷基及（NRarb)烷基，或 R4與&與其所附接之氮原子共同形成如下式之非芳香環··One of Ri and R2 is selected from the group consisting of halogen, cyano, and L2R6; the other of Ri and R2 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, Cycloalkyl, halogen, cyano, and thioalkoxy, but the limitation is that when Z 'is N, then 1 does not exist; when X' is N, then r3 does not exist or r3 is selected from the group consisting of In the group: hydrogen, alkyl, alkoxy, southernin, cyano, and thiocarbamyloxy;-when Z is N, then R3a does not exist or R3a is selected from the group consisting of: When X is N, then R3b is absent or R3b is selected from the group consisting of hydrogen, alkyl, alkoxy, functional element, hydroxy, cyano And thioalkoxy; R4 and I are independently selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, and (NRarb) alkyl , Or R4 and & and the nitrogen atom attached to it form a non-aromatic ring of the following formula ...

R6係選自下列組成之群中：芳基、雜芳基、雜環與環坡 基； R7、Rs、119與&1()每次出現時分別獨立選自下列組成之群 中：氫、羥烷基、氟烷基與烷基；或一對心與以或一對r 與Rio共同形成C3_C0環，其中·〇、1或2個選自〇、N*s之雜 原子置換環中碳原子； R"、Rn、R13與RM分別獨立選自下列組成之群中：气、 經基、羥烷基、烷基與氟； Q係選自下列組成之群中：一鍵結、〇、s與nr15 ; L4 -[C(Ri6)(Ri7)]n-il-[C(R16)(R17)]p〇-； L2為一鍵結或L2係選自下列組成之群中：-〇_、 、-S-、-[c^sKRdV、-〇·[(：(Κΐ8)(Κΐ9)](Γ、_NH•與·叫烷 89248.doc -9- 200418454R6 is selected from the group consisting of: aryl, heteroaryl, heterocyclic and cyclopolyl; R7, Rs, 119 and & 1 () are each independently selected from the group consisting of: hydrogen , Hydroxyalkyl, fluoroalkyl and alkyl; or a pair of hearts, or a pair of r and Rio together form a C3_C0 ring, in which · 〇, 1 or 2 heteroatoms selected from the group consisting of 0, N * s Carbon atom; R ", Rn, R13 and RM are independently selected from the group consisting of: gas, meridian, hydroxyalkyl, alkyl and fluorine; Q is selected from the group consisting of: one-bonded, , S and nr15; L4-[C (Ri6) (Ri7)] n-il- [C (R16) (R17)] p〇-; L2 is a bond or L2 is selected from the group consisting of:- 〇_,, -S-,-[c ^ sKRdV, -〇 · [(:( Κΐ8) (Κΐ9)] (Γ, _NH • and · called alkanes 89248.doc -9- 200418454

Rl5係選自下列組成之群中 與甲醯基； 氫、烷基、醯基、醯胺基、 心與Rl7每次出現時分別獨立選自下列組成之群中：氫、 基、烷氧基與氟； 與r19每次出現時分別獨立選自下列組成之群中：氯、 羥基、烷基、烷氧基與氟； 每次出現時分別獨立選自下列組成之群中：氫、 羥基、烷基、烷氧基、烷胺基、二烷胺基與氟，或Rx«y 中之，鄰碳原子上共同代表-共價鍵，因此使 相鄰碳原子之間形成雙鍵； m為1至5之整數； η為1至6之整數； ρ為2至6之整數；及 q為1至4之整數； /、 Y "^、2與2’中〇、1或2者可為氮；但其限 制條件為當X，為N時，則Μ存在；當zAn時，則R3a不存 在’两Z為N時’則反2不存在；及當時，則&不存在 本晷明另方法係有關包含本發明化合物之醫藥組合物 。此等組合物可依據本發明方法投藥，典型地作為治療或 預防與Kb文體活性有關之病症與病變之療程之一部份。 本發明另一方面係有關選擇性調節受體活性之方法。 该方法適用於治療與/或預防哺乳動物與H3受體調節作角 有關之病症與病變。更特定言之，該方法適用於與記憶及 認知過私、神經病變過程、心血管功能、及體重等有關之 89248.doc -10- 200418454 病症與病變。 亦包括製備本發明化合物之方、去 、製備該化合物之方 病症與病變之方法進 該化合物、包含該化合物之組合物 法與藉由投與該化合物來治療或預防 一步說明於本文中。 【實施方式】 本說明書中所使用某些術語之定義詳細說明如下。Rl5 is selected from the group consisting of methylamino and hydrogen; hydrogen, alkyl, fluorenyl, fluorenylamino, and oxo are each independently selected from the group consisting of hydrogen, alkyl, and alkoxy With fluorine; with each occurrence of r19 independently selected from the group consisting of: chlorine, hydroxyl, alkyl, alkoxy, and fluorine; at each occurrence, independently selected from the group consisting of: hydrogen, hydroxyl, Alkyl, alkoxy, alkylamino, dialkylamino, and fluorine, or Rx «y, represent a covalent bond on adjacent carbon atoms, so a double bond is formed between adjacent carbon atoms; m is Integers from 1 to 5; η is an integer from 1 to 6; ρ is an integer from 2 to 6; and q is an integer from 1 to 4; /, Y " ^, 2 and 2 'may be 0, 1 or 2 Is nitrogen; but its limitation is that when X is N, then M exists; when zAn, then R3a does not exist; when two Z is N, then anti-2 does not exist; and at that time, & does not exist The other method relates to a pharmaceutical composition comprising a compound of the present invention. These compositions can be administered according to the method of the invention, typically as part of a course of treatment or prevention of conditions and pathologies associated with Kb stylistic activity. Another aspect of the invention is a method for selectively modulating the activity of a receptor. This method is suitable for the treatment and / or prevention of mammalian conditions and lesions associated with the regulation of H3 receptor horns. More specifically, this method is applicable to 89248.doc -10- 200418454 disorders and lesions related to memory and cognitive distrust, neuropathy processes, cardiovascular function, and weight. It also includes methods for preparing the compounds of the present invention, methods for preparing the compounds, methods for the treatment of diseases and disorders, methods for the compounds, compositions containing the compounds, and treatment or prevention by administering the compounds. One step is described herein. [Embodiment] The definitions of certain terms used in this specification are explained in detail as follows.

本使用之術語"酸基”指如本文中定義之燒基她 :中足義之羰基附接在母分子部份基團上。酿基之幻 '貫例蜒基包括(但不限於)：乙醯基、1-氧代丙基、2,2r 甲基-1-氧代丙基、1-氧代丁基與丨_氧代戊基。 ’ 一本文所使用之術語"酿氧基"指如本文中定義之酿基利月 -乳原子附接在母分子部份基團上。醯氧基之代表性實命 包括(但不限於)：乙醯氧基、丙醯氧基與異丁醯氧基。The term " acid group " as used herein refers to a alkynyl group as defined herein: a carbonyl group with a sufficient meaning is attached to a part of the parent molecular group. Examples of the "base group" include (but are not limited to): Ethyl, 1-oxopropyl, 2,2r methyl-1-oxopropyl, 1-oxobutyl, and __oxopentyl. 'A term used in this text " " Refers to the geryl-lactate atom as defined herein attached to the parent molecular moiety. Representative examples of ethoxy include (but are not limited to): ethoxy, propyloxy With isobutyryloxy.

本又所使用之術語”缔基"指含有2至10個碳原子及含有 至少—個由兩個氫脫除後所形成之碳_碳雙鍵之直鏈或分 支鏈經。埽基之代表性實例包括（但不限於）：乙埽基、 丙缔基、2-甲基_2-丙缔基、3_丁烯基、4_戊烯基、5_己缔基 、2-庚缔基、2_甲基小庚烯基、及弘癸烯基。 本文所使用之術語”貌氧基”指如本文中定義之烷基利用 一虱原子附接在母分子部份基團上。烷氧基之代表性實例 包括（但不限於）：甲氧基、乙氧基、丙氧基、2-丙氧基、丁 氧基、第三丁氧基、戊氧基、與己氧基。 89248.doc -11- 200418454 本文所使用之術語”燒氣栌g並”化r丄 乳凡乳基扣如本文中定義之烷氧 基利用另一個如本文中定蓋士 ^ 疋我足fe氧基附接在母分子部份基 團上。力元氧挺I氧i基之代表柯奋点丨A r ^ '衣性貝例包括（但不限於）：第三丁氧 甲氧基、2 -乙氧乙氧基、2 -甲蓋 ^虱乙虱基、及甲氧甲氧基。 本文所使用之術語"院氧境基”指如本文中定義之燒氧基 利用如本X中定義之燒基附接在母分子部份基圏上。燒氧 燒基之代表性實例包括（但不限人 广 U小限於）·罘二丁氧甲基、2-乙氧 乙基、2 -甲氧乙基、及甲氧甲基。 本文戶斤,使用之術語，，垸氧幾基，，指如本文中定義之燒氧基 :用如本文中定義之羰基附接在母分子部份基團上。燒氧 致基（代表性實例包括（但不限於）：甲氧幾基、乙氧幾基與 第三丁氧羰基。 本文所使用之術”燒氧亞胺基，·指如本文中定義之燒氧 基利用如本又中定義之亞胺基附接在母分子部份基團上。 烷氧亞胺基之代表性實例包括(但不限於）：乙氧(亞胺基) 甲基與甲氧（亞胺基）甲基。 本又所使用之術語"垸氧磺醯基，，指如本文中定義之烷氧 基利用如本文中定義之❹基附接在母分子部份基團上。 =磺酿基之代表性實例包括(但不限於)：甲氧磺酸基、乙 氧’驢基、與丙氧續醯基。 本文所使用之術語”烷基”指含有 至10個碳原子之直鏈 或分支 基、正 丁基、 鏈烴。烷基之代表性實例包括（但不限於）：甲基、乙 丙基、異丙基、正丁基、第二丁基、異丁基、第三 正戊基、異戊基、新戊基、正己基、夂甲基己基、 89248.doc -12- 200418454 2,2-二甲基戊基、2 基與正癸基。 2，3-二甲基戊基、正庚基、 正辛基、正壬 本文所使用之術語 燒胺基”指如本文中定義之烷基利用The term "alkenyl" as used herein refers to a straight or branched chain containing 2 to 10 carbon atoms and containing at least one carbon-carbon double bond formed by removal of two hydrogens. Representative examples include (but are not limited to): ethenyl, propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptyl Alkenyl, 2-methylheptenyl, and decenoyl. As used herein, the term "macrooxy" refers to an alkyl group, as defined herein, attached to a moiety of a parent molecule using a tick atom. Representative examples of alkoxy include, but are not limited to: methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tertiary butoxy, pentyloxy, and hexyloxy 89248.doc -11- 200418454 As used herein, the term "burning gas" and "r" is used to synthesize milk. The alkoxy group as defined herein utilizes another alkoxy group as defined herein. The feoxy group is attached to the group of the parent molecule. The representative Cofen point of the Li-oxygen radical I-oxyl group 丨 A r ^ 'Examples of clothing properties include (but are not limited to): the third butoxymethoxy group , 2 -ethoxyethoxy, 2- Lithium, ethoxyl, and methoxymethoxy. The term "oxygenated" as used herein refers to an alkoxy group, as defined herein, attached to the parent molecular moiety using an alkoxy group, as defined in this X. Share on the base. Representative examples of alkoxy groups include (but are not limited to, human beings) U-dibutoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl. In this article, the term used, fluorenyl, refers to an alkoxy group as defined herein: a carbonyl group as defined herein is attached to the parent molecular moiety. Oxygen-generating groups (representative examples include (but are not limited to): methoxy-kidoxy, ethoxy-kidoxy, and tertiary-butoxycarbonyl. As used herein, the term "oxy-imino" refers to as defined herein Carbooxy is attached to the parent molecular moiety using an imino group as defined herein. Representative examples of alkoxyimino include (but are not limited to): ethoxy (imino) methyl and Methoxy (imino) methyl. The term " fluorenylsulfonyl, as used herein, refers to an alkoxy group, as defined herein, attached to a parent molecular moiety using a fluorenyl group, as defined herein. Representative examples of sulfo groups include (but are not limited to): mesylate, ethoxy ', and propoxyl. The term "alkyl" as used herein means containing up to 10 Linear or branched group of 1 carbon atom, n-butyl, chain hydrocarbon. Representative examples of alkyl include (but are not limited to): methyl, ethylpropyl, isopropyl, n-butyl, second butyl, Isobutyl, third n-pentyl, isopentyl, neopentyl, n-hexyl, fluorenylmethylhexyl, 89248.doc -12- 200418454 2,2-dimethylpentyl, 2 groups and n-decyl. 2,3-dimethylpentyl, n-heptyl, n-octyl, n-non, as used herein, the term "carbamino" refers to an alkyl group as defined herein

本文所使用之術語，， 、乙胺基、異丙胺基與丁胺基。 燒羰基”指如本文中定義之烷基利用 、本文中走義之幾基附接在母分子部份基團上。烷羰基之 代表性實例包括（但不限於）：㈣基、乙羰基與異丙基凝基 、正丙基^羰基，等等。 本文所使用之術語”烷基磺醯基，，指如本文中定義之烷基 利用如本文中定義之續醯基附接在母分子部份基團上。烷 基磺醯基之代表性實例包括（但不限於）：甲磺醯基與乙磺醯 基。 本文所使用之術語”块基”指含有2至1〇個碳原子及含有 土少一個竣-碳參键之直鏈或分支鏈烴。块基之代表性實例 包括（但不限於）：乙炔基、1-丙块基、丙炔基、弘丁炔基 、2-戊炔基、與1-丁炔基。 本文所使用之術語”醯胺基，，指胺基、烷胺基或二烷胺基 利用如本文中定義之羰基附接在母分子部份基團上。醯胺 基之代表性實例包括（但不限於）：胺羰基、甲胺羰基、二甲 胺羰基與乙基甲胺羰基。 本文所使用之術語’f胺基HNH2基團。 _ 本文所使用之術語”芳基’’指單環芳香環系。芳基之代表 性實例包括（但不限於）：苯基。 89248.doc -13 - 200418454 本發明之芳基經〇、i、2、3、4或5個分別獨立選自下列 之取代基取代· g篮基、酿氧基、烯基、院氧基、燒氧嫁氧 基、fe氧:基、烷氧羰基、烷氧亞胺基、烷氧磺醯基、烷 基、烷羰基、烷磺醯基、炔基、醯胺基、羧基、氰基、環 烷羰基、甲醯基、由烷氧基、_烷基、_素、羥基、羥烷 基、氫硫基、硝基、硫烷氧基、NraR^(NRarb)磺醯基。 本文所使用之術語”芳基烷氧基”指如本文中定義之芳 基利用如本文中定義之烷氧基附接在母分子部份基團上。 芳基燒‘基之代表性實例包括（但不限於）：2_苯基乙氧基、 3-莕-2-基丙氧基與5-苯基戊氧基。 本文所使用之術語”芳基烷氧羰基”指如上述定義之芳 基烷氧基利用如本文中定義之羰基附接在母分子部份基團 上。方基烷氧羰基之代表性實例包括（但不限於）：苯甲氧羰 基。 本文所使用之術浯”芳基垸基”指如本文中定義之芳基利 用如本文中定義之烷基附接在母分子部份基團上。芳基烷 基之代表性實例包括（但不限於）：苯甲基、2_苯乙基與夂苯 丙基。 本文所使用之術㊂吾’’窥基"指_C(=〇）_基團。 本文所使用之術語，，羧基”指_C〇2H基團，其可呈酯基圏 -co2-烷基被保護。 本文所使用之術語π氰基"指-CN基團。 - 本文所使用之術語’’環缔基”指含有3至8個碳原子及含有 至少一個由兩個氫脫除後所形成之碳_碳雙键之環狀烴。環 89248.doc -14- 200418454 烯基之代表性實例包括（但不限於）·· 2-環己烯基、3_環己 婦-1-基、2,4-環己二缔-基與3_環戊烯基。 本文所使用之術語"環烷基”指含有3至8個碳原子之飽和 壤狀烴。環烷基實例包括··環丙基、環丁基、環戊基、環 己基、環庚基與環辛基。 本發明之環烷基經〇、1、2、3或4個分別獨立選自下列之 取代基取代：醯基、醯氧基、烯基、烷氧基、烷氧烷氧基 、烷氧烷基、烷氧羰基、烷氧亞胺基、烷基、炔基、醯胺 基、焱基，、氰基、伸乙二氧基、甲醯基、卣烷氧基、鹵烷基 、鹵素、羥基、羥烷基、亞甲二氧基、硫烷氧基與_NRaRb。 本文所使用之術語”環燒基燒基”指如本文中定義之環垸 基利用如本文中定義之烷基附接在母分子部份基圏上。環 烷基烷基之代表性實例包括（但不限於）：環丙基甲基、2_ 環丁基乙基、環戊基甲基、環己基甲基與4-環庚基丁基。 本文所使用之術語”環烷基羰基"指如上述定義之環烷基 利用如本文中足義之談基附接在母分子部份基團上。環垸 基羰基之代表性實例包括（但不限於）：環丙基羰基、環戊基 羰基、環己基羰基與環庚基羰基。 本文所使用之術語”二烷基胺基"指兩個分別獨立之如本 文中定義之烷基利用氮原子附接在母分子部份基團上。二 烷基胺基之代表性實例包括（但不限於）··二甲基胺基、二乙 基胺基、乙基甲基胺基、丁基甲基胺基。 - 本文所使用之術語"伸乙二氧基”指-〇(CH2)2〇-基團，其中 伸乙一氧基之氧原子利用一碳原子附接在母分子部份基團 89248.doc -15 - 200418454 /成5員％或伸乙二氧基之氧原子利用兩個相鄰碳原 附接在母分子部份基團上，形成6員環。 ’、 本又所使用之術語"氟”指_F。 〃文所使用d吾”氟烷基"指至少一個如本文中定義之 鼠基團利用如本又中定義之烷基附接在母分子部份基團上 。歧基之代表性實例包括（但不限於）：氟甲基、二氣甲基 、二風甲基、五氟乙基與2,2,2-三氟乙基。 本文所使用之術語”甲醯基，，指_c(〇)H基團。 本又所，使用之術語”齒”或”自素”指-C1、-Br、_u_F。 本又所使用之術語” _烷氧基，，指如本文中定義之至 用如本文Μ義之燒氧基附接在母分子部份基圈 ^_<代表性實例包括（但不限於）：氯甲氧基、2_ 乳基、三氟曱氧基與五氟乙氧基。 :又所使用之術語”南烷基"指如本文中定義之至少一個 二：用如本又：疋義之烷基附接在母分子部份基團上。 代表性實例包括（但不限於）：氯 三氣甲基、五氣乙基與2_氯_3_氣戊基。 氟乙基 本文所使用之術語”雜芳基，，指芳香系5或The terms used herein are,, ethylamino, isopropylamino, and butylamino. "Carbonyl" refers to the use of alkyl groups as defined herein and the attachment of several groups to groups on the parent molecule. Representative examples of alkylcarbonyl groups include (but are not limited to): fluorenyl, ethylcarbonyl, and isopropyl Propyl condensate, n-propyl ^ carbonyl, etc. As used herein, the term "alkylsulfonyl" refers to an alkyl group, as defined herein, attached to the parent molecular moiety using a continyl group, as defined herein. Part of the group. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl. The term "block group" as used herein refers to a straight or branched chain hydrocarbon containing 2 to 10 carbon atoms and containing less than one complete-carbon parameter. Representative examples of bulk groups include (but are not limited to): ethynyl, 1-propanyl, propynyl, butynyl, 2-pentynyl, and 1-butynyl. As used herein, the term "amidoamino" refers to an amine, alkylamino, or dialkylamino group attached to a parent molecular moiety using a carbonyl group as defined herein. Representative examples of amido groups include ( (But not limited to): aminecarbonyl, methylaminecarbonyl, dimethylaminecarbonyl and ethylmethylaminecarbonyl. The term 'faminoHNH2 group' as used herein. _ The term "aryl" as used herein refers to a monocyclic ring Aromatic ring system. Representative examples of aryl include, but are not limited to, phenyl. 89248.doc -13-200418454 The aryl group of the present invention is substituted with 0, i, 2, 3, 4 or 5 substituents each independently selected from the group consisting of: g-base, alkoxy, alkenyl, oxo, Burned oxygen, oxygen, fe: yl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, sulfonyl, carboxyl, cyano, Naphthenic carbonyl, formamyl, alkoxy, alkyl, hydroxy, hydroxy, hydroxyalkyl, hydrogenthio, nitro, thioalkoxy, NraR (NRarb) sulfonyl. The term "arylalkoxy" as used herein refers to an aryl group, as defined herein, attached to a parent molecular moiety using an alkoxy group, as defined herein. Representative examples of arylalkyl include, but are not limited to, 2-phenylethoxy, 3-fluoren-2-ylpropoxy, and 5-phenylpentyloxy. The term "arylalkoxycarbonyl" as used herein refers to an arylalkoxy group, as defined above, attached to a parent molecular moiety using a carbonyl group, as defined herein. Representative examples of square alkoxycarbonyl include, but are not limited to, benzyloxycarbonyl. As used herein, "arylaryl" refers to an aryl group, as defined herein, attached to a parent molecular moiety using an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenethyl, and phenylphenyl. As used herein, the term "suffix" refers to a _C (= 〇) _ group. As used herein, the term "carboxyl" refers to a -CO2H group, which may be protected as an ester group fluorene-co2-alkyl. The term π cyano as used herein refers to the -CN group.- The term "cycloalkenyl" is used to refer to a cyclic hydrocarbon containing 3 to 8 carbon atoms and containing at least one carbon-carbon double bond formed after removal of two hydrogens. Representative examples of ring 89248.doc -14- 200418454 alkenyl include, but are not limited to, 2-cyclohexenyl, 3-cyclohexyl-1-yl, 2,4-cyclohexadienyl- and 3-cyclopentenyl. The term " cycloalkyl " as used herein refers to a saturated soil-like hydrocarbon containing 3 to 8 carbon atoms. Examples of cycloalkyl include ... cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl And cyclooctyl. The cycloalkyl of the present invention is substituted with 0, 1, 2, 3, or 4 substituents independently selected from the following: fluorenyl, fluorenyl, alkenyl, alkoxy, and alkoxyalkoxy Alkyl, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkyl, alkynyl, fluorenyl, fluorenyl, cyano, ethylenedioxy, formamyl, fluorenyl, halogen Alkyl, halogen, hydroxy, hydroxyalkyl, methylenedioxy, thioalkoxy and _NRaRb. As used herein, the term "cycloalkynyl" refers to a cyclofluorenyl group as defined herein, as used herein The defined alkyl group is attached to the parent moiety. Representative examples of cycloalkylalkyl include (but are not limited to): cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, Cyclohexylmethyl and 4-cycloheptylbutyl. As used herein, the term "cycloalkylcarbonyl" refers to a cycloalkyl group, as defined above, using a radical as defined herein Molecular moiety. Representative examples of cyclofluorenylcarbonyl include, but are not limited to, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, and cycloheptylcarbonyl. The term "dialkylamino group" as used herein refers to two independent alkyl groups, as defined herein, attached to the parent molecular moiety with a nitrogen atom. Representative examples of dialkylamino groups include (But not limited to) ·· dimethylamino, diethylamino, ethylmethylamino, butylmethylamino.-The term "ethylenedioxy" as used herein refers to -〇 (CH2 ) 20- group, in which the oxygen atom of ethylene glycol is attached to the parent molecular group using a carbon atom 89248.doc -15-200418454/5% or the oxygen atom of ethylene glycol Two adjacent carbon atoms are attached to a part of the parent molecule to form a 6-membered ring. 'The term " fluoro " as used herein refers to _F. As used in the text, "fluoroalkyl" refers to at least one murine group, as defined herein, attached using an alkyl group, as defined herein On the parent molecular moiety. Representative examples of amido include (but are not limited to): fluoromethyl, difluoromethyl, difluoromethyl, pentafluoroethyl, and 2,2,2-trifluoroethyl. As used herein, the term "formamyl" refers to the _c (〇) H group. As used herein, the terms "dental" or "autogen" refer to -C1, -Br, and _u_F. As used herein The term "alkoxy" refers to a base ring attached to a parent molecular moiety as defined herein through a alkoxy group as defined herein, and representative examples include (but are not limited to): chloromethoxy, 2_ Milk-based, trifluorofluorenyl and pentafluoroethoxy. : The term "south alkyl" as used herein refers to at least one of the two as defined herein: the alkyl group attached to the parent molecule is attached to the parent molecule. Representative examples include (but are not limited to) ): Trichloromethyl, pentaethyl and 2-chloro-3-pentyl. Fluoroethyl The term "heteroaryl" as used herein refers to the aromatic 5 or

:、:=、7別獨立為選自氮、氧或疏，或其互： 原予㈣ 實例包括（但不限於）：其中-個碳被0或S 香：置=…2或3_原子依合適方式排列形成之芳 衣衣中兩個碳原子被-個Oils原子與—個N原子皇 換<環。雜芳基利用一個 ‘、 團上。雜Μ、 U 接在母分子部份基 4方基《代表性實例包括（但不限於）：味喃基、味峻 89248.d〇, -16- 200418454 基、異4 4基、異遠唾基、p号二吐基、今峻基、P比啼基、 P比嗅基、嗒畊基、嗒畊酮基、吡啶基、吡啶酮基、嘧啶基 、说洛基、四唑基、噻二唑基、p塞唑基、噻吩基或硫苯基 、三畊基與三唑基。明確之雜芳基包括（但不限於）：2H-嗒 畊-3-酮-2-基。 本發明之雜芳基經〇、1、2、3或4個分別獨立選自下列之 取代基取代：醯基、醯氧基、烯基、烷氧基、烷氧烷氧基 、燒氧fe基、燒氧羰基、烷氧亞胺基、烷氧磺醯基、烷基 、烷羰4、烷磺醯基、块基、醯胺基、羧基、氰基、甲醯 基、自烷氧基、_烷基、鹵素、羥基、羥烷基、氫硫基、 硝基、硫烷氧基、NRaR4(NRaRb)磺醯基。 本文所使用之術語”雜環”指含有1、2或3個分別獨立選自 下列組成义群中之雜原子：氮、氧與硫之3、4、$、6、7或 8員環。含有至少四員之環可為飽和或不飽和。例如：與 5員％具有〇或1個雙鍵。6員環具有〇、丨或2個雙鍵。7與8員 农/、有0 1、2或3個雙鍵。本發明之雜環基可利用碳原子 或氮原子附接在母分子邵份基團上。含氮雜環之代表性實 例包括（但不限於）：，丫咩基、十旦基、口丫 口元基、叶碎燒基、、 嗎，基、六氫吡呼基、六氫说淀基、吡咯啶基、吡咯啶基、 -虱Μ基與硫嗎4基。非含氮雜環之代表性實例包括（但 不限於）：四氫呋喃基與四氩吡喃基。 本發明雜環經0、卜2、3或4個分別獨立選自下列之取代 基取代：酶氧基、烯基、燒氧基、垸氧燒氧基、燒 狀基、μ羰基、㈣亞胺基1氧❹基、縣、燒 89248.doc 17 200418454 磺醯基、炔基、醯胺基、芳烷基、芳烷氧羰基、羧基、氰 基、甲醯基、齒烷氧基、齒烷基、卣素、羥基、羥烷基、 氫硫基、硝基、氧代基、硫烷氧基、NRaRb與（NRaRb)磺醯 基。 本文所使用之術語"羥基”指-〇H基團。 本文所使用之術語”羥烷基”指至少一個如本文中定義之 羥基利用如本文中定義之烷基附接在母分子部份基團上。 羥烷基之代表性實例包括（但不限於）：羥甲基、2_羥乙基、 2 -甲基乙基、3-邊丙基、2,3-二經戊基與2-乙基-4-護庚 基。 本文所使用之術語”羥基保護基，，指可於合成過程中保護 羥基對抗不期望反應之取代基。羥基保護基實例包括（但不 限於）：甲氧甲基、苯甲氧甲基、2-甲氧乙氧甲基、2气三甲 矽烷基）乙氧甲基、苯甲基、三苯甲基、2,2,2•三氯乙基、 第三丁基、三甲矽烷基、第三丁基二甲矽烷基、第三丁基 二苯矽烷基、亞甲基縮醛、亞異丙基、亞苯甲基縮醛、環 狀原酸甲氧亞甲基、環狀碳酸酯與環狀二輕删酸酯。 羥基保護基係藉由含有羥基之化合物與鹼（如··三乙胺）與選 自下列 < 試劑反應而附接在羥基上··烷基鹵化物、烷基三 氟甲砀酸酉曰、二烷基石夕烷基幽化物、三垸基矽院基三氟甲 磺酸酯、芳基二烷基矽烷基三氟甲磺酸酯或烷基氣甲酸酯 、CHd2或二鹵二羥硼酸酯，例如：與甲基碘、苯甲基碘' 三乙基矽烷基三氟甲磺酸酿、乙醯氯、苯甲基氣或二甲基 碳酸醋反應。保護基亦可藉由含有羥基之化合物與酸及烷 89248.doc -18 - 200418454 基縮酸反應而附接在經基上。 本文所使用之術語”亞胺基，，指_C(=NH)-基團。 本文所使用之術語”氫硫基，，指_SH基團。 本文所使用之術語”亞甲二氧基”指屮ch2〇_基團，其中亞 甲二氧基之氧原子利用兩個相鄰碳原子附接在母分子部份 基團上。 本文所使用之術語"-nrarb”指兩個基團：〜與RB利用氮 原子附接在母分子部份基團上。！^與、分別獨立選自：氫 、烷基、濟基與甲醯基。_NRaRb之代表性實例包括（但不限 於）··胺基、二甲基胺基、甲基胺基、乙醯基胺基與乙醯基 甲基胺基。 本文所使用之術語”（NRaRb)烷基，，指如本文中定義之 氺^、基團利用如本文中定義之烷基附接在母分子部份基 團上。（NRARB)烷基之代表性實例包括（但不限於）·· 2_(甲基 胺基）乙基、2-(二甲基胺基）乙基、2-(胺基）乙基、2气乙基甲 基胺基）乙基，等等。 本文所使用之術語”（NRaRb)羰基，，指如本文中定義之烷 基利用如本文中足義之故基附接在母分子部份基團上。垸 基羰基之代表性實例包括（但不限於）··甲基羰基、乙基羰基 、異丙基羰基、正丙基羰基，等等。 本文所使用之術語"（NRaRb)磺醯基”指如本文中定義之 -nrarb利用如本文中定義之磺醯基附接在母分子部份基團 上。（nrarb)磺醯基之代表性實例包括（但不限於广胺基磺 醯基、（甲基胺基）磺醯基、（二甲基胺基）磺醯基與（乙基甲 89248.doc -19- 200418454 基胺基）橫酿基。 本文所使用之術語，，硝基，，指-NOS基團。 本文所使用之術語，，氮保護基”指彼等計畫用於合成過程 中保護氮原子對抗不期望反應之基團。氮保護基包括胺甲 酸醋、驢胺類、N-苯甲基衍生物、與亞胺衍生物、較佳氮 保護基為乙酿基、苯甲醯基、苯甲基、苯甲氧羰基（cbz)、 甲醯基、苯磺醯基、特戊醯基、第三丁氧羰基（B〇c)、第三 丁基乙醯基、三氟乙醯基與三苯甲基。氮保護基係藉由含 胺基灸化，合物與鹼（如：三乙胺）與選自下列之試劑反應而附 接在一級或二級胺基上：烷基函化物、烷基三氟甲磺酸酯 、二烷基酸酐（例如：由（烷基_〇)2〇〇所代表）、二芳基酸酐 (例如：由（芳基-〇)2〇0所代表）、醯基鹵化物、烷基氣甲酸 酉曰或烷&醯基鹵化物、芳磺醯基鹵化物或鹵-CON(烷基）2 ，例如·乙醯氣、苯甲醯氯、苯甲基溴、苯甲氧羰基氯、 甲醯氟、苯磺醯氯、特戊醯氯、（第三丁基-〇-〇〇）2〇、三 氟乙酸酐與三苯甲基氯。 本文所使用之術語”羥基保護基"或，，0_保護基，，或,，氧保護 基扎於合成過程中保護羥基對抗不期望反應之取代基。羥 基保護基實例包括（但不限於）：經取代之甲基駿例如：甲氧 甲基、苯甲氧甲基、2-甲氧乙氧曱基、2-(三甲钱基）乙氧 甲基、苯甲基與二苯甲| ;四氫批喃基醚；經取代之乙基 醚例如· 2,2,2-二氯乙基與第三丁基；石夕燒基_，例如 三甲矽烷基、第三丁基-甲一 丞一甲矽烷基與第二丁基二苯矽燒基 •，環狀酸酸與縮酮，你I 1 t J例如·亞甲基縮醛、亞異丙基、亞苯 89248.doc • 20 - 200418454 甲基縮醛；環狀原酸酯，例如：甲氧亞甲基；環狀碳酸酯 ;與環狀二羥硼酸酯。 本文所使用之術語π氧代基"指（二〇）。 本文所使用之術語"續醯基’Hs(0)2-基團。 本文所使用之術語”硫烷氧基”指如本文中定義之烷基利 用硫原子附接在母分子部份基團上。硫烷氧基之代表性實 例包括（但不限於）：甲硫基、乙硫基、與丙硫基。 本文所使用之術語π擴抗劑’’包括及說明僅可防止受體被 Η3义月豆促，效劑（如·組織月；）活化之化合物，亦包括已知為，， 反促效劑’’之化合物。反促效劑為一種不僅防止受體被％ 艾m促效劑（如·組織胺）活化，而且會抑制内因性％受體活 性之化合物。 本發明化会物 本發明化合物如上述通式（I)。 如上述，Y與Y，分別為CH、CF*N’ χ、X，、2與2，分別 獨立選自C或N。 ^可為函素、氰基、或L2r6.，其係選自下列組成之群中 :-鍵結、-〇-、-c(哪、各、如本文中定義之-[c(Ri8)(R· 、如本文中定義之-0_[C(Rl8)(Ri9)]q…NH_與娜完基）_，與 尺6係選自下列組成之群中：芳基、雜芳基、雜環與環燒基。 典型地，Rl之取代基係選自：漠、氰基、或UR6.Rl之取 代基明確實例姆或氰基，包括(但不限於)：溴盘氰其、 較佳者，L2係選自：一鍵結、_〇_、_c(=〇)_、_s_或 -[C(R18)(Rl9)]q-。LA明確實例包括（但不限於）：调㈣-89248.doc -21 - 200418454 、-c(=〇)_，其中二2為一鍵結。:,: =, 7 are independently selected from nitrogen, oxygen, or sparse, or each other: Yuan Yu㈣ Examples include (but are not limited to): where-one carbon is 0 or S fragrance: set = ... 2 or 3_atoms The two carbon atoms in the fragrant clothes that are arranged in a suitable manner are replaced by an Oils atom and an N atom. Heteroaryl groups are used on a group. HeteroM, U are attached to the parent molecule part of the 4-square group "Representative examples include (but are not limited to): Weinan group, Weijun 89248.d〇, -16- 200418454 group, iso-4 4 group, isodistance Base, p-dithryl, succinyl, p-pyridyl, p-pyridyl, dacrotyl, dacrodone, pyridyl, pyridinyl, pyrimidinyl, rockyl, tetrazolyl, thiazyl Diazolyl, p-sedazolyl, thienyl or thiophenyl, triphenyl and triazolyl. Specific heteroaryl groups include (but are not limited to): 2H-daken-3-one-2-yl. The heteroaryl group of the present invention is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the following: fluorenyl, fluorenyloxy, alkenyl, alkoxy, alkoxyalkoxy, and oxofe Alkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkoxycarbonyl 4, alkylsulfonyl, block, fluorenyl, carboxyl, cyano, formamyl, self-alkoxy , -Alkyl, halogen, hydroxy, hydroxyalkyl, hydrogenthio, nitro, thioalkoxy, NRaR4 (NRaRb) sulfonyl. The term "heterocycle" as used herein refers to a heteroatom containing 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, which are 3, 4, $, 6, 7, or 8 members. A ring containing at least four members may be saturated or unsaturated. For example: 0 or 1 double bond with 5% member. The 6-membered ring has 0, 丨 or 2 double bonds. 7 and 8 farmers /, have 0 1, 2 or 3 double bonds. The heterocyclic group of the present invention can be attached to the parent molecular moiety using a carbon atom or a nitrogen atom. Representative examples of nitrogen-containing heterocycles include (but are not limited to): amidinyl, tendenyl, glutamyl, phyllyl, phenyl, hexahydropyridyl, hexahydropyridyl , Pyrrolidinyl, pyrrolidinyl, -M, and thiol. Representative examples of non-nitrogen-containing heterocyclic rings include, but are not limited to, tetrahydrofuranyl and tetrahydropyranyl. The heterocyclic ring of the present invention is substituted by 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of an enzyme oxy group, an alkenyl group, a carboxy group, a carbamoyl group, a carbolic group, a μcarbonyl group, and a fluorene group. Amino 1 oxo, oxo, keto 89248.doc 17 200418454 sulfo, alkynyl, hydrazino, aralkyl, aralkyloxycarbonyl, carboxyl, cyano, methylamido, alkoxy, dent Alkyl, halogen, hydroxy, hydroxyalkyl, hydrothio, nitro, oxo, thioalkoxy, NRaRb and (NRaRb) sulfonyl. The term "hydroxy" as used herein refers to a -OH group. The term "hydroxyalkyl" as used herein refers to at least one hydroxyl group, as defined herein, attached to the parent molecular moiety using an alkyl group, as defined herein. Representative examples of hydroxyalkyl include (but are not limited to): hydroxymethyl, 2-hydroxyethyl, 2-methylethyl, 3-sided propyl, 2,3-dipentyl and 2-ethyl-4-heptyl. As used herein, the term "hydroxy-protecting group" refers to a substituent that can protect a hydroxyl group against undesired reactions during synthesis. Examples of hydroxyl protecting groups include, but are not limited to: methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-trimethylsilyl) ethoxymethyl, benzyl, trityl , 2,2,2 trichloroethyl, third butyl, trimethylsilyl, third butyldimethylsilyl, third butyldiphenylsilyl, methylene acetal, isopropylidene, Bentyl acetals, cyclic ortho methoxymethylene, cyclic carbonates, and cyclic diheptyl esters. The hydroxyl protecting group is attached to a hydroxyl group by reacting a compound containing a hydroxyl group with a base (such as triethylamine) with a reagent selected from the following: alkyl halide, alkyl trifluoromethane , Dialkyllithium alkyl succinate, trimethylsilyl trifluoromethanesulfonate, aryldialkylsilyl trifluoromethanesulfonate or alkyl formate, CHd2 or dihalodihydride Borates, for example: react with methyl iodide, benzyl iodide 'triethylsilyl triflate, ethyl chloride, benzyl gas or dimethyl carbonate. The protecting group can also be attached to the meridian by reacting a compound containing a hydroxyl group with an acid and an alkane. 89248.doc -18-200418454 As used herein, the term "imino" refers to a -C (= NH)-group. As used herein, the term "hydrothio" refers to a -SH group. The term "methylenedioxy" as used herein refers to a 屮 ch20_ group in which the oxygen atom of the methylenedioxy group is attached to the parent molecular moiety group using two adjacent carbon atoms. The term " -nrarb " as used herein refers to two groups: ~ and RB are attached to a part of the parent molecular group using a nitrogen atom. ^ And are independently selected from the group consisting of hydrogen, alkyl, zirconium and Formamyl. Representative examples of _NRaRb include (but are not limited to) · Amine, Dimethylamino, Methylamino, Ethylamino and Ethylmethylamino. Terms used herein "(NRaRb) alkyl" refers to a group as defined herein, and the group is attached to the parent molecular moiety using an alkyl group as defined herein. Representative examples of (NRARB) alkyl groups include, but are not limited to, 2- (methylamino) ethyl, 2- (dimethylamino) ethyl, 2- (amino) ethyl, Ethylmethylamino) ethyl, and so on. The term "(NRaRb) carbonyl," as used herein, refers to an alkyl group, as defined herein, attached to the parent molecular moiety using a radical as defined herein. Representative examples of fluorenylcarbonyl include (but not Limited to) · methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, n-propylcarbonyl, etc. The term "(NRaRb) sulfonyl" as used herein means "nrarb" as defined herein The sulfofluorenyl group as defined in the above is attached to the group of the parent molecule. Representative examples of (nrarb) sulfofluorenyl include (but are not limited to, wide aminosulfofluorenyl, (methylamino) sulfofluorenyl, (dimethylamino) sulfofluorenyl, and (ethylmethyl 89248.doc -19- 200418454 based amino group). As used herein, the term, nitro, refers to the -NOS group. As used herein, the term "nitrogen protecting group" refers to their use in the synthesis process. Groups protecting nitrogen atoms against undesired reactions. Nitrogen protecting groups include carbamates, donkey amines, N-benzyl derivatives, and imine derivatives. Preferred nitrogen protecting groups are ethyl alcohol and benzamidine. Methyl, benzyl, benzyloxycarbonyl (cbz), formamyl, benzylsulfonyl, pentamyl, tert-butoxycarbonyl (Boc), tert-butylethylfluorenyl, trifluoroethyl Amidino and trityl. The nitrogen protecting group is attached to the primary or secondary amine group by reacting with amine-containing moxibustion, the compound and a base (such as: triethylamine) with a reagent selected from the following: Alkyl functional compounds, alkyl triflate, dialkyl anhydrides (eg, represented by (alkyl_〇) 200), diaryl anhydrides (eg, by (aryl-〇) 2 〇0)), fluorenyl halide, alkyl formate, or alkane & fluorenyl halide, arylsulfonyl halide or halo-CON (alkyl) 2, such as acetamidine, benzyl Fluorenyl chloride, benzyl bromide, benzyloxycarbonyl chloride, formamidine fluoride, benzenesulfonyl chloride, pentamidine chloride, (third butyl-〇-〇〇) 20, trifluoroacetic anhydride and triphenylmethyl The term "hydroxy-protecting group" or "0-protecting group" or "oxy-protecting group" as used herein is a substituent that protects a hydroxyl group against undesired reactions during the synthesis process. Examples of the hydroxyl-protecting group include ( But not limited to): Substituted methyl groups such as: methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethyloxy) ethoxymethyl, benzyl and dimethyl Benzyl |; tetrahydropyranyl ether; substituted ethyl ethers such as 2,2,2-dichloroethyl and third butyl; -Methyl-a-monosilyl and second butyldiphenylsilyl group, cyclic acid and ketal, you I 1 t J such as methylene acetal, isopropylidene, phenylene 89248. doc • 20-200418454 methyl Acetals; cyclic orthoesters, such as: methoxymethylene; cyclic carbonates; and cyclic dihydroxyborate. The term π oxo as used herein refers to (20). The term used " continuyl'Hs (0) 2- group. As used herein, the term "thioalkoxy" refers to an alkyl group, as defined herein, attached to the parent molecular moiety using a sulfur atom. Representative examples of thioalkoxy groups include (but are not limited to): methylthio, ethylthio, and propylthio. The term π antagonist as used herein includes and explains that it only prevents the receptor from being blocked. Yiyue Douyue, activators (such as tissue month;) activated compounds, also includes compounds known as, "anti-agonist". An anti-agonist is a compound that not only prevents the receptor from being activated by a% m agonist (such as histamine), but also inhibits the intrinsic% receptor activity. Compounds of the present invention The compounds of the present invention have the general formula (I). As described above, Y and Y are CH, CF * N 'χ, X, 2 and 2, respectively, and are independently selected from C or N. ^ Can be a halogen, cyano, or L2r6. It is selected from the group consisting of: -bond, -0-, -c (where, each, as defined herein-[c (Ri8) ( R ·, as defined herein -0_ [C (Rl8) (Ri9)] q ... NH_ and Na Wanji) _, and the ruler 6 are selected from the group consisting of aryl, heteroaryl, hetero Ring and cycloalkyl. Typically, the substituents of R1 are selected from the group consisting of: mo, cyano, or UR6. Examples of substituents of R1 or cyano include, but are not limited to, bromocyanine, preferably Or, L2 is selected from: one-bond, _〇_, _c (= 〇) _, _s_, or-[C (R18) (Rl9)] q-. Specific examples of LA include (but are not limited to): Tune -89248.doc -21-200418454, -c (= 〇) _, where 2 and 2 are a bond.

La為一键結最佳。R0之較佳基團為芳基、雜芳基、與環 坑基。芳基、雜芳基、與雜環基可未取代或經取代，例如 :如上述"術語之定義”中所說明。 尺6之芳基實例包括（但不限於）：苯基。苯基可經至少〇、j 或2個取代基取代。芳基之較佳取代基為氰基、鹵素、_NRaRb 、燒氧基、羥烷基、烷羰基、烷氧羰基、環烷羰基、硫烷 氧基、烷磺醯基與烷基。更佳之取代基為氰基。明確實 例包括（傳不限於）：4-氣苯基、3-氰基苯基、4-氰基苯基、 3,5-—氟苯基、4-(二甲基胺基）苯基、4-乙氧苯基、3-氟苯 基、4-氟苯基、3-羥甲基苯基、4-(.1-羥基-1-甲基乙基）苯基 、3-(甲基羰基）苯基、4-(甲基羰基）苯基、4-(甲基硫烷基） 苯基、4-(甲基磺醯基）苯基、4-甲氧苯基、4-(環丙基羰基） 表基、4-(曱氧鎪基）苯基與4-(三氟甲基）苯基。 一項特定具體實施例為式⑴化合物，其中Ri、L2R6，^ 為一鍵結，&為芳基，其中芳基為經〇、i或2個選自下列組 成之群中之取代基取代之苯基：氰基、函素、-NRaRb、烷 氧基、羥烷基、烷羰基、烷氧羰基、環烷羰基、烷磺醯基 、鹵烷基、與硫烷氧基。 R6之明確雜芳基包括（但不限於）：呋喃基、咪唑基、異哼 唑基、異噻唑基、哼二唑基、，唑基、吡畊基、吡唑基、 嗒畊基、嗒畊酮基、吡啶酮基、吡啶基、嘧啶基、吡咯塞 、四唑基、噻二唑基、p塞唑基、噻吩基、三畊基與三唑基 。本發明明確之雜芳基包括（但不限於）：呋喃-3-基、吡畊 89248.doc -22- 200418454 -2-基、吡唑-3-基、吡唑-4-基、吡啶-2-基、吡啶-3-基、吡 症-4-基、喃淀-2-基、喃淀-5-基、p比p各-2-基、l，3-p塞峻-2-基、l，3-4^-5-基、硫苯-3-基、與繞苯-2-基。本發明之雜 芳基亦包括2H-塔畊-3-酮，特定言之2H-嗒畊-3-酮-2-基，與 1H-吡啶-2-酮，特定言之1H-吡啶-2-酮-1-基。較佳雜芳基為 2H-嗒畊-3-酮-2-基。 雜芳基可經至少0、1、2或3個取代基取代。雜芳基之較 佳取代基為-NRARB、鹵素、烷基、氰基 '烷氧亞胺基、燒 氧談基、/NRARB)羰基、燒黢基、_垸基、與燒氧基。本發 明經取代之雜芳基之明確實例包括（但不限於）：胺基嘧啶 -5-基、3-溴異呤唑-5-基、3-氣吡啶-4-基、6-氯吡啶-3-基、 5- 氰基吡啶-3-基、3-氰基-2,6-二甲基吡啶-3-基、2,6-二氯 吡哫-3-基、2,6-二曱基吡啶-3-基、l，3-二甲基吡唑-4·•基、 1，5-—甲基p比峻-4-基、3,5-二甲基叶!：。坐-4-基、5-氰基p塞吩-2-基、2-氰基嘧啶-5-基、2,5-二甲基呋喃-3-基、3，5-二甲基噻 吩-2-基、5-(乙氧亞胺甲基）嘍吩^基、6-氟吡啶基、2,6_ 二氟说咬-3-基、4-(乙氧羰基）-3_甲基異崎唑基、3,5-二 甲基異4峻-4-基、3-(乙氧羰基）異吟唑-5_基、甲基吡畊-2_ 基、6-氟吡哫-3-基、6-甲基吡啶-3-基、2,6-二甲基-5-(胺基 羰基穴比啶-3-基、2,6-二甲基-5-(甲基羰基）说啶-3-基、4-羥 基-2-(三氟甲基）吡啶基、6-(甲基羰基”比啶_2_基、2，心 二甲氧’呢-5-基、6-甲氧吡啶-3 —基、5_甲氧吡啶_3-基、2,4-二甲基嘧唑-5-基、2,4-二甲基噚唑_5_基、6_氣嗒畊-3-基、 6- 甲氧塔讲-3-基、6_甲基嗒畊酮基、‘甲基吡啶酮基、與 89248.doc -23 - 200418454 l -(第二丁氧緵基）p比咯-2 -基。La is best for one bond. The preferred groups for R0 are aryl, heteroaryl, and cyclohexyl. Aryl, heteroaryl, and heterocyclic groups may be unsubstituted or substituted, for example, as described in the above " Definition of Terms ". Examples of aryl groups in Rule 6 include (but are not limited to): phenyl. Phenyl Can be substituted with at least 0, j or 2 substituents. Preferred substituents for aryl are cyano, halogen, _NRaRb, alkoxy, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, naphthenecarbonyl, thioalkoxy Groups, alkylsulfonyl groups and alkyl groups. More preferred substituents are cyano. Specific examples include (but are not limited to): 4-aminophenyl, 3-cyanophenyl, 4-cyanophenyl, 3,5 --- fluorophenyl, 4- (dimethylamino) phenyl, 4-ethoxyphenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxymethylphenyl, 4-(. 1 -Hydroxy-1-methylethyl) phenyl, 3- (methylcarbonyl) phenyl, 4- (methylcarbonyl) phenyl, 4- (methylsulfanyl) phenyl, 4- (methyl Sulfonyl) phenyl, 4-methoxyphenyl, 4- (cyclopropylcarbonyl) epi, 4- (fluorenyl) phenyl, and 4- (trifluoromethyl) phenyl. One specific A specific example is a compound of formula (I), wherein Ri, L2R6, ^ is a bond, & is an aryl group, wherein the aryl group is i or 2 phenyl substituted with a substituent selected from the group consisting of: cyano, functional group, -NRaRb, alkoxy, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, alkanesulfonium Aryl, haloalkyl, and thioalkoxy. R6's specific heteroaryl groups include (but are not limited to): furyl, imidazolyl, isoxazolyl, isothiazolyl, humidizolyl, oxazolyl, pyridyl Cultyl, pyrazolyl, dacrotyl, dacrodone, pyridone, pyridyl, pyrimidinyl, pyrrolidine, tetrazolyl, thiadiazolyl, pselazolyl, thienyl, tricronyl and Triazolyl. The heteroaryl groups specified in the present invention include (but are not limited to): furan-3-yl, pyran 89248.doc -22- 200418454-2-yl, pyrazol-3-yl, pyrazole-4- , Pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyran-2-yl, pyran-5-yl, p-to-p each 2-yl, 1, 3-p plug Jun-2-yl, 1,3-4 ^ -5-yl, thiophen-3-yl, and phen-2-yl. Heteroaryl groups of the present invention also include 2H-taghen-3-one, specifically In other words, 2H-daquin-3-one-2-yl, and 1H-pyridin-2-one, specifically 1H-pyridin-2-one-1-yl. A preferred heteroaryl group is 2H-daquin- 3-keto- 2-yl. Heteroaryl can be substituted with at least 0, 1, 2 or 3 substituents. Preferred substituents for heteroaryl are -NRARB, halogen, alkyl, cyano'alkoxyimine, and oxygen. Tanyl, / NRARB) carbonyl, alkynyl, fluorenyl, and alkoxy. Clear examples of substituted heteroaryl groups in the present invention include (but are not limited to): aminopyrimidin-5-yl, 3-bromo Isorazol-5-yl, 3-pyridyl-4-yl, 6-chloropyridin-3-yl, 5-cyanopyridine-3-yl, 3-cyano-2,6-dimethylpyridine- 3-yl, 2,6-dichloropyridin-3-yl, 2,6-dimethylpyridin-3-yl, 1,3-dimethylpyrazole-4-yl, 1,5 --- Methyl p than Jun-4-yl, 3,5-dimethyl leaves!:. Xy-4-yl, 5-cyano p-phenen-2-yl, 2-cyanopyrimidin-5-yl, 2,5-dimethylfuran-3-yl, 3,5-dimethylthiophene- 2-yl, 5- (ethoxyimidomethyl) fluorenyl, 6-fluoropyridyl, 2,6-difluoroalkoxy-3-yl, 4- (ethoxycarbonyl) -3-methyliso Oxazolidyl, 3,5-dimethyliso-4-benzyl-4-yl, 3- (ethoxycarbonyl) isoindazol-5-yl, methylpyridin-2-yl, 6-fluoropyridine-3- Group, 6-methylpyridin-3-yl, 2,6-dimethyl-5- (aminocarbonylpyridin-3-yl, 2,6-dimethyl-5- (methylcarbonyl) Pyridin-3-yl, 4-hydroxy-2- (trifluoromethyl) pyridyl, 6- (methylcarbonyl) than pyridin-2-yl, 2, cardiodimethoxy '?-5-yl, 6- Methoxypyridin-3-yl, 5-methoxypyridin-3-yl, 2,4-dimethylpyrazol-5-yl, 2,4-dimethyloxazole_5_yl, 6_yl Phen-3-yl, 6-methoxypyridin-3-yl, 6-methylpyridone, 'methylpyridone, and 89248.doc -23-200418454 l-(second butoxyfluorenyl ) P is slightly more than 2-base.

一項特定具體實施例為式⑴化合物，其中1為L2R6，L2 為一鍵結’汉6係選自下列組成之群中：呋喃基、異吟唑基 、’ σ坐基、吡唯基、吡唑基、吡啶基、吡啶酮基、嗒畊基 、< Ρ井網基、嘧啶基、吡咯基、噻唑基與嘧吩基，其係經〇 、1、2或3個選自下列組成之群中之取代基取代：-nrarb 、齒素、坑基、氰基、烷氧亞胺基、烷氧羰基、（nrarb) 談基、燒羰基、卣烷基、與烷氧基。 R6之紙環基包括（但不限於）：吖咩基、吖咀基、吖呒基、 4 k基、二氫噻唑基、嗎啉基、六氫吡畊基、六氫吡啶 基、说p各咬基、吡咯啶基、硫嗎啉基、四氫吡啶基及非含 氮雜環例如：四氫呋喃基與四氫呋喃基。雜環可經0、1或2 個如術#吾之定義”中所說明之取代基取代。本發明雜環之 明確實例包括（但不限於）：嗎啉-4-基、硫嗎啉-4-基、與4,5-A specific embodiment is a compound of formula ⑴, wherein 1 is L2R6, and L2 is a one-bonded 'Han 6 series is selected from the group consisting of furyl, isoxazolyl,' σ sitting group, pyrimidin, Pyrazolyl, pyridyl, pyridone, daphnyl, < P wellsyl, pyrimidinyl, pyrrolyl, thiazolyl, and pyrenyl, which are selected from the group consisting of 0, 1, 2 or 3 Substituents in the group are substituted: -nrarb, halo, pit, cyano, alkoxyimino, alkoxycarbonyl, (nrarb) alkoxy, carbonyl, fluorenyl, and alkoxy. Paper ring groups of R6 include (but are not limited to): acridine, acryl, acridine, 4k, dihydrothiazolyl, morpholinyl, hexahydropyridyl, hexahydropyridyl, and p Respective groups, pyrrolidinyl, thiomorpholinyl, tetrahydropyridyl, and non-nitrogen-containing heterocyclic groups such as tetrahydrofuryl and tetrahydrofuryl. The heterocyclic ring may be substituted with 0, 1 or 2 substituents as described in "the definition of" 我 ". Clear examples of the heterocyclic ring of the present invention include (but are not limited to): morpholin-4-yl, thiomorpholine- 4-based, and 4,5-

氣塞*1 2基。車父佳雜環為二氫p塞嗤基、嗎琳基、六氫外匕 哫基、吡咯哫基、硫嗎啉基與四氫吡喃基。 R6<明確環烷基包括（但不限於）：環丙基、環丁基、環戊 基、與環己基。 式⑴化合物中’當Z，為N時，R2不存在。當z，為C時，F :可分別獨立選自下列組成之群中：氫、烷基、烷氧基 万基、環〶基、自素、氰基、與硫燒氧基。R2之較佳基@ 、氫&基與環火見基。或者，R2可為鹵素、氰基、或l2e (如上述Rl之定義）。化合物中，R2為如式l2r6基團時，B 、選自下列、、且成之群中··氫、烷基、烷氧基、芳基、環务 89248.doc -24- 200418454 基、鹵素、氰基、與硫嫁氧基。 式⑴化合物中，當X’為N時’ I不存在。此外，當X，為〔 時，R;分別獨立選自下列組成之群中：氫、烷基、烷氧基 、環烷基、鹵素、氰基、與硫烷氧基。&之較佳基團為氫 、烷基、與環烷基。 式（I)化合物中，當2；為N時’ R^a不存在。此外，當z為〔 時，Rh分別獨立選自下列組成之群中：氫、甲基、燒氧基 、鹵素、與氰基。R3a之較佳基團為氫與甲基。 式⑴义合物中，當父為^^時，不存在。此外，當X為c 時，Rn分別獨立選自下列組成之群中：氫、烷基、烷氧基 _素·^基、氰基、與硫氧基。&之較佳基團為氣與 經基。 、 式（I)化合物中之R 4與R 5分別獨立選自下列組成之群中 k·基e5 k基、⑬燒基、燒氧燒基、環燒基、環燒基燒Air plug * 1 2 base. Chevron heterocycles are dihydropyridinyl, morphinyl, hexahydropyridinyl, pyrrolidinyl, thiomorpholinyl, and tetrahydropyranyl. R6 < clear cycloalkyl includes (but is not limited to): cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In the compound of formula VII, when Z is N, R2 is absent. When z is C, F: may be independently selected from the group consisting of hydrogen, alkyl, alkoxylyl, cyclofluorenyl, autogen, cyano, and sulfanyloxy. Preferred bases for R2 are @, hydrogen & Alternatively, R2 may be halogen, cyano, or 12e (as defined by R1 above). In the compound, when R2 is a group of the formula l2r6, B is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, ring, 89248.doc -24-200418454, halogen , Cyano, and sulfuryloxy. In the compound of formula (I), when X 'is N, I is absent. In addition, when X is [, R; is independently selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, halogen, cyano, and thioalkoxy. & The preferred groups are hydrogen, alkyl, and cycloalkyl. In the compound of formula (I), when 2; is N 'R ^ a does not exist. In addition, when z is [, Rh is independently selected from the group consisting of hydrogen, methyl, alkoxy, halogen, and cyano. Preferred groups of R3a are hydrogen and methyl. In the compound of formula 当, when the parent is ^^, it does not exist. In addition, when X is c, Rn is independently selected from the group consisting of hydrogen, an alkyl group, an alkoxy group, a cyano group, and a thio group. & A preferred group is qi and meridian. R 4 and R 5 in the compound of the formula (I) are independently selected from the group consisting of k · group e5 k group, fluorenyl group, oxyalkyl group, cycloalkyl group, cycloalkyl group

、與(NRaRb)烷基。較佳式⑴化合物中，R4與R5分別獨立 自：甲基、乙基、與丙基，特定言之異丙基。 R4/、R5吓可與其所附接之氮原子共同形成如下式之 香環：, And (NRaRb) alkyl. In the preferred compound of the formula (I), R4 and R5 are each independently selected from methyl, ethyl, and propyl, specifically isopropyl. R4 /, R5 can form a fragrance ring with the nitrogen atom attached to them together:

R13、R14、Rx、Rjm如R13, R14, Rx, Rjm such as

V 或 其中 R7、R8、r9、RlQ、Rii、Ri2、 89248.doc -25 - 200418454 本文中說明。 一項具體實施例中，D a R4M R5與其所附接之氮原子a同形 成4-至8_員如式⑷代表之非芳香環。 屬 8 9人Rl0可分別獨立選自下列組成之群中··筒、 羥烷基、氟烷基、血俨其 ^ ”砭基。或者，各成對之心與 R1〇可共同形成（：346環，勺g 衣包括其所附接之碳原子。 可包括0、1或2個選白η Λτ 4、 6衣 、自〇、Ν或S之雜原子來置換環 子。C3-C6環之實例白扛" 人眾 J匕括（但不限於）：環丙基、環丁芙 戊基、環,己基、吖口日其 &々、 土衣 「一基、吡咯哫基、環氧乙烷基，等V or where R7, R8, r9, RlQ, Rii, Ri2, 89248.doc -25-200418454 are described in this article. In a specific embodiment, D a R 4 M R 5 and the nitrogen atom a to which it is attached form the same 4- to 8-membered non-aromatic ring as represented by formula (I). The genus 89 people R10 can be independently selected from the group consisting of a tube, a hydroxyalkyl group, a fluoroalkyl group, a blood group, and other groups. Alternatively, each pair of hearts and R10 can form together (: 346 rings, including the carbon atom attached to it. It may include 0, 1 or 2 optional white η ττ 4, 6 and heteroatoms from 0, N or S to replace the ring. C3-C6 ring Examples of white carry " People's J (including but not limited to): Cyclopropyl, Cyclopentyl, Cyclo, Hexyl, Acryl & 々, Earthen coat "I base, Pyrrolyl, Ring Oxyethane, etc.

Rx與Ry分別獨立選自：氨、 胺基、二燒基胺“氟， 基，基、垸基 &amp;與鼠。此外，Rx與心中之一亦可代表 一键結，當與相鄰碳原子卜 &gt; 人眾于上足rx# Ry共同形成時 鄰碳原子之間之雙鍵。 由喊表之數值係選自山（包括5)_之較佳數值為2幻。 式⑴化合物亦為彼等式中，mR5與其所附接之氮原子 共同形成式（b)非芳香環之化合物，其中hi與‘如 上述式⑷中之定義；Rll、恥、Ri3與〜分別獨立選自下列 組成（群中：氫、羥基、羥烷基 '烷基與氟；Q為一鍵結， 或Q係選自下列組成之群中：◦、轉败&quot;，其中^係選自 下列組成〈群中.虱、燒基、醯基、醯胺基與甲驢基。較 佳者，r7、r8、別獨立選自··氫、甲基、乙芙、 氟甲基與羥甲基。土 土 13〃 Kl4刀別為氫較佳。或者 ，11與12為氫較佳。尺㈠與心4分別獨立選自··氫戋俨芙， R7、R8、119與RI〇如上述定義。 土 89248.doc -26- 200418454 式中I與RS與其所附接之氮原子共同形成式（&amp;)4_至8_員 非芳香環之化合物包括（但不限於）：彼等其中‘至、員非芳 香環係選自：.丫咀基、吖咩基、吖吁基、吡咯啶基、吡咯 啉基、六氫吡啶基、六氫吡畊基與四氫吡啶基。該環可經〇 、1或2個如上述”術語之定義”中所說明之雜環基之取代基Rx and Ry are independently selected from the group consisting of: ammonia, amine, dialkylamine, "fluoro, phenyl, phenyl, fluorenyl & and rat. In addition, one of Rx and the heart can also represent a bond, and when adjacent to carbon Atomic Bulk> Double bonds between adjacent carbon atoms when people form together on the upper leg rx # Ry. The value from the table is a value selected from the mountain (including 5). In their formulas, mR5 and the nitrogen atom to which it is attached together form a non-aromatic ring compound of formula (b), where hi and 'are as defined in the above formula ⑷; Rll, sha, Ri3 and ~ are independently selected from the following Composition (in the group: hydrogen, hydroxy, hydroxyalkyl 'alkyl and fluorine; Q is a bond, or Q is selected from the group consisting of: ◦, turnover &quot;, where ^ is selected from the following composition < In the group, lice, sulphenyl, amidine, amido and medonyl. Preferably, r7, r8, are independently selected from the group consisting of hydrogen, methyl, ethyl, fluoromethyl and hydroxymethyl. Soil 13〃 Kl4 knife is preferably hydrogen. Or, 11 and 12 are preferably hydrogen. Ruler and heart 4 are independently selected from ... Hydrogen, R7, R8, 119 and RI〇 are as defined above. Soil 89 248.doc -26- 200418454 In the formula, I and RS together with the nitrogen atom to which they are attached form a 4 to 8 member non-aromatic ring compound including (but not limited to): among them, to, The non-aromatic ring system is selected from the group consisting of: acyl, acryl, acryl, pyrrolidinyl, pyrrolinyl, hexahydropyridyl, hexahydropyridyl, and tetrahydropyridyl. The ring can be passed through. , 1 or 2 substituents of heterocyclic group as described in "Definition of Terms" above

取代。較佳取代基係選自下列組成之群中：烷基、_素、 經烷基、氟烷基與_NRaRTo replace. Preferred substituents are selected from the group consisting of: alkyl, _ prime, via alkyl, fluoroalkyl and _NRaR

、rar5基團亦可與其所附接之氮原子共同形成4_至8_員 式⑷或&lt;(b)非芳香環，其中該環經至少—個選自下列之取 代基取代：基、ώ素、氟垸基或經基燒基。 rar5之更明確基團包括例如：彼等其中r^r5與其所 附接之氮原子共同形成選自下列之4_至8_員非芳香環者:嗎 «與硫嗎#基，及未取代或經取代之峨w基，例如： 甲基術基’乙基峨嘻淀基、二甲基胺基術基、異 丙基？比㈣基、異τ基峨略«、幾甲基㈣咬基、與氟The rar5 group may also form a 4_ to 8_ member ⑷ or &lt; (b) non-aromatic ring together with the nitrogen atom to which it is attached, wherein the ring is substituted with at least one substituent selected from the group: Free vegetarian, fluorenyl or mesyl. More specific groups of rar5 include, for example: those in which r ^ r5 and the nitrogen atom to which they are attached together form a 4_ to 8_ member non-aromatic ring selected from the following:? «与 thio 吗 # group, and unsubstituted Or substituted oxenyl groups, such as: methylethynyl'ethylethionyl, dimethylaminoethynyl, isopropyl? Titanyl, Iso-tyl-Eluyl «, Isomethylpyridyl, and Fluorine

甲基吡各哫基。較佳為吡咯啶基，特定言之甲基吡咯啶基 ，例如：2-甲基吡嘻咬基。 R4與I與其所附接之氮原子共同形 '項具體貫施例中 其中R7、R8、R@R1〇中至少一個 氟烷基或烷基。此具體實施例中 成式（a)或式（b)非芳香環， 取代基係選自··輕纟完基、 7 / 8 R9人Rl0中至少一個係選自：甲基、乙基、氟甲 基匕1基等等。此等具體實施例中，特別佳為R7、r8 、R9與R丨0所代表之一徊 個取代基為烷基，特定言之甲基，其 他三個取代基則為氫。 89248.doc &gt;27- 200418454 一項明確之具體實施例係有關式⑴化合物，其中114與r5 與其所附接之氮原子共同形成式（b)非芳香環，Q為NR15。 此等具體實施例中，R15最好選自··氫、烷基、醯胺基、或 甲酿基。 L所代表足邵份基團可為， 其中Ri6與R!7分別獨立選自下列組成之群中··氫、烷基、烷 氧基、與氟’η為選自1至6 (包括6)之整數，p為選自2至6 (包Methylpyridinyl. Preferred is pyrrolidinyl, specifically methylpyrrolidinyl, such as 2-methylpyridinyl. R4 and I are co-formed with the nitrogen atom attached thereto. In the specific embodiment, at least one of R7, R8, and R @ R1〇 is a fluoroalkyl group or an alkyl group. In this specific embodiment, the formula (a) or formula (b) is a non-aromatic ring, and the substituent is selected from the group consisting of: light fluorenyl, 7/8 R9 human R10 and at least one selected from: methyl, ethyl, Fluoromethyl dagger, etc. In these specific examples, it is particularly preferred that one of the substituents represented by R7, r8, R9, and R0 is an alkyl group, specifically methyl, and the other three substituents are hydrogen. 89248.doc &gt; 27- 200418454 A specific specific example relates to compounds of formula (I), in which 114 and r5 together with the nitrogen atom to which they are attached form a non-aromatic ring of formula (b), and Q is NR15. In these embodiments, R15 is preferably selected from the group consisting of hydrogen, alkyl, amido, or methyl. The foot group represented by L may be, wherein Ri6 and R! 7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, and fluorine'η is selected from 1 to 6 (including 6 ), P is an integer selected from 2 to 6 (including

括6)之整數。尺^與Ri7為氫較佳。Ν之較佳數值為2或3。ρ 之較佳兔值為2。 L2可為一鍵結或係選自·· _〇_、_c(=⑺_、、_[c(r〗以Ri9)]q_ 、-NH-、-N(烷基）-，其中^^與心9分別獨立選自下列組成之 群中·氫、羥基、烷基、烷氧基與氟，與q選自丨至4(包括 4)之整數。-N(烷基）_中之烷基最好包含丨至6個碳。本發明 化口物可如式（I) ’其中一為_[c(Ri8)(Ri9)k，〜與Ri9為氣 ’ q為1、2、3或4。q之較佳數值為i。 式（I)化合物為彼等式 甲h為暴圈L2R( 敉佳Include the integer of 6). Ruler and Ri7 are preferably hydrogen. The preferred value of N is 2 or 3. The preferred rabbit value for ρ is 2. L2 may be one-bonded or selected from the group consisting of _〇_, _c (= ⑺_ ,, _ [c (r] to Ri9)] q_, -NH-, -N (alkyl)-, where ^^ and Heart 9 is independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, and fluorine, and q is selected from integers from 4 to 4 inclusive. -N (alkyl) _ alkyl in It preferably contains 6 to 6 carbons. The chelating substance of the present invention can be represented by the formula (I) 'one of which is _ [c (Ri8) (Ri9) k, ~ is gas with Ri9', and q is 1, 2, 3, or 4 The preferred value of q is i. Compounds of formula (I) are their formulas. H is a burst L2R ((佳

鍵結’以為雜芳基或雜環.；R2、R3、4與^為氮；L -[C(R16)(R17)]n- ; n為 2 ; Ri6 與 Rn每次出現時，為氫；κ R5共同形成式⑷甲基,比㈣基環，其中R7、R8、r^Ri( 之一為甲基，其餘三個取代基為氫；丫與¥，為ch; χ、 、ζ與ζ’為〇較佳雜芳基為㈣酮基，更特定言之“答 -3 -嗣-2-基。 在環系方面，由X、X， 個原子可為氮。 Υ’、Ζ與Ζ，所代表之〇、丨或2 89248.doc -28- 200418454 本發明化合物可如式⑴，其中¥與¥，為ch ; χ、χ,、2與 Z，為 c ;且 r2、R3、R3a與 R3b為氫。 或者’本發明化合物可如式（I)，其中Y與Y，為CH ; x、 人Z為c，且R3、u 為氫；z,為N ;且不存在。 本务明化合物亦可如式⑴，其中Y與丫，為CH ; X，' z，與 為C，R2 h與R3a為氫；X為n ;且R3b不存在。 、本發明亦包括式⑴化合物，其中¥與丫，為CH ; χ、乂，與汐 為c ’ R2、R3與R3b為氫；Z*N ;且尺&amp;不存在。 另一項，具體實施例中，本發明化合物可如式（〗），其中丫為 CH ’ X、X、z與 Z’為 c ; R2、r3、R3a與 R3b為氫；γ^Ν。 另一項具體實施例中，本發明化合物可如式（I)，其中γ 與Υ為CH，X與Ζ’為c ; R2與R3b為氫；x，gN ; ;且心 與不存在。 另一項具體實施例係有關本發明式⑴化合物，其中X、χ, 、2與2’為 C ; R2、R3、R3a與 R3b為氫；且 Υ為 Ν ;且 YAN。 另一項具體實施例中係有關本發明式⑴化合物，其中Y， 為 CH，X、X’與 z為 c ;且 R3、R3a與 R3b為氫；且 ΥΛΝ ; z， 為Ν，且R〗不存在。 另一項具體實施例係有關本發明式⑴化合物，其中γ，為 CH ’ X、Ζ與 Ζ’為 C ; R2、R3a與 u為氫；γ、Ν ; χ’為 Ν ;且 R3不存在。 另一項具體實施例係有關本發明式⑴化合物，其中γ，為 CH ’ X、X’與Ζ’為C ; R2、厌3與^為氫；γ為Ν ; ζ為Ν ;且 R3a不存在。 B9248.doc -29- 200418454 另一項具體實施例係有關本發明式（i)化合物，其中γ CH，Χ、Χ 與义為^^ ; R3、R3a與R3b為氫；Υ4Ν ; Ζ，為 Ν ; ϋ 不存在。 另一項具體實施例係有關本發明式（I)化合物，其中Y與 Υ為CH，Ζ與ζ為C ; RjR3a為氳；X,為Ν ; χ為Ν ;且化與 R3b不存在。 、本毛月亦可為式⑴化合物，其中Y，為CH ; X、X，、Z與 z 為 c，R2、r3、R3a、與 為氫；且 γ為 N。 另一灵具體實施例中，本發明可為式⑴化合物，其中γ 與Υ’為CH; X’與Z4C; R^R3為氫；χ為Ν; ζ為&amp;且心 與R*3b不存在。 另一項具體實施例係有關本發明式⑴化合物，其中γ為 CH ’ X、z’與 Z4C ; R2、R3a與 R3b為氫；Y，為 N ; X，為 N ;且 R3不存在。Bonded 'is a heteroaryl or heterocyclic ring; R2, R3, 4 and ^ are nitrogen; L-[C (R16) (R17)] n-; n is 2; Ri6 and Rn are hydrogen each time they appear ; Κ R5 together form a fluorene methyl group, a fluorenyl ring, in which one of R7, R8, r ^ Ri (one is methyl, and the remaining three substituents are hydrogen; y and ¥, ch; χ,, ζ and ζ 'is 0. The preferred heteroaryl group is fluorenone, more specifically "A-3-fluoren-2-yl. In the ring system, from X, X, atoms can be nitrogen. Υ', Z and Z, represented by 0, 丨 or 2 89248.doc -28- 200418454 The compound of the present invention can be represented by formula ⑴, where ¥ and ¥ are ch; χ, χ, 2 and Z are c; and r2, R3, R3a and R3b are hydrogen. Alternatively, the compound of the present invention can be represented by formula (I), wherein Y and Y are CH; x, human Z is c, and R3 and u are hydrogen; z is N; and does not exist. The compound can also be as shown in formula ⑴, where Y and y are CH; X, 'z, and C, R2 h and R3a are hydrogen; X is n; and R3b does not exist. The present invention also includes compounds of formula ⑴ , Where ¥ and y are CH; χ, 乂, and xi are c 'R2, R3 and R3b are hydrogen; Z * N; and the rule &amp; does not exist. In embodiments, the compound of the present invention can be represented by formula (), wherein y is CH ′, X, z, and Z ′ are c; R2, r3, R3a, and R3b are hydrogen; γ ^ N. Another specific implementation In the example, the compound of the present invention can be represented by formula (I), wherein γ and Υ are CH, X and Z ′ are c; R2 and R3b are hydrogen; x, gN; It is related to the compound of formula ⑴ according to the present invention, wherein X, χ,, 2 and 2 'are C; R2, R3, R3a and R3b are hydrogen; and Υ is N; and YAN. Another embodiment relates to the present invention. A compound of formula VII, wherein Y is CH, X, X 'and z are c; and R3, R3a and R3b are hydrogen; and ΥΛN; z is N, and R is absent. Another specific embodiment is related The compound of formula (I) according to the present invention, wherein γ is CH ′, X, Z, and Z ′ are C; R2, R3a, and u are hydrogen; γ, N; χ ′ is N; and R3 does not exist. Another specific embodiment is Regarding the compound of formula VII of the present invention, wherein γ is CH ′ X, X ′ and Zn ′ are C; R2, anion 3 and ^ are hydrogen; γ is N; ζ is N; and R3a does not exist. B9248.doc -29 -200418454 Another specific implementation The examples are related to the compound of formula (i) of the present invention, wherein γ CH, χ, χ, and ^ are ^^; R3, R3a, and R3b are hydrogen; Ν4N; Z, Ν; ϋ does not exist. Another specific embodiment relates to the compound of formula (I) of the present invention, wherein Y and Υ are CH, Z and ζ are C; RjR3a is 氲; X is Ν; χ is Ν; and R3b does not exist. The present month may also be a compound of formula ⑴, where Y is CH; X, X, Z, and z are c, R2, r3, R3a, and are hydrogen; and γ is N. In another specific embodiment, the present invention may be a compound of formula ⑴, wherein γ and Υ 'are CH; X' and Z4C; R ^ R3 is hydrogen; χ is N; ζ is &amp; and R * 3b is not presence. Another specific embodiment relates to the compound of formula VII of the present invention, wherein γ is CH'X, z 'and Z4C; R2, R3a and R3b are hydrogen; Y is N; X is N; and R3 is absent.

田出現由R2、R3、R3a與R3b代表之取代基時，Z丨、X丨、Z fX分別代表可經R2、Rs、Rsa與R3b所代表之取代基取代之 · 蛟原子。本發明化合物之明確實例包括（但不限於）： 4-(6-{2-[(2幻-2-甲基-1-吡咯啶基]乙基卜2_莕基）苯基氰； (2R)-l-[2-(6-溴-2-萘基）乙基甲基吡咯啶； 1 [3-(6- {2-[(2R)-2-甲基-1-吡咯啶基]乙基卜2_萘基）苯基] 乙酮； 2-[3-(6-{2-[(211)-2-甲基_1-吡咯啶基]乙基}_2-萘基）苯基-] -2 -丙醇； 6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜2-莕基氰； 89248.doc -30- 200418454 4-(6-{[(2R)-2-甲基-1-吡咯啶基]甲基卜2_萘基）苯基氰； 3- (6-{2-[(2R)-2-甲基-1-说，各啶基]乙基}·2_茶基）苯基氯； 4- (6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基莕基）ρ比啶； 3- (6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基萘基）吡啶； (3-氟苯基）（6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜2_萘基） 甲醇； 3,5-—甲基-4-(6-{2-[(211)-2-甲基-1-吡咯啶基]乙基卜2_萘 基）異呤唑； 4- (6-{^[(2S)-2-(羥甲基）-1-吡咯啶基]乙基卜孓莕基）苯基 氰； 4-(6-{2-[(3R)-3-羥基-1-吡咯啶基]乙基萘基）苯基氰； 4-{6-[2-(2-異丁基-1-吡咯啶基）乙基]-2_莕基}苯基氰； 4-{6-[2-(2-異丙基-1-吡咯啶基）乙基]-2_茬基}苯基氰； 4-(6-{2-[(3R)-3-(二甲基胺基卜丨-吡咯啶基]乙基卜2_萘基） 苯基氰； 4-{6-[2-(二乙基胺基）乙基]-2-萘基}苯基氰； 4-{6-[2-(二甲基胺基）乙基;μι莕基丨苯基氰； 4-(6-{2-[乙基（異丙基）胺基]乙基卜2_萘基）苯基氰； 4-(6-{2-[第二丁基（甲基）胺基]乙基卜2_莕基）苯基氰； 4-(6-{2-[(2S)-2-甲基-1-吡咯啶基]乙基卜2_莕基）苯基氰； 4-(6-{2-[(2R)-2-甲基-1-六氫吡啶基]乙基卜2·萘基）苯基 氰； - 4-{6-[2-(2,5-二氫-1Η-吡咯-1-基）乙基]-2-萘基}苯基氰； 4-(6-{2-[甲基（丙基）胺基]乙基卜2_莕基）苯基氰； 89248.doc -31- 200418454 4- (6-{2-[(2-經乙基）（甲基）胺基]乙基卜2-¾:基）苯基氰； 5- (6-{2-[(211)-2-甲基_14比咯啶基]乙基卜2_萘基）嘧啶； 4-(6-{2_[(2R)-2-甲基-Ι-p比洛淀基]乙基卜2·萘基）嗎啉； 2-(6-{2-[(2R)-2 -甲基- Ι-p比口各咬基]乙基卜2-審基）·〗3-?塞 口坐； 4-(6-{2-[(2S)-2-(氟甲基）-1-p比哈咬基]乙基卜2_審基）苯基 氰： (3-氟苯基）（6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜2_萘基） 甲酮；， 2 -（6-{2-[(2R)-2-甲基- Ι-p比洛咬-1-基]-乙基卜2_茶基） -2H_嗒畊-3-酮； 2- 甲氧- 5-(6-{2-[(2R)-2-甲基-1-吡洛淀基]乙基卜2-莕基） 吡啶； 4-(6- {2-[(2R)-2-(#呈甲基）小吡洛啶基]乙基卜h莕基）苯基 氰； 4-{6-[2-(2-甲基-1-吡咯啶基）乙基]_2_莕基}苯基氰； 4-{6-[2-(1-吡咯啶基）乙基]-2-莕基}苯基氰； 4-(6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜2-莕基）硫嗎啉； 1-{2-[(6-&gt;臭-2 -秦基）氧]乙基}?比口各淀； 3- {6-[2-(1-吡咯啶基）乙氧基]-2-莕基}苯基氰； 3-{6-[2-(1-吡咯啶基）乙氧基]_2-莕基}吡啶； 3-(6-{2-[(2R)-2-甲基-1^比咯啶基]乙氧基卜2-莕基）苯基 氰； 3-(6-{2-[(2R)-2-甲基-Ι-p比洛淀基]乙氧基}_2_莕基）p比淀； 89248.doc -32- 200418454 4-(2-{2-[(2R)-2-甲基-1-叶匕略淀基]乙基卜奎琳基）苯基 氰； 6-(4-氟苯基）-2-{2-[(211)-2-甲基_14比咯啶基]乙基}喳啉； 3- (2-{2-[(2R)-2-甲基- Ι-p比洛淀基]乙基}-6-口奎α休基）苯基 氰； 1- [3-(2-{2-[(2R)-2-甲基-1-吡洛啶基]乙基}_6-?奎π林基）苯 基]乙酮； 6-（4-甲氧苯基）-2-{2-[(2R)-2-甲基-1-吡咯啶基]乙基}峻 淋； ， 2- {2-[(2R)-2 -甲基-l-p比洛淀基]乙基}-6-[4-(三氟甲基）苯 基]邊琳； 2 - {2-[(2R)-2-甲基-1-吡咯啶基]乙基}-6-[4-(甲續醯基）苯 基]峻琳； 6-(3,5-二氟苯基）-2-{2-[(2R)-2-甲基-1-吡咯啶基]乙基} 口奎口林； (3-氟苯基）（2-{2-[(2R)-2-甲基-1-P比咯啶基]乙基卜6-喹琳 基）甲酮； 2- {2-[(2R)-2-甲基- Ι- p比嘻淀基]乙基}-6-(3-p比淀基）ργ奎琳； 4- (3- {2-[(2R)-2-甲基-1-吡咯啶基]乙基卜7-異喳啉基）苯 基氰； 3- (3-{2-[(2R)-2-甲基-1-吡咯啶基]乙基}-7-異喳啉基）笨 基氰； ~ 6 - {2 - [ (2 R) - 2-甲基- Ι- p比p各咬基]乙基}-2-(3-ρ比淀基）p奎琳； 6-{2-[(2R)-2 -甲基- Ι- p比ρ各咬基]乙基}-2·(4-ρ比淀基）p奎琳； 89248.doc -33 - 200418454 6 - {2-[(2R)-2 -甲基-l-p比p各淀基]乙基} - 2-(2-p比啶基）。奎琳； 6-{2-[(2R)-2 -甲基-1-吡咯啶基]乙基}·2_(ι，3-嘧唑-2-基） Ρ奎淋； 2 -（2,4-二甲基-1，3-喧唾_5-基）-6-{2-[(21^)-2-甲基-1-外匕咯 啶基]乙基}喹啉； 6- {2-[(2R)-2-甲基-1-吡咯啶基]乙基卜2-(2-吡畊基）喳啉； 1- [6-(6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜喳啉基）-2-吡啶基]乙酮； 4-(2-{L[(2R)-2-甲基-1-吡咯啶基]乙基卜奎噚啉基）苯 基氰； 4-(3-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜6_喹噚啉基）笨 基氰； 7- (2,6-二氟-3-p比啶基）-3-{2-[(2R)-2-甲基_;μΡ比咯啶基]乙 基}異ρ奎淋； 3- {2-[(2R)-2-甲基-1-吡咯啶基;]乙基卜7^3-ρ比啶基）異口查 P林； 3- (苯甲氧基）-2-甲基-6-{2-[(2R)-2-甲基-l_P比咯啶基]乙 基} 0奎琳； 2- 環丙基冬{2-[(2R)-2 -甲基-l-p比洛淀基]乙基}峻P林； 4- (6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜奎啉基）苯基 氰； 2,6-一甲基_5-(6-{2-[(211)-2-甲基-1-17比洛淀基]乙基卜2-4 啉基）菸基氰； 2-(3-甲基-2-吡畊基）-6-{2-[(2R)-2-甲基-1-吡咯啶基]乙 89248.doc -34- 200418454 基}7奎#木； 5-(6-{2-[(2R)-2 -甲基- Ι-p比洛咬基]乙基卜2-嗜#木基）-3-異 吟唑羧酸乙酯； 5-(6-{2-[(2R)-2 -甲基- Ι-p比哈淀基]乙基卜2-。奎#木基）-2-p塞 吩腈； 5- (6-{2-[(2R)-2-甲基-l-p比p各口定基]乙基卜2 -峻琳基）-2-p塞 吩羧基亞胺酸乙酯； 2-(2,4-二甲基-1，3-口号唑_5_基）-6-{2-[(211)-2-甲基_1-吡咯 啶基]乙朞}喹啉； 3 -甲基- 5- (6-{2-[(2R)-2-甲基- Ι- p比洛淀基]乙基}-2 -峻琳 基）-4-異噚唑羧酸乙酯； 4- (7-{2-[(2R)-2 -甲基- Ι- p比洛淀基]乙基卜3-異峻琳基）苯 基氰； 6- {2-[(2R)-2-甲基-1-吡咯啶基]乙基}-2-(4-甲氧苯基）喹 口咢口林； 7- {2-[(2R)-2-甲基- Ι- p比洛咬基]乙基}-2-(4-甲氧苯基奎 口咢.； 6- {2-[(2R)-2 -甲基- Ι- p比洛淀基]乙基}-2 -苯基峻。号琳； 7- {2-[(2R)-2-甲基-Ι-p比洛咬基]乙基卜2-苯基峻口号琳； 6-{2-[(2R)-2-甲基- Ι-p比咯啶基]乙基卜2-(3-p比啶基）喳唑 淋； 6-甲基- 2-{6_[2-((2R)-2-甲基比洛淀-i_基）_乙基]-莕_2-基}-21嗒畊-3-酮； 5- {6-[2-((2R)-2-甲基比咯啶-^基）_乙基]_莕基卜嘧啶 89248.doc 、35 - 200418454 -2-腈； 1- {6-[2-(2(R)·甲基-ρ 比嘻·淀-1-基）-乙基]比 淀-2 -酉同； 5 - {6-[2-(2(R)-甲基-π比洛淀-1-基）-乙基]-奈-2-基}-於基氰; 4-甲基-l-{6-[2-(2(R)-甲基-吡咯啶-1-基）-乙基]-萘_2-基} -1H-吡啶-2-酮； 2- {6-[2-((2R)-2 -甲基-峨^7各淀-1-基）-乙基]-奈-2-基}-??比啡； 2-{6-[2-((2R)-2-甲基-2,5-二氫-吡咯-1-基）-乙基]-莕-2-基} -2H-嗒畊，-3-酮； 4-(6-{2-[(2-二甲基胺基-乙基）-甲基-胺基]-乙基}-莕_2_ 基）-苯基氰； 4-{6-[2-(4-甲基-六氫吡畊-1-基）-乙基]-莕-2-基卜苯基氰； 2-(2,5--一 甲基&quot;咬喃-3-基）-6-{2-[(2R)- 2-甲基-1-ρ比洛淀基] 乙基卜喳啉； 6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基}-2-(4-甲硫烷基-苯 基）-口奎p林； 2-(6-甲基-晚啶-3-基）-6-{2-[(2R)-2-甲基-1-吡咯啶基]乙 基} - p奎淋； 2-(1,3-二甲基-1H-吡唑-4-基）-6-{2-[(2R)-2-甲基-1-吡咯 淀基]乙基}-ρ奎淋； 6-{2-[(211)-2-甲基-1-吡咯啶基]乙基}-2-硫苯-3-基-喹啉； 6-{2-[(2尺)-2-甲基-1^比咯啶基]乙基}-2-嘧啶-5-基-喳啉_; 2-(2,6-二甲基-吡啶-3-基）-6-{2-[(211)-2-甲基-1-吡咯啶基] 乙基] -p奎淋， 89248.doc -36- 1- [2,6-二甲基- 5-(6-{2-[(2R)-2 -甲基吡咯啶基]乙基卜 口奎琳-2 -基）-p比淀-3 -基]-乙酮； 6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜2_(2H_吡唑_3-基）_ 口奎琳； 2 (3-/大-兴崎吐-5-基）-6-{2-[(2R)-2-甲基- Ι- p比p各淀基]乙 基}-嗜琳； 2- (6-氯-吡哫-3-基）-6_{2-[(2R)-2-甲基-1-吡咯啶基]乙基} -口奎琳； 2-(3,5-，二甲基-硫苯基-2-基）-6-{2-[(211)-2-甲基-1-吡咯啶 基]乙基} - ρ奎淋； 6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜2_硫苯-2_基_喹啉； 2- 吱喃-3-基-6 - {2-[(2R)-2 -甲基-l-p比洛淀基]乙基卜峻琳； 2 -（4,5-二氫-噻唑-2-基）-6-{2-[(2R)-2-甲基-1-吡咯啶基] 乙基} - 口奎淋； 1- [4-(6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜喹啉_2-基）_ 苯基]-乙酮； 3- (6-{2-[(2R)-2 -甲基- l-p比p各淀基]乙基卜p奎琳基）-2-三 氟甲基4比淀-4-醇； 2- (3,5-二甲基-1H-吡唑-4-基）-6-{2-[(2R)-2-甲基-1-吡咯 淀基]乙基} * ^奎p林， 6-{2-[(2R)-2-甲基- i-P比咯啶基]乙基卜2-(1Η-吡唑-4-基）- 口奎口林； ' 2,6-二甲基-5-(6_{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜喹 啉-2-基）-菸醯胺； -37- 89248.doc 200418454 2-[2-(2R-甲基-p比洛淀-1-基）一乙基]_6_淀-4-基-峻 ; 6-(6-甲氧-峨啶-3-基）-2-[2(R)-(2-甲基-哎咯啶-^基）·乙基]_ 口奎4木； 6-(2,6 - —氟-外匕淀-3-基）-2-[2-(2(R) -甲基-口比p各淀-1·基）_乙 基]-P奎淋； 6-(6-氯-咕淀-3-基）-2-[2-(2(R) -甲基-峨嘻咬_^基）_乙基]_ 口奎p林； 6-(2,6-—氯-叶匕淀-3-基）-2-[2-(2(11)-甲基-17比洛淀_11-基）_乙 基]-峻琳，； 2-[2-(2(R)-甲基-?比咯啶小基）_乙基]·6·吡畊士基^套琳； 2-[2-(2(R) -甲基-ρ比ρ各淀-1-基）-乙基]_6-喊咬-5-基-ρ奎淋； 6-(2,4-一甲氧- π密咬-5-基）-2-[2-(2(R) -甲基-p比洛違-1_基）_ 乙基]-峡p林； 二甲基-(4-{2-[2-(2(R)-甲基4咯啶-1-基）-乙基]^奎啉_6-基卜苯基:l·胺； l-(4-{2-[2-(2(R) -甲基- 各咬-1-基）-乙基]查淋-6—基}_ 苯基）-乙酮； 6-(4-氣-苯基）-2-[2-(2(R)-甲基-吡咯啶-1-基）_乙基]_喹啉； 6-(2,6-二甲基-叶匕淀-3-基）-2-[2-(2(尺)-甲基-^比哈淀-1-基）-乙基]-π奎淋； 6-(5 -甲氧- π比淀-3-基）-2-[2-(2(R) -甲基-p比p各淀-1_基）-乙 基]-p奎p林， 6-(3,5-二甲基-異。号1?坐-4-基）-2-[2-(2(义)-甲基-0比洛淀-1-基）-乙基]-0奎啉； 89248.doc -38- 200418454 4- {2-[2-(2(R)-甲基-批咯啶-1-基）-乙基]-喳啉-6-基卜苯甲 酸甲酯； 2- [2-(2(R)-甲基-被咯啶-1-基）-乙基]-6-(4-甲硫烷基-苯基) -口奎口林； 6-(6-氟-说啶-3-基）-2-[2-(2(R)-甲基-吡咯啶-1-基）-乙基]- 口奎口林； 5- {2-[2-(2(11)-甲基-吡咯啶-1-基）-乙基]-喹啉-6-基}-菸基 氰； 2,4-二，甲氧-5-{6-[2-((2R)-甲基-峨咯啶-1-基）-乙基]-莕 _2_基} -口密症 ； 2,6-二氟-3-{6-[2-((2R)-2-甲基-吡咯啶-1-基）-乙基]-莕-2- 基卜p比淀； 環丙基-(4-{6-[2-((2R)2-甲基-说咯啶-1-基）-乙基]-莕-2-基}-苯基）甲銅； 3- 甲氧-6-{6-[2-((2R)2-甲基^比咯啶-1-基）-乙基]-莕-2-基} -嗒口井； 4- {6-[2-(2 -甲基鼠p比咬.-1-基）-乙基]-奈-2-基}-木基氣， 4 - {6-[2-((2R)-2-乙基-p比p各淀-1-基）-乙基]••奈-2 -基}-本基 氰； 2-{6-[2-((23)-2-甲基-说咯啶-1-基）-乙基]-莕-2-基}-211-嗒畊-3-酮； 2-[6-((2R)-2-六氫吡啶-1-基-乙基）-莕-2-基]-2H-嗒畊-3-酮； 2-{6-[2-(弟二丁基-甲基-胺基）-乙基]-奈-2 -基} - 2 Η -塔口井 89248.doc -39- 200418454 -3-酮； 2-[6-(2-二乙基胺基-乙基）-莕-2-基]-2H-嗒畊-3-酮； 2-[6-(2-嗎啉-4-基-乙基）-茶-2-基]-2H-嗒畊-3-酮； 2-{6-[2-(乙基-甲基-胺基）-乙基]-莕-2-基}-211-嗒畊-3-酮； 2-{6-[2-((2S)-2-氣甲基-p比洛淀-1 -基）-乙基]-奈-2-基} -2H-嗒畊-3-酮； 2-{6-[2-(2-羥基甲基-峨咯啶-1-基）-乙基]-莕-2-基}-21^ 嗒畊-3-酮； 2-{6-[K(R)-2-乙基-吡咯啶-1-基）-乙基]-莕-2-基卜2H-嗒 畊-3-酮； 2-[6-(2-吖哩-1-基-乙基）-莕-2-基]-2H-嗒畊-3-酮； 2-{6-[2-((2S)-2-氟甲基-吖口旦-1-基）-乙基]-莕-2-基}-211-嗒畊-3-酮； 2-{6-[2-((2S)-2-羥甲基-吖口旦-1-基）-乙基]-萘-2-基卜2H-嗒畊-3-酮； 2-{6-[2-((2R，5R)-2,5-二甲基-吡咯啶-1-基）-乙基]-莕-2-基}-211-嗒畊-3-酮； 2-{6-[2-((2R，6S)-2,6-二甲基-六氫吡啶-1-基）-乙基]-萘-2-基}-211-嗒畊-3-酮； 2 - {6-[2_((R)- 3-¾ 基-7T 鼠 p比淀-1-基）-乙基]奈-2-基}_211- 嗒畊-3-酮； 2-{6-[2-((R)-2-甲基-六氫吡啶-1-基）-乙基]-莕-2-基卜2H-嗒畊-3-酮； 2,6-二甲基-3-{6-[2-((2R)-2-甲基^比咯啶-1-基）-乙基]-莕 89248.doc -40- 200418454 -2 -基卜p比症； 5-{6-[2-((R)-2-甲基-说咯啶-1-基）-乙基]-莕-2-基}-噻唑； 2- {6-[2-((R)-2-甲基^比咯啶-1-基）-乙基]-萘-2-基卜嘧啶； 3- 氯-6-{6-[2-((R)-2-甲基-说咯啶-L·基）-乙基]-莕-2-基}- 嗒畊； 5-{6-[2-((R)-2-甲基-吡咯啶-1-基）-乙基]-萘-2-基}-嘧啶 -2-基胺； 2- 甲基-5-{6-[2-((2R)2-甲基-吡咯啶-1-基）-乙基]-莕-2-基} -p比淀；， 3- 溴-7-(2-吡咯啶-1-基-乙基）-[1，5]莕啶； 3-溴-7-[2-(2R-2-甲基^比咯啶-1-基）-乙基]-[1，5]萘啶； 3-溴-7-(2-六氫吡啶-1-基-乙基）-[1，5]莕啶； 3-(2,6-二甲基^比啶-3-基）-7-[2-(211-2-甲基-吡咯啶-1-基） -乙基]-[1，5]莕啶； 3-(2,4-二甲氧-嘧啶-5-基）-7-[2-(2R-2-甲基-吡咯啶-1-基） -乙基；1_[1，5]莕啶； 3-(2,6--一甲基-p比淀-3 -基）-7 - (2 - p比哈淀-1 -基-乙基）-[1，5 ] 莕啶； 3-(2,4--一甲氧-士淀-5-基）-7-(2-叶匕p各淀-1-基-乙基）-[1，5] 莕啶； 3-(2,6- —•甲基-?比淀-3-基）-7-(2 -7T鼠p比淀-1 -基-乙基） -[1，5]萘啶； _ 3-(2,4-二甲氧-嘧啶-5-基）-7-(2-六氫吡啶-1-基-乙基） -[1，5]莕啶； 89248.doc -41 - 200418454 3-[2-(2(R)-甲基比咯啶-1-基）-乙基]-7-嘧啶-4-基-異哇啉； 7-（6-甲氧^比啶-3-基）-3-[2-(2(R)-甲基^比咯啶-1-基）-乙 基]-異喹啉； 3- [2-(2(R)-曱基^比咯啶-1-基）-乙基]-7-嘧啶-5-基-異喹啉； 7-(6-氟^比啶-3-基）-3-[2-(2(R)-甲基比咯啶-1-基）-乙基]- 異喳啉； 5-{3-[2-(2(R)-甲基-吨咯啶-1-基）-乙基]-異喳啉-7-基卜菸 基氰；- 7-(3-表^比啶-4-基）-3-[2-(2(R)-曱基-吡咯啶-1-基）-乙基]- 異琳； 7-溴-3-[2-((2R)-2-甲基^比咯啶-1-基）-乙基]-噌啉-4-醇； 4- {3-[2-(2-甲基^比咯啶-1-基）-乙基]-噌啉-7-基卜苯基氰； 7-溴-4-氯-3-[2-((2R)-2-甲基-吡咯啶-1-基）-乙基]-噌啉； 4-{4-羥基-3-[2-((2R)-2-甲基-吡咯啶-1-基）-乙基]-噌啉 -7 -基}-冬基氣， 4- {4-異丙氧-3-[2-((2R)-2-甲基-吡咯啶-1-基）-乙基]-噌啉 -7-基卜苯基氰； 4-{3-[2-(4-甲基-六氫吡畊-1-基）-乙基]-噌啉-7-基卜苯基 氰； 4-[3-(2-六氫吡啶-1-基-乙基）-噌啉-7-基]-苯基氰； 4-[3-(2-吡咯啶-1-基-乙基）-噌啉-7-基]-苯基氰； 4-{3-[2-((211)-2-甲基4比咯啶-1-基）-乙基]-噌啉-7-基}-采 基氰； 4 - {3-[2-((2R)-2 -岁空甲基-叶匕p各淀-1 -基）-乙基]-p曾ρ林-7-基} · 89248.doc -42- 200418454 苯基氰； 4一[3-(2-嗎啉-4-基-乙基）-噌啉-7-基]-苯基氰； 4-{3-[2-(4-甲基-六氫吡啶-1-基）-乙基]-噌啉-7-基}-苯基 氰； 4- {3-[2-(乙基-甲基-胺基）-乙基]-噌啉-7-基卜苯基氰； 7-(2,6-二甲基-吡啶-3-基）-3-[2-((2R)-2-甲基-吡咯啶-1- 基）-乙基]-噌啉； 7-(2,4-二甲氧-嘧啶-5-基）-3-[2-((2R)-2-甲基-吡咯啶-1-基）-乙基h噌啉； 7-(6-甲氧^比啶-3-基）-3-[2-((2R)-2-甲基-外匕咯啶-1-基）-乙 基]-嗜淋； 3-{3-[2-((2R)-2-甲基^比咯啶-1-基）-乙基]-噌啉-7-基卜苯 基氰； 5- {3-[2-((2R)-2-甲基-吡咯啶-1-基）-乙基]-噌啉-7-基卜菸 基氰； 7-(4-氟-苯基）-3-[2-((2R)-2-甲基比咯啶-1-基）-乙基]-噌 2- {3-[2-((2R)-2-甲基^比咯啶-1-基）-乙基]-噌啉-7-基卜吡 咯-1-羧酸第三丁酯； (3-{3-[2-((2R)-2-甲基-说咯啶-1-基）-乙基]-噌啉-7-基}-苯基）-甲醇； 7-(3,5-二氟-苯基）-3-[2-((2R)-2-甲基 ^比咯啶-1-基）-乙‘] -嗜琳； 3- [2-((2R)-2-甲基^比咯啶-1-基）-乙基]-7-硫苯-3-基-噌啉； 89248.doc -43 - 200418454 7-(4-氯_苯基）-3-[2-((2R)-2 -甲基-吡咯啶_^基）_乙基卜噌 口林； 7-(4-乙氧基-苯基丨^-^兴^幻^-甲基-吡咯啶-卜基卜乙基] -嗜口林； 3-[2-((2R)-2-甲基-吡咯啶-:^基）·乙基]_7_(1Η_吡咯_2_基） -嗜ρ林；與 2-(1，5-二甲基-1Η-吡唑-4-基）_6-{2-[(2R)-2-甲基-1-吡咯When the substituents represented by R2, R3, R3a, and R3b appear, Z 丨, X 丨, and Z fX represent the · atoms that can be substituted with the substituents represented by R2, Rs, Rsa, and R3b, respectively. Specific examples of the compounds of the present invention include, but are not limited to: 4- (6- {2-[(2-2--2-methyl-1-pyrrolidinyl) ethylb 2-fluorenyl) phenylcyanide; ( 2R) -l- [2- (6-bromo-2-naphthyl) ethylmethylpyrrolidine; 1 [3- (6- {2-[(2R) -2-methyl-1-pyrrolidinyl ] Ethyl ethyl 2-naphthyl) phenyl] ethyl ketone; 2- [3- (6- {2-[(211) -2-methyl_1-pyrrolidinyl] ethyl} _2-naphthyl) Phenyl-]-2 -propanol; 6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl 2-fluorenyl cyanide; 89248.doc -30- 200418454 4- ( 6-{[((2R) -2-methyl-1-pyrrolidinyl] methylb-2-naphthyl) phenyl cyanide; 3- (6- {2-[(2R) -2-methyl-1 -Said, each pyridyl] ethyl} 2-theanyl) phenyl chloride; 4- (6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethylfluorenyl) ρ Bipyridine; 3- (6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethylnaphthyl) pyridine; (3-fluorophenyl) (6- {2-[(2R ) -2-methyl-1-pyrrolidinyl] ethylbu-2-naphthyl) methanol; 3,5--methyl-4- (6- {2-[(211) -2-methyl-1 -Pyrrolidinyl] ethylpyridinyl) isopurinazole; 4- (6-{^ [(2S) -2- (hydroxymethyl) -1-pyrrolidinyl] ethylpyridinyl) Phenylcyanine; 4- (6- {2-[(3R) -3-hydroxy-1-pyrrolidinyl] ethyl Naphthyl) phenyl cyanide; 4- {6- [2- (2-isobutyl-1-pyrrolidinyl) ethyl] -2-fluorenyl} phenyl cyanide; 4- {6- [2- (2-isopropyl-1-pyrrolidinyl) ethyl] -2_yl} phenyl cyanide; 4- (6- {2-[(3R) -3- (dimethylamino group)- Pyrrolidinyl] ethylb-2-naphthyl) phenyl cyanide; 4- {6- [2- (diethylamino) ethyl] -2-naphthyl} phenyl cyanide; 4- {6- [ 2- (dimethylamino) ethyl; μm phenyl phenyl cyanide; 4- (6- {2- [ethyl (isopropyl) amino] ethyl phenyl 2-naphthyl) phenyl cyanide ; 4- (6- {2- [Second-butyl (methyl) amino] ethylbu 2-fluorenyl) phenyl cyanide; 4- (6- {2-[(2S) -2-methyl -1-pyrrolidinyl] ethylpyridinyl) phenyl cyanide; 4- (6- {2-[(2R) -2-methyl-1-hexahydropyridyl] ethylpyridine 2.naphthalene Phenyl) cyanide;-4- {6- [2- (2,5-dihydro-1Η-pyrrole-1-yl) ethyl] -2-naphthyl} phenyl cyanide; 4- (6- { 2- [methyl (propyl) amino] ethylbu 2-fluorenyl) phenyl cyanide; 89248.doc -31- 200418454 4- (6- {2-[(2-Ethyl) (methyl ) Amino] ethyl 2- 2-:: yl) phenyl cyanide; 5- (6- {2-[(211) -2-methyl-14 pyrrolidyl] ethyl 2- 2-naphthyl) pyrimidine ; 4- (6- {2 _ [(2R) -2-methyl-1-p-bilodine [Ethyl] ethylnaphthyl-2 · naphthyl) morpholine; 2- (6- {2-[(2R) -2 -methyl-l-p-pyridyl] ethylnaphthyl-2-naphthyl) ·〗 3-? Plug mouth seat; 4- (6- {2-[(2S) -2- (fluoromethyl) -1-p bihalidyl] ethyl triphenyl 2-phenyl) cyanocyanine: (3 -Fluorophenyl) (6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethylbuthen-2-naphthyl) methanone;, 2-(6- {2-[(2R ) -2-methyl-l-p-pyrrolidine-1-yl] -ethylbutanyl-2-theyl) -2H_dagen-3-one; 2-methoxy- 5- (6- {2- [(2R) -2-methyl-1-pyridolyl] ethylpyridinyl) pyridine; 4- (6- {2-[(2R) -2-(# present methyl) small pyridine Lloridinyl] ethylbuhyl) phenyl cyanide; 4- {6- [2- (2-methyl-1-pyrrolidinyl) ethyl] _2_fluorenyl} phenylcyanide; 4- { 6- [2- (1-pyrrolidinyl) ethyl] -2-fluorenyl} phenylcyanide; 4- (6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl Gib 2-fluorenyl) thiomorpholine; 1- {2-[(6- &gt; 2 -Qinyl) oxy] ethyl}? Bikoudian; 3- {6- [2- (1 -Pyrrolidinyl) ethoxy] -2-fluorenyl} phenylcyanide; 3- {6- [2- (1-pyrrolidinyl) ethoxy] _2-fluorenyl} pyridine; 3- (6- {2-[(2R) -2-methyl-1 ^ pyrrolidinyl] ethoxyb- 2-fluorenyl) phenyl cyanide; 3- (6- {2-[(2R) -2-methyl -I-p bilocidyl] ethoxy} _2_fluorenyl) p bidian; 89248.doc -32- 200418454 4- (2- {2-[(2R) -2-methyl-1-leaf Dyridyl] ethylbuquilinyl) phenyl cyanide; 6- (4-fluorophenyl) -2- {2-[(211) -2-methyl-14pyrrolidinyl] ethyl} pyridinoline ; 3- (2- {2-[(2R) -2-methyl-l-p-pylonidyl] ethyl} -6-oxoquinolyl) phenyl cyanide; 1- [3- (2 -{2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} _6-? Quinolinyl) phenyl] ethanone; 6- (4-methoxyphenyl) -2 -{2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl}; and 2- {2-[(2R) -2-methyl-lp-pylonidyl] ethyl } -6- [4- (trifluoromethyl) phenyl] bianline; 2-{2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} -6- [4- ( Formamidine) phenyl] Junlin; 6- (3,5-difluorophenyl) -2- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} Hou Lin; (3-fluorophenyl) (2- {2-[(2R) -2-methyl-1-P-pyrrolidinyl] ethylbu 6-quinolinyl) methanone; 2- {2 -[(2R) -2-methyl-I-p-pyridyl] ethyl} -6- (3-p-pyridyl) ργ quelin; 4- (3- {2-[(2R)- 2-methyl-1-pyrrolidinyl] ethyl 7-isofluorinyl) phenyl cyanide; 3- (3- {2-[(2R) -2-methyl-1-pyridine Pyridyl] ethyl} -7-isofluorinyl) benzyl cyanide; ~ 6-{2-[(2 R)-2-methyl-l-p to p each p-yl] ethyl} -2- (3-ρ ratio yl) p-Querin; 6- {2-[(2R) -2 -methyl-l-p ratio ρ each bityl] ethyl} -2 · (4-ρ ratio yl) p quelin; 89248.doc -33-200418454 6-{2-[(2R) -2-methyl-lp to p each yl] ethyl} -2- (2-p to pyridyl). Quilin; 6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} · 2_ (ι, 3-pyrazol-2-yl) quinucline; 2-(2, 4-dimethyl-1,3-salyl-5-yl) -6- {2-[(21 ^)-2-methyl-1-exordinyl] ethyl} quinoline; 6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl 2- (2-pyridinyl) phosphonium; 1- [6- (6- {2-[(2R)- 2-methyl-1-pyrrolidinyl] ethylpyridinyl) -2-pyridyl] ethanone; 4- (2- {L [(2R) -2-methyl-1-pyrrolidinyl] Ethyl buquinolyl) phenyl cyanide; 4- (3- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl buquinolyl) benzyl cyanide; 7- (2,6-difluoro-3-p-pyridinyl) -3- {2-[(2R) -2-methyl_; μP-pyrididinyl] ethyl} isoρ-quineline; 3- {2-[(2R) -2-Methyl-1-pyrrolidinyl;] ethylbenzene 7 ^ 3-ρ than pyridinyl) heterologous Plin; 3- (benzyloxy) -2-methyl Yl-6- {2-[(2R) -2-methyl-l-P than pyrrolidinyl] ethyl} 0 quinine; 2-cyclopropyl dong {2-[(2R) -2 -methyl-lp Bilopidyl] ethyl} pyrimidine; 4- (6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethylbuquinolyl) phenylcyanide; 2,6 -Monomethyl_5- (6- {2-[(211) -2-methyl-1-17 biloridyl] ethylb 2-4olinyl) nicotinyl cyanide; 2- (3- Phenyl-2-pyridyl) -6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl 89248.doc -34- 200418454 yl} 7quinol # 5- (6- (6- {2-[(2R) -2 -Methyl-I-p-pyrrolidyl] ethyl ethyl 2-isopropylimyl) -3-isoindazolecarboxylic acid ethyl ester; 5- (6- {2- [(2R) -2 -Methyl-l-p bihalidyl] ethylbu-2-.quinolyloxy] -2-p cephenonitrile; 5- (6- {2-[(2R)- 2-methyl-lp ratio p each azimuth group] ethyl bu 2-junyl) 2-p thiophene carboxyimidic acid ethyl ester; 2- (2,4-dimethyl-1,3- slogan Azole_5_yl) -6- {2-[(211) -2-methyl_1-pyrrolidinyl] acetyl} quinoline; 3-methyl-5- (6- {2-[(2R ) -2-methyl-l-p-pylonidyl] ethyl} -2 -junyl) -4-isoxazole carboxylic acid ethyl ester; 4- (7- {2-[(2R) -2 -Methyl-I-p-pylonidyl] ethylbu 3-isojunyl) phenyl cyanide; 6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} 2- (4-Methoxyphenyl) quinoline; 7- {2-[(2R) -2-methyl-l-p-pyrolidyl] ethyl} -2- (4-methyl Oxyphenyl quinoxaline. 6- {2-[(2R) -2-methyl-l-p-pylonidyl] ethyl} -2-phenyl. No. Lin; 7- {2-[(2R) -2-methyl-l-p-Bilocidyl] ethylbu 2-phenyljun slogan Lin; 6- {2-[(2R) -2-A -I-p-pyrrolidyl] ethyl 2- (3-p-pyridinyl) oxazolyl; 6-methyl- 2- {6_ [2-((2R) -2-methylpyrrolyl Dian-i_yl) _ethyl] -fluorene_2-yl} -21 dalkin-3-one; 5- {6- [2-((2R) -2-methylpyrrolidin- ^ yl) _Ethyl] _pyridylpyrimidine 89248.doc, 35-200418454 -2-carbonitrile; 1- {6- [2- (2 (R) · methyl-ρ bis · yodo-1-yl) -ethyl Radical] Biyodo-2-the same; 5-{6- [2- (2 (R) -methyl-πbilodine-1-yl) -ethyl] -naphthalenyl-2-yl} -yl Cyanide; 4-methyl-l- {6- [2- (2 (R) -methyl-pyrrolidin-1-yl) -ethyl] -naphthalene_2-yl} -1H-pyridin-2-one ; 2- {6- [2-((2R) -2 -Methyl-E7-7-1-yl) -ethyl] -naphthyl-2-yl}-? Biffine; 2- {6 -[2-((2R) -2-methyl-2,5-dihydro-pyrrole-1-yl) -ethyl] -fluoren-2-yl} -2H-dakon, -3-one; 4 -(6- {2-[(2-dimethylamino-ethyl) -methyl-amino] -ethyl} -fluoren-2-yl) -phenylcyanide; 4- {6- [2- (4-methyl-hexahydropyridin-1-yl) -ethyl] -fluoren-2-ylphenylphenyl cyanide; 2- (2,5--monomethyl &quot; anan-3-yl) -6- {2-[(2R)-2-methyl-1-ρbilodenyl] B Glyphosate; 6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} -2- (4-methylsulfanyl-phenyl) -coquinone; 2 -(6-methyl-latepyridin-3-yl) -6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl}-p-quinine; 2- (1,3 -Dimethyl-1H-pyrazol-4-yl) -6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} -rhodron; 6- {2- [ (211) -2-methyl-1-pyrrolidinyl] ethyl} -2-thiophen-3-yl-quinoline; 6- {2-[(2 feet) -2-methyl-1 ^ ratio Pyridinyl] ethyl} -2-pyrimidin-5-yl-pyridinyl_; 2- (2,6-dimethyl-pyridin-3-yl) -6- {2-[(211) -2- Methyl-1-pyrrolidinyl] ethyl] -p quinine, 89248.doc -36- 1- [2,6-dimethyl- 5- (6- {2-[(2R) -2 -methyl Pyrrolidinyl] ethylbuquilin-2 -yl) -p-pyridine-3 -yl] -ethanone; 6- {2-[(2R) -2-methyl-1-pyrrolidinyl] Ethyl ethyl 2_ (2H_pyrazol_3-yl) _ guolin; 2 (3- / Da-Xing Qi Tu-5-yl) -6- {2-[(2R) -2-methyl- I-p to p each ytyl] ethyl} -phosphorin; 2- (6-chloro-pyridin-3-yl) -6_ {2-[(2R) -2-methyl-1-pyrrolidinyl ] Ethyl} -quinone; 2- (3,5-, dimethyl-thiophenyl-2-yl) -6- {2-[(211) -2-methyl-1-pyrrolidinyl ] Ethyl}-ρQUIRIN; 6- {2-[(2R) -2-A -1-pyrrolidinyl] ethylbuthyl 2-thiophene-2-yl_quinoline; 2-crean-3-yl-6-{2-[(2R) -2 -methyl-lp-bilodine Yl] ethyl bujunlin; 2- (4,5-dihydro-thiazol-2-yl) -6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl}-koukui Leaching; 1- [4- (6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl quinoline_2-yl) _phenyl] -ethanone; 3- ( 6- {2-[(2R) -2 -methyl-lp ratio p each ytyl] ethyl p p quinolinyl) -2-trifluoromethyl 4-pyridine-4-ol; 2- (3, 5-dimethyl-1H-pyrazol-4-yl) -6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} * quinine, 6- {2 -[(2R) -2-methyl-iP than pyrrolidinyl] ethyl 2- (1fluorene-pyrazol-4-yl) -kouqueline; '2,6-dimethyl-5- ( 6_ {2-[(2R) -2-methyl-1-pyrrolidinyl] ethylbquinolin-2-yl) -nicotinamine; -37- 89248.doc 200418454 2- [2- (2R- Methyl-p-bilodine-1-yl) -ethyl] _6_dian-4-yl-jun; 6- (6-methoxy-eridin-3-yl) -2- [2 (R)- (2-methyl-pyridinyl- ^ yl) · ethyl] _Kuokui 4 wood; 6- (2,6- -fluoro-exo-3-yl) -2- [2- (2 ( R) -Methyl-port ratio p-Yodo-1 -yl) -ethyl] -P quinine; 6- (6-chloro-glutin-3-yl) -2- [2- (2 (R) -Methyl-eho Bite_ ^ yl) _ethyl] _ Kou Kui plin; 6- (2,6--chloro-leafyl-3-yl) -2- [2- (2 (11) -methyl-17 ratio Luodian_11-yl) _ethyl] -Junlin; 2- [2- (2 (R) -methyl-? Pyrrolidine smaller group) _ethyl] · 6 · Pyracinyl ^ Lin; 2- [2- (2 (R) -methyl-ρ ratio ρ each yt-1-yl) -ethyl] _6-sound bite-5-yl-ρ quelin; 6- (2,4- Monomethoxy-π-peptidyl-5-yl) -2- [2- (2 (R) -methyl-p-pyrrolidine-1_yl) _ethyl] -xiaplin; dimethyl- ( 4- {2- [2- (2 (R) -methyl4pyridin-1-yl) -ethyl] ^ quinolin-6-ylphenyl: l · amine; l- (4- {2 -[2- (2 (R) -Methyl-Each-1-yl) -ethyl] Chalin-6-yl} _phenyl) -ethanone; 6- (4-Ga-phenyl)- 2- [2- (2 (R) -methyl-pyrrolidin-1-yl) _ethyl] _quinoline; 6- (2,6-dimethyl-physinoline-3-yl) -2 -[2- (2 (feet) -methyl- ^ Bihadien-1-yl) -ethyl] -π querin; 6- (5 -methoxy-πbidian-3-yl) -2- [2- (2 (R) -Methyl-p than p-yodo-1 -yl) -ethyl] -p-quinine, 6- (3,5-dimethyl-iso. No. 1-sit-4-yl) -2- [2- (2 (sense) -methyl-0-bilodine-1-yl) -ethyl] -0 quinoline; 89248.doc -38- 200418454 4 -{2- [2- (2 (R) -methyl-pyrrolidin-1-yl) -ethyl] -pyridin-6-ylbenzoic acid methyl ester; 2- [2- (2 (R ) -Methyl-pyrrolidin-1-yl) -ethyl] -6- (4-methylsulfanyl-phenyl) -kouquiline; 6- (6-fluoro-supridin-3-yl ) -2- [2- (2 (R) -methyl-pyrrolidin-1-yl) -ethyl] -koukouline; 5- {2- [2- (2 (11) -methyl- Pyrrolidin-1-yl) -ethyl] -quinolin-6-yl} -nicotinyl cyanide; 2,4-di, methoxy-5- {6- [2-((2R) -methyl-E Pyridin-1-yl) -ethyl] -fluoren-2-yl} -stomach syndrome; 2,6-difluoro-3- {6- [2-((2R) -2-methyl-pyrrolidine -1-yl) -ethyl] -fluoren-2-yl p-pyridine; cyclopropyl- (4- {6- [2-((2R) 2-methyl-supridin-1-yl) -Ethyl] -fluoren-2-yl} -phenyl) methyl copper; 3-methoxy-6- {6- [2-((2R) 2-methyl ^ pyrrolidin-1-yl) -ethyl Phenyl] -fluoren-2-yl} -daguchi; 4- {6- [2- (2- (methyl-methyl-p-ratio.-1-yl) -ethyl] -naphthyl-2-yl} -wood Base gas, 4-{6- [2-((2R) -2-ethyl-p than p each yt-1-yl) -ethyl] •• nai-2 -yl} -benzyl cyanide; 2- {6- [2-((23) -2-methyl-salrolidin-1-yl) -ethyl]- -2-yl} -211-dagen-3-one; 2- [6-((2R) -2-hexahydropyridin-1-yl-ethyl) -fluoren-2-yl] -2H-dagen -3-one; 2- {6- [2- (di-dibutyl-methyl-amino) -ethyl] -naphthalene-2 -yl}-2 hydrazone-tower mouth well 89248.doc -39- 200418454 -3-one; 2- [6- (2-diethylamino-ethyl) -fluoren-2-yl] -2H-dagen-3-one; 2- [6- (2-morpholine- 4-yl-ethyl) -tea-2-yl] -2H-dagen-3-one; 2- {6- [2- (ethyl-methyl-amino) -ethyl] -fluorene-2 -Yl} -211-dagen-3-one; 2- {6- [2-((2S) -2-Gamethyl-p-bilodine-1 -yl) -ethyl] -naphthalene-2- } -2H-Dagen-3-one; 2- {6- [2- (2-hydroxymethyl-errolidin-1-yl) -ethyl] -fluoren-2-yl} -21 ^ Phen-3-one; 2- {6- [K (R) -2-ethyl-pyrrolidin-1-yl) -ethyl] -fluoren-2-ylb 2H-dagen-3-one; 2 -[6- (2-Azol-1-yl-ethyl) -fluoren-2-yl] -2H-daikon-3-one; 2- {6- [2-((2S) -2-fluoro Methyl-azol-1-yl) -ethyl] -fluoren-2-yl} -211-daikon-3-one; 2- {6- [2-((2S) -2-hydroxymethyl -Azetidin-1-yl) -ethyl] -naphthalene-2-ylb 2H-daikon-3-one; 2- {6- [2-((2R, 5R) -2,5-dimethyl -Pyrrolidin-1-yl) -ethyl] -fluoren-2-yl} -211-daikon-3-one; 2- {6- [2-((2R, 6S) -2,6- Dimethyl-hexahydropyridin-1-yl) -ethyl] -naphth-2-yl} -211-da-gen-3-one; 2-{6- [2 _ ((R)-3-¾yl- 7T p-pyridine-1-yl) -ethyl] naphthalenyl-2-yl} -211-dakin-3-one; 2- {6- [2-((R) -2-methyl-hexahydropyridine) -1-yl) -ethyl] -fluoren-2-ylb 2H-da-croton-3-one; 2,6-dimethyl-3- {6- [2-((2R) -2-methyl ^ Pyrrolidin-1-yl) -ethyl]-荇 89248.doc -40-200418454-2 2-kibbs pip disease; 5- {6- [2-((R) -2-methyl-speak Pyridin-1-yl) -ethyl] -fluoren-2-yl} -thiazole; 2- {6- [2-((R) -2-methyl ^ pyrrolidin-1-yl) -ethyl ] -Naphthalene-2-ylpyrimidine; 3-chloro-6- {6- [2-[((R) -2-methyl-salrolidine-L.yl) -ethyl] -fluoren-2-yl }-Dagen; 5- {6- [2-((R) -2-methyl-pyrrolidin-1-yl) -ethyl] -naphth-2-yl} -pyrimidin-2-ylamine; 2 -Methyl-5- {6- [2-((2R) 2-methyl-pyrrolidin-1-yl) -ethyl] -fluoren-2-yl} -p-pyridine ;, 3-bromo-7 -(2-pyrrolidin-1-yl-ethyl)-[1,5] pyridine; 3-bromo-7- [2- (2R-2-methyl ^ pyrrolidin-1-yl) -ethyl [Yl]-[1,5] naphthyridine; 3-bromo-7- (2-hexahydropyridin-1-yl-ethyl)-[1,5] pyridine; 3- (2,6-dimethyl ^ Pyridin-3-yl) -7- [2- (211-2-methyl-pyrrolidin-1-yl) -ethyl ]-[1,5] pyridine; 3- (2,4-dimethoxy-pyrimidin-5-yl) -7- [2- (2R-2-methyl-pyrrolidin-1-yl) -ethyl 1- [1,5] pyridine; 3- (2,6--monomethyl-p-pyridine-3 -yl) -7-(2 -p Bihadyn-1 -yl-ethyl)- [1,5] pyridine; 3- (2,4--monomethoxy-Shiyodo-5-yl) -7- (2-physyl-1-yl-ethyl)-[1, 5] pyridine; 3- (2,6- — • methyl-? Bito-3-yl) -7- (2 -7T mouse pbito-1 -yl-ethyl)-[1,5] Naphthyridine; _ 3- (2,4-Dimethoxy-pyrimidin-5-yl) -7- (2-hexahydropyridin-1-yl-ethyl)-[1,5] pyridine; 89248.doc -41-200418454 3- [2- (2 (R) -methylpyrrolidin-1-yl) -ethyl] -7-pyrimidin-4-yl-isowaline; 7- (6-methoxy ^ Bipyridin-3-yl) -3- [2- (2 (R) -methyl ^ pyrrolidin-1-yl) -ethyl] -isoquinoline; 3- [2- (2 (R)- Fluorenyl ^ pyridin-1-yl) -ethyl] -7-pyrimidin-5-yl-isoquinoline; 7- (6-fluoro ^ pyridin-3-yl) -3- [2- (2 (R) -Methylpyrrolidin-1-yl) -ethyl] -isoxoline; 5- {3- [2- (2 (R) -methyl-t-pyrrolidin-1-yl) -ethyl Yl] -isoxoline-7-ylpicotinyl cyanide; 7- (3-epipyridin-4-yl) -3- [2- (2 (R) -fluorenyl-pyrrolidine-1- ) -Ethyl] -Isoline; 7-bromo-3- [2-((2R) -2 -Methyl ^ pyrrolidin-1-yl) -ethyl] -pyridin-4-ol; 4- {3- [2- (2-methyl ^ pyrrolidin-1-yl) -ethyl] -Pyridinoline-7-ylphenylphenylcyanide; 7-bromo-4-chloro-3- [2-((2R) -2-methyl-pyrrolidin-1-yl) -ethyl] -pyridinoline; 4- {4-hydroxy-3- [2-((2R) -2-methyl-pyrrolidin-1-yl) -ethyl] -pyridin-7-yl} -dongyl gas, 4- {4 -Isopropoxy-3- [2-((2R) -2-methyl-pyrrolidin-1-yl) -ethyl] -pyridin-7-ylphenylphenylcyanide; 4- {3- [2 -(4-methyl-hexahydropyridin-1-yl) -ethyl] -pyridin-7-ylphenylphenylcyanide; 4- [3- (2-hexahydropyridin-1-yl-ethyl ) -Pyridin-7-yl] -phenylcyanide; 4- [3- (2-pyrrolidin-1-yl-ethyl) -pyridin-7-yl] -phenylcyanide; 4- {3- [2-((211) -2-methyl 4 than pyrrolidin-1-yl) -ethyl] -pyridin-7-yl} -cyanocyanine; 4-{3- [2-((2R) -2 -Sucrose methyl-leafyl p-one-l-yl) -ethyl] -p-zolin-7-yl} · 89248.doc -42- 200418454 phenylcyanide; 4- [3- ( 2-morpholin-4-yl-ethyl) -fluorin-7-yl] -phenylcyanide; 4- {3- [2- (4-methyl-hexahydropyridin-1-yl) -ethyl ] -Pyridin-7-yl} -phenylcyanide; 4- {3- [2- (ethyl-methyl-amino) -ethyl] -pyridin-7-ylphenylphenylcyanide; 7- (2,6-dimethyl- Pyridin-3-yl) -3- [2-((2R) -2-methyl-pyrrolidin-1-yl) -ethyl] -pyridoline; 7- (2,4-dimethoxy-pyrimidine- 5-yl) -3- [2-((2R) -2-methyl-pyrrolidin-1-yl) -ethylheptoline; 7- (6-methoxy ^ pyridin-3-yl)- 3- [2-((2R) -2-methyl-exopyrrolidin-1-yl) -ethyl] -lymphotropic; 3- {3- [2-((2R) -2-methyl ^ Pyrrolidin-1-yl) -ethyl] -pyridin-7-ylphenylphenyl cyanide; 5- {3- [2-((2R) -2-methyl-pyrrolidin-1-yl)- Ethyl] -pyridin-7-ylbicotinyl cyanide; 7- (4-fluoro-phenyl) -3- [2-((2R) -2-methylbipyridin-1-yl) -ethyl Yl] -fluorene 2- {3- [2-((2R) -2-methyl ^ pyrrolidin-1-yl) -ethyl] -pyridin-7-ylpyrrole-1-carboxylic acid Butyl ester; (3- {3- [2-((2R) -2-methyl-salrolidin-1-yl) -ethyl] -pyridin-7-yl} -phenyl) -methanol; 7 -(3,5-difluoro-phenyl) -3- [2-((2R) -2-methyl ^ pyrrolidin-1-yl) -ethyl ']-thinine; 3- [2- ( (2R) -2-methyl ^ pyrrolidin-1-yl) -ethyl] -7-thiophen-3-yl-fluorenline; 89248.doc -43-200418454 7- (4-chloro-phenyl ) -3- [2-((2R) -2 -methyl-pyrrolidin_ ^ yl) _ethylbuproline; 7- (4-ethoxy-phenyl 丨 ^-^ 兴 ^ 幻 ^ -Methyl-pyrrolidine-Bibylethyl]- Kobayashi; 3- [2-((2R) -2-methyl-pyrrolidin-: ^ yl) · ethyl] _7_ (1Η_pyrrole_2_yl) -philophylline; and 2- (1, 5-dimethyl-1Η-pyrazol-4-yl) _6- {2-[(2R) -2-methyl-1-pyrrole

淀基]乙基}-峻琳；或其醫藥上可接受之鹽類。 較佳％合物為2-(6-{2-[(2R)-2-甲基-；ι-吡咯啶_丨_基]_乙基} -2-茶-2-基）-2H-嗒畊·3-酮，亦稱為2_(6_{2_[(2R)_2_甲基-卜 吡咯啶基]乙基}-2-苯基）_3(2H)-嗒畊酮。 本發明化合物含有不對稱或對掌性中心時，可能出現」 體異構物。此等立體異構物依料性碳原子周邊取代心 組態而定，而呈&quot;R”或”S”。本文所使用之術語％&quot;虚&quot;s&quot;係电 舰C测R⑽職endatl〇ns f〇r心如⑽e，_繼此Yodo] ethyl} -Junlin; or a pharmaceutically acceptable salt thereof. The preferred compound is 2- (6- {2-[(2R) -2-methyl-; ι-pyrrolidine_ 丨 _yl] _ethyl} -2-tea-2-yl) -2H- Dagen · 3-ketone, also known as 2_ (6_ {2 _ [(2R) _2_methyl-pyrrolidinyl] ethyl} -2-phenyl) _3 (2H) -dakinone. When the compounds of the present invention contain asymmetric or palmar centers, "isomers" may occur. These stereoisomers depend on the configuration of the surrounding carbon atoms instead of the heart configuration, and are represented as "R" or "S". The term "virtual" used in this article is "virtual" C test R job endatl〇ns f〇r heart as ⑽e, _ follow this

Stere〇chemistry，Pure Appl Chem，1976, 45l所定義々 組態。本發明包括各種不同立體異構物與其混合物，此考 ΙΓΓ月確包括在本發明㈣内。立體異構物包括對映屬 2 =對映異構物，及對映異構物或料映異構物之混 ::,r明化合物之個別立體異構物可由含有不對稱或 物商品合成或由消旋混合物製備後 ::此相關技藝之人士習知之方法解析製成。此等解 ，所得非對映異構…物附接構 用再結晶法或層析法分離 89248.doc -44- 200418454 ，可視需要依Furniss，Hannaford，Smith，與 Tatchell 之&quot;Vogel’s Textbook of Practical Organic Chemistry’’ 第 5 版（1989)， Longman Scientific &amp; Technical，Essex CM20 2JE，England所 述，自輔劑釋出純光學產物，或（2)於對掌性層析管柱上直 接分離光學對映異構物之混合物，或（3)分段再結晶法。 本發明化合物之製法 本發明化合物可依據下列說明製備化合物之合成圖與方 法進一步了解。 反應圖^與實例說明中使用之縮寫如下·· Ac指乙醯基；atm 指大氣壓；BINAP指2,2’-雙（二苯基膦基）-1，Γ-聯莕；Boc指 丁氧基羰基；Bu指丁基；DCM指二氯甲烷；DMAP指4-(N，N-二甲基胺基）吡啶；DMF指N，N-二甲基甲醯胺；DMSO指二 甲亞颯；Et指乙基；EtOH指乙醇；EtOAc指乙酸乙酯；HPLC 指高壓液相層析法；IPA指異丙醇；IPAC或IPAc指乙酸異丙 酯；LDA指二異丙基胺化鋰；NBS指N-溴琥珀醯亞胺；NIS 指N-碘琥珀醯亞胺；Me指甲基；MeOH指甲醇；Ms指甲磺 醯基；MTBE指第三丁基甲基醚；Pd指鈀；tBu指第三丁基 ;TEA指三乙胺；TFA指三氟乙酸；THF指四氫呋喃；與Ts 指 p-MePhS(〇）2-。 本發明化合物可依多種合成法製備。代表性製法示於（但 不限於）：反應圖1-24。 89248.doc -45 - 200418454 反應圖1Configuration defined by Stereochemistry, Pure Appl Chem, 1976, 45l. The present invention includes a variety of different stereoisomers and mixtures thereof. This study is indeed included in the present invention. Stereoisomers include enantiomers 2 = enantiomers, and mixtures of enantiomers or enantiomers ::, individual stereoisomers of bright compounds can be synthesized from products containing asymmetry Or after the racemic mixture is prepared :: Analyzed by methods known to those skilled in the art. In these solutions, the diastereomers obtained are separated by recrystallization or chromatography. 89248.doc -44- 200418454, if necessary, according to Furniss, Hannaford, Smith, and Tatchell's "Vogel's Textbook of Practical" Organic Chemistry '' 5th edition (1989), described by Longman Scientific &amp; Technical, Essex CM20 2JE, England, releases pure optical products from adjuvants, or (2) separates optics directly on a palm chromatography column A mixture of enantiomers, or (3) a stepwise recrystallization method. Preparation method of the compound of the present invention The compound of the present invention can be further understood according to the synthetic scheme and method for preparing the compound according to the following description. The abbreviations used in the reaction diagrams and the examples are as follows: Ac refers to ethanoyl; atm refers to atmospheric pressure; BINAP refers to 2,2'-bis (diphenylphosphino) -1, Γ-bifluorene; Boc refers to butoxy Carbonyl; Bu means butyl; DCM means dichloromethane; DMAP means 4- (N, N-dimethylamino) pyridine; DMF means N, N-dimethylformamidine; DMSO means dimethylarsine Et means ethyl; EtOH means ethanol; EtOAc means ethyl acetate; HPLC means high pressure liquid chromatography; IPA means isopropanol; IPAC or IPAc means isopropyl acetate; LDA means lithium diisopropylamine; NBS refers to N-bromosuccinimide; NIS refers to N-iodosuccinimide; Me refers to methyl; MeOH refers to methanol; Ms is sulfonyl; MTBE refers to the third butyl methyl ether; Pd refers to palladium; tBu refers to the first Tributyl; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; and Ts means p-MePhS (〇) 2-. The compounds of the present invention can be prepared by a variety of synthetic methods. The representative manufacturing method is shown in (but not limited to): Reaction Figure 1-24. 89248.doc -45-200418454 Reaction Figure 1

hnr4r5hnr4r5

k2co3/ch3cn 60°Ck2co3 / ch3cn 60 ° C

(〇h)2br6 (7) Pd，鹼 40-80〇C 1-48小時(〇h) 2br6 (7) Pd, base 40-80 ° C 1-48 hours

〇〇

R. (6)R. (6)

ReRe

式（8)與（10)中In equations (8) and (10)

，X、X，、γ、γ，、z、z，、r2、r3、rar5 浚式（1)中定義，R6為芳基或雜芳基之化合物可依反應圖1之 說明製備。式（丨）溴化物係購得或採用習此相關技藝之人士 已手口、 、 炙万去製備，其可經二異丙基胺化鋰及氣甲酸酯如（但 不限於）.氯'酸乙S旨處理，產生式（2)目旨。式（2)g旨可經還 =如（但不限於）：氫爛化麵處理，產生式⑺醇。式⑺韓 了:驗如（但不限於）：三乙胺及績酸鹽如（但不限於）：曱續 酿土鼠或對τ苯伽氯或三氟甲㈣*處理，產生式⑷續 89248.doc -46- 200418454 酸醋。式（4)績酸酯可經可視需要選用之鹼如（三不限於）： 石反酸鉀或碳酸鈉及式胺，加熱或不加熱下處理，產生式 (6)胺。 可採用鈴木（Suzuki)反應來製造式⑴中Rl為芳基、雜芳基 、雜環或環烷基環之化合物。此等鈐木反應中·由式⑴中 心為二氟甲磺酸根或鹵素之化合物與式（7)二獲碩酸、金屬 觸媒如（但不限於）：二乙酸鈀或pd(pph3)4，可提雲要添加pd 配位體如：（二環己基氧膦基）聯苯或三呋喃基雖及鹼如（但 不限於）；0.2 Μ K3P〇4水溶液，反應產生式⑴產物，其中 Ri為芳基、雜芳基、雜環或環烷基環。可改用式（7a)二羥侧 酸醋替代二羥硼酸。二羥硼酸可經醇如··曱哮或二元醇如 •四甲基乙二醇酯化產生相應之二羥硼酸酯。罔樣地，式 (6)胺可進行鈴木反應，產生式（8)胺。 许多種芳基、雜芳基、與雜環二經领酸與二考删酸酯可 自商品取得或可依合成有機化學之科學文獻中說明之方法 製備。適合加至合成法中供製備式⑴化合物之二藉侧酸與 二經酸酯試劑之製法更明確說明於本文之參考實例2中。 或者’式（8)化合物可採用史迪爾偶合法（Stine c〇upUng) 製備’其係由式（6)化合物經芳基、雜芳基、與雜環錫燒 (Me3SnR6，Bu3SnR6)、鈀來源如：參（二亞苯甲基丙酮）二鈀 (CAS# 52409-22-0)或二乙酸免，及配位鱧如：參（2_吱喃基） 膦（CAS # 55 18-52-5)或三苯基胂，於溶劑例如：DMF中； 於25-150°C下處理。雖然史迪爾偶合法之許多有機錫試劑 可自商品取得或可依文獻中之方法製備，但新穎之有機錫 89248.doc -47· 200418454 試劑可由芳基函化物、芳基三氣3磺酸酯、雜芳基由化物 、雜芳基三氟甲磺酸酯與二錫烷釦：（Me3Sn)2(六甲基二錫 烷），於鈀來源如：Pd(Ph3P)4之存在下反應。此等方法說明 例如：Knsche，et· al·，Helvetlca Chlmica Acta 81(11): 1909-1920 (1998)與 Benagha，et al., Tetrahedron Letters 38: 4737-4740 (1997)。此等試劑可依鈐木反應條件或例如：依 Lhtke，Schwartz，與 Fu 說明於 Journal of the Amencan, X, X ,, γ, γ, z, z ,, r2, r3, rar5 As defined in formula (1), compounds in which R6 is aryl or heteroaryl can be prepared according to the description of reaction FIG. The formula (丨) bromide is purchased or prepared by those skilled in the art, which can be prepared by lithium diisopropylamide and gas formate such as (but not limited to). Chlorine ' The acid ethyl S is processed to produce the formula (2). The purpose of formula (2) g can be further reduced, such as (but not limited to): hydrogen decay surface treatment, to produce formula methanol. The formula is as follows: Examine (but not limited to): Triethylamine and sodium salt such as (but not limited to): Continue brewing gerbils or p-τ benzogalacine or trifluoromethane * treatment to produce formulas continued 89248.doc -46- 200418454 Sour vinegar. The acid ester of formula (4) can be selected according to the need of the base such as (three is not limited to): potassium stone acid or sodium carbonate and formula amine, with or without heating treatment, to produce the amine of formula (6). The Suzuki reaction can be used to make compounds in which R1 is an aryl, heteroaryl, heterocyclic or cycloalkyl ring. In these Tochigi reactions, compounds of formula ⑴ with difluoromethanesulfonate or halogen as the center and formula (7) are obtained from the acid and metal catalyst such as (but not limited to): palladium diacetate or pd (pph3) 4 You can add pd ligands such as: (dicyclohexyloxyphosphino) biphenyl or trifuranyl and bases such as (but not limited to); 0.2 M K3P04 aqueous solution, the reaction produces the product of formula ⑴, where Ri is an aryl, heteroaryl, heterocyclic or cycloalkyl ring. Dihydroxyboronic acid of formula (7a) can be used instead of dihydroxyboronic acid. Dihydroxyboronic acid can be esterified with alcohols such as wheezing or diols such as tetramethylglycol to produce the corresponding dihydroxyborates. Similarly, an amine of formula (6) can undergo a Suzuki reaction to produce an amine of formula (8). Many kinds of aryl, heteroaryl, and heterocyclic dibasic acids and dicoates are available from commercial sources or can be prepared according to the methods described in the scientific literature on synthetic organic chemistry. The preparation method of the diboronic acid and the dibasic acid ester reagent suitable for adding to the compound of the formula VII in the synthetic method is more clearly described in Reference Example 2 herein. Or 'the compound of formula (8) can be prepared by Stine Coupling', which is prepared from the compound of formula (6) via aryl, heteroaryl, and heterocyclic tin (Me3SnR6, Bu3SnR6), palladium Sources: ginseng (diphenylene acetone) dipalladium (CAS # 52409-22-0) or diacetic acid, and complexes such as: ginseng (2_creanyl) phosphine (CAS # 55 18-52 -5) or triphenylphosphonium, in a solvent such as: DMF; treat at 25-150 ° C. Although many of the organotin reagents available from Stylist can be obtained from commercial products or can be prepared according to methods in the literature, the novel organotin 89248.doc -47 · 200418454 reagents can be aryl functional compounds, aryl trigas 3 sulfonic acid Esters, heteroaryl radicals, heteroaryl trifluoromethanesulfonates and distannes: (Me3Sn) 2 (hexamethyldistannane), react in the presence of palladium sources such as: Pd (Ph3P) 4 . Examples of these methods are, for example, Knsche, et al., Helvetlca Chlmica Acta 81 (11): 1909-1920 (1998) and Benagha, et al., Tetrahedron Letters 38: 4737-4740 (1997). These reagents can be based on Alder reaction conditions or, for example, according to Lhtke, Schwartz, and Fu as described in Journal of the Amencan

Chemical Society 124: 6343-6348 (2002)中之條件，與⑹反 應，產生，（8)。 式（8)中，R6基團為利用氮連接雙環核心之含氮雜芳基或 雜環之化合物之製法為由式（6)化合物與H-R6 (R6=雜芳基 或雜環基）與鹼如（但不限於）：第三丁醇鈉或碳酸铯，於金 屬觸媒如（但不限於）銅金屬或CuI、二乙酸鈀之存在下，及 亦可視需要選用配位體如（但不限於）：BINAP、三-第三丁 基膦。三_第三丁基膦，於溶劑如··二嘮烷、甲苯與吡啶中 加熱。說明此等方法之參考文獻可見於下列文獻：j. Hartwig et al.5 Angew. Chem. Int. Ed.37: 2046-2067 (1998); J. P.The conditions in Chemical Society 124: 6343-6348 (2002), which react with tritium, produce, (8). In the formula (8), the R6 group is a nitrogen-containing heteroaryl or heterocyclic compound which is connected to the bicyclic core by nitrogen. The method is to use a compound of the formula (6) and H-R6 (R6 = heteroaryl or heterocyclic group). And bases such as (but not limited to): sodium tert-butoxide or cesium carbonate in the presence of metal catalysts such as (but not limited to) copper metal or CuI, palladium diacetate, and ligands such as ( But not limited to): BINAP, tri-tertiary butyl phosphine. Tri-third butylphosphine is heated in a solvent such as dioxane, toluene and pyridine. References describing these methods can be found in the following: j. Hartwig et al. 5 Angew. Chem. Int. Ed. 37: 2046-2067 (1998); J. P.

Wolfe et al·，Acc· Chem. Res.，13:805-818 (1998); M·Wolfe et al ·, Acc · Chem. Res., 13: 805-818 (1998); M ·

Sugahara et al.? Chem. Pharm. Bull.r 45:719-721 (1997); J. P. Wolfe et al·，J· 〇rg· Chem·，65:1158-1174，（2000); F.Y. Kwong et al.5 Org. Lett., 4:581-584, (2002); A. Klapars et al.5 J. Amer· Chem. Soc.，123:7727-7729 (2001); B. H.Yang et al:， J. Organomet. Chem·，576:125-146 (1999);與 A· Kiyomori et al·，Tet· Lett·，40:2657-2640 (1999)。其他文獻亦可參見 89248.doc -48 - 200418454Sugahara et al.? Chem. Pharm. Bull.r 45: 719-721 (1997); JP Wolfe et al., J. Org. Chem., 65: 1158-1174, (2000); FY Kwong et al. 5 Org. Lett., 4: 581-584, (2002); A. Klapars et al. 5 J. Amer · Chem. Soc., 123: 7727-7729 (2001); BHYang et al :, J. Organomet Chem., 576: 125-146 (1999); and A. Kiyomori et al., Tet Lett., 40: 2657-2640 (1999). See also other literature 89248.doc -48-200418454

Hartwig，J· Org.Chem·，64(15):5 575-5 5 80 (1999)，其中結構 式（6)化合物可轉形成結構式（8)或（11)化合物，其係與胺類 、苯胺、驢胺’及參-第三丁基膦與鈀來源如：pd(〇Ac)2反 應。結構式（6)化合物可轉形成結構式（8)*R6部份基團為例 如：N-嗒畊酮之雜環或雜芳基化合物，其係與 酮（或雜環中含有酸性Nh基如：吡啶-2-酮之可視需要官能 化之雜環）及銅粉與鹼，依w〇 〇〇24719，ρ· 127，實例62中 之說明加熱。 式（6)#合物亦可經有機經試劑如（但不限於）：正丁基鋰 、甲基鋰或第三丁基鋰及式（9)醯胺處理，產生式（1〇)化合 物0 式（11)中L2為-ΝΗ-或-Ν(烷基）-且R6為如式（I)化合物之定 義之化合物製法為由式(6)化合物與如式h2N-R64 HN(烷基） -R6化合物使用鹼如（但不限於）第三丁醇鈉或碳酸铯，於金 屬觸媒如（但不限於）：銅金屬或Cul、二乙酸鈀之存在下， 及亦可視需要選用配位體如（但不限於）：BINAP、三-第三 丁基膦；於溶劑如：二崎燒苯、甲苯與峨啶中加熱。說明 此等方法之參考文獻可見於下列文獻：j. Hartwig，et al.， Angew. Chem. Int. Ed.? 37:2046-2067 (1998); J. P. Wolfe et al·，Acc· Chem· Res.，13:805-818 (1998); J. p· Wolfe et al·，J·Hartwig, J. Org. Chem., 64 (15): 5 575-5 5 80 (1999), wherein the compound of structural formula (6) can be transformed into a compound of structural formula (8) or (11), which is related to amines , Aniline, donkey amine 'and p-tert-butylphosphine react with palladium sources such as: pd (〇Ac) 2. Compounds of structural formula (6) can be transformed into structural formula (8) * R6. Some of the groups are, for example, heterocyclic or heteroaryl compounds of N-dacrotonone, which are related to ketones (or heterocyclic rings containing acidic Nh groups). For example, pyridine-2-one can be functionalized heterocyclic) and copper powder and alkali, and heated according to the instructions in 200024719, ρ · 127, Example 62. The compound of formula (6) # can also be treated with organic reagents such as (but not limited to): n-butyllithium, methyllithium or tertiary butyllithium and amidine of formula (9) to produce a compound of formula (10). 0 In the formula (11), L2 is -NΗ- or -N (alkyl)-and R6 is a compound as defined by the compound of the formula (I). The method is to prepare a compound of the formula (6) and a compound of the formula h2N-R64 HN (alkyl ) -R6 compound uses a base such as (but not limited to) sodium tert-butoxide or cesium carbonate, in the presence of a metal catalyst such as (but not limited to): copper metal or Cul, palladium diacetate, and can also be selected as required Sites such as (but not limited to): BINAP, tri-third butyl phosphine; heating in solvents such as: Nisaki benzene, toluene and eridine. References describing these methods can be found in the following: j. Hartwig, et al., Angew. Chem. Int. Ed.? 37: 2046-2067 (1998); JP Wolfe et al., Acc. Chem. Res. 13: 805-818 (1998); J. p. Wolfe et al., J.

Org. Chem.? 65.1158-1174 (2000); F. Y. Kwong et al.5 Org.Org. Chem.? 65.1158-1174 (2000); F. Y. Kwong et al. 5 Org.

Lett·，4.581-584，（2002) ’ 與 B. H.Yang et.al·，J· Organomet. Chem.，576:125-146 (1999)。 式（11)中L2為氧且R6如式（I)化合物之定義之化合物之製 89248.doc -49- 200418454 法為由式（6)化合物與式HOR6化合物使用鹼如（但不限於）： 氫化鈉，於溶劑如：甲苯或N，N-二甲基甲醯胺，於含金屬 之觸媒如：Cul或二乙酸鈀之存在下加熱。說明此等方法之 參考文獻可參見下列參考文獻：J. Hartwig et al·，Angew. Chem. Int. Ed.? 37:2046-2067 (1998); J.F. Marcoux et al.J. Am. Chem. Soc·，119:10539-10540 (1997); A· Aranyos et al·， J. Amer. Chem. Soc., 121:4369-4378 (1999); M. Palucki et al.，J. Amer. Chem. Soc·，119:3395-3396 (1997);及 T. Yamamotg et al·，Can· J· Chem·，61:86-91 (1983)。適用於合 成式（11)中L2為氧，R6如式（1)中之定義之化合物之其他製 法可參見下列文獻·· A. Aranyos et al·，J· Amer· Chem· Soc·， 121:4369-4378 (1999)；與 E. Baston et al·，Synth· Commun.， 28:2725-2730 (1998) ° 式（11)中L2為硫，R6如式（I)化合物之定義之化合物製法為 由式（6)化合物與HSR6化合物使用鹼，使用或不使用金屬觸 媒如：Cul或二乙酸鈀，於鹼之存在下，於溶劑如：二甲基 甲醯胺或甲苯中加熱.。說明.此等方法之文獻可參見下列文 獻：G. Y. Li et al·，J. 〇rg. Chem·，66:8677-8681 (2001); G. Y. Li et al.，Angew· Chem. Int. Ed.? 40:1513-1516 (2001); U. Schopfer et al·，Tetrahedron，57;3069-3074 (2001);與 C· Palomo et al·，Tet.Lett·，41:1283-1286 (2000)。其他適用於合 成式（11)中L2為氧，R6如式（I)化合物定義之化合物之方法可 參見下列文獻·· A· Toshimitsu et al·，Het· Chem·，12:392-397 (2001)。 89248.doc -50- 200418454 式（11)中 L2 為-[C(R18)(R19)]q，且 R6, R18 與 Ri9 如式⑴化合 物之定義且q=l之化合物可由式（10)化合物製備。式（1〇)化 合物可採用習此有機化學技藝之人士已知之方式處理，如 :格林納（Grignard)反應、催化性氫化反應、金屬氯化物反 應、醇之烷化反應、使用（二乙胺基）硫三氟化物進行之氣化 反應、使用[雙（2-甲氧乙基）胺基]硫三氟化物進行之氣化反 應，產生式（11)化合物，其中1^2為-[(：(1118)(汉19)]€1，且R6、 R18與R19如上述式（I)化合物之定義，且q=l。 式（11)，中 L2 為-[C(R18)(R19)]q，R6、R18、r19 與 q如上述式⑴ 化合物之定義之化合物製法為採用習此相關技藝之人已知 之交叉偶合反應。此等反應之實例為庫目達（Kumada)、铃 木（Suzuki)、海克（Heck)、史迪爾（Stille)、鈴木-米亞魯 (Suzuki-Miyaaura)、嗒馬-卡目達（Tamao-Kamuda)與索卡希Lett., 4.581-584, (2002) and B. H. Yang et.al., J. Organomet. Chem., 576: 125-146 (1999). In formula (11), L2 is oxygen and R6 is as defined in the compound of formula (I). 89248.doc -49- 200418454 The method is to use a base such as (but not limited to) the compound of formula (6) and the compound of formula HOR6: Sodium hydride is heated in a solvent such as toluene or N, N-dimethylformamide, in the presence of a metal-containing catalyst such as Cul or palladium diacetate. References describing these methods can be found in the following references: J. Hartwig et al., Angew. Chem. Int. Ed.? 37: 2046-2067 (1998); JF Marcoux et al. J. Am. Chem. Soc ·, 119: 10539-10540 (1997); A. Aranyos et al., J. Amer. Chem. Soc., 121: 4369-4378 (1999); M. Palucki et al., J. Amer. Chem. Soc ·, 119: 3395-3396 (1997); and T. Yamamotg et al ·, Can · J · Chem ·, 61: 86-91 (1983). Suitable for the synthesis of compounds where L2 is oxygen in formula (11) and R6 as defined in formula (1) can be found in the following documents: A. Aranyos et al, J. Amer, Chem, Soc, 121: 4369-4378 (1999); and E. Baston et al ·, Synth · Commun., 28: 2725-2730 (1998) ° In formula (11), L2 is sulfur, and R6 is a compound preparation method as defined for a compound of formula (I) To use a base from a compound of formula (6) and a HSR6 compound, use or not use a metal catalyst such as Cul or palladium diacetate, and heat in a solvent such as dimethylformamide or toluene in the presence of a base. Note. The literature of these methods can be found in the following literature: GY Li et al., J. Org. Chem., 66: 8677-8681 (2001); GY Li et al., Angew. Chem. Int. Ed.? 40: 1513-1516 (2001); U. Schopfer et al., Tetrahedron, 57; 3069-3074 (2001); and C. Palomo et al., Tet. Lett., 41: 1283-1286 (2000). Other methods suitable for synthesizing compounds where L2 is oxygen and R6 is defined as a compound of formula (I) can be found in the following documents: A. Toshimitsu et al., Het. Chem., 12: 392-397 (2001 ). 89248.doc -50- 200418454 In the formula (11), L2 is-[C (R18) (R19)] q, and R6, R18 and Ri9 are as defined for the compound of formula 且 and the compound of q = 1 can be selected from the compound of formula (10) preparation. Compounds of formula (10) can be treated in a manner known to those skilled in organic chemistry, such as: Grignard reaction, catalytic hydrogenation reaction, metal chloride reaction, alkylation reaction of alcohol, use of (diethylamine) Group) sulfur trifluoride gasification reaction, [bis (2-methoxyethyl) amino] sulfur trifluoride gasification reaction to produce a compound of formula (11), wherein 1 ^ 2 is-[ (: (1118) (Chinese 19)] € 1, and R6, R18, and R19 are as defined for the compound of formula (I) above, and q = 1. In formula (11), L2 is-[C (R18) (R19 )] q, R6, R18, r19 and q are as defined above. The compound is prepared by a cross-coupling reaction known to those skilled in the art. Examples of these reactions are Kumada, Suzuki ( Suzuki, Heck, Stille, Suzuki-Miyaaura, Tamao-Kamuda and Sokaki

拉（Sonogashira)反應。由適當試劑例如：烷基格林納試劑、 二輕·酸或酯類、錫中間物、烯與決，與式（6)化合物，於 金屬觸媒如··免、鎳、銀或銦之存在下偶合，製備式（j j) 中L2為經取代或未經取代之烷基、烯基或炔基鏈化合物。 式（11)中L2為稀·基或块基鏈之化合物可採用習此相關技藝 之人士已知之方法如：催化性氫化反應，還原成式（丨丨）中l2 為fe基之化合物。說明此等方法之參考文獻可參見下列： G. A. Molander et al.5 Tetrahedron, 58:1465-1470 (2002); WPull (Sonogashira) reaction. By appropriate reagents such as: alkyl Grignard reagents, diacids or esters, tin intermediates, alkenes, and compounds of formula (6) in the presence of metal catalysts such as nickel, silver, or indium In the following coupling, L2 in the formula (jj) is a substituted or unsubstituted alkyl, alkenyl or alkynyl chain compound. In the formula (11), the compound in which L2 is a diphenyl group or a block chain can be reduced to a compound in which (2) is a fe group by a method known to those skilled in the art, such as catalytic hydrogenation. References describing these methods can be found in the following: G. A. Molander et al. 5 Tetrahedron, 58: 1465-1470 (2002); W

Dohle et. al·，Org. Lett，3:2871-2873 (2001); G. Zou et al，Dohle et. Al., Org. Lett, 3: 2871-2873 (2001); G. Zou et al,

Tet. Lett., 42 · 7213-7216 (2001); A. J. Suzuki, Organomet. Chem.?576:147-168 (1999); A. F. Littke, J. Amer. Chem. Soc.5 89248.doc -51 - 200418454 122:4020-4028 (2000); N. Miyaura et al.，Chem. Rev·， 95:2457-2483 (1995); H. Horie et al·，J. Mater. Chem.， 11:1063-1071 (2001); C. Dai et al.J. Amer. Chem. Soc.? 123:2719-2724 (2001);F. Diederich et al.? Metal-catalyzed Cross-Coupling Reactions, Wiley-VCH; Weinheim, 1998; A. Mohanakrishnan et al., Syn. Lett, 7:1097-1099 (1999); B. H.Lipshutz et al·，Org. Lett，3:1869-1872 (2001); B. H. Lipshutz et al.，Tet. Lett，40:197-200 (1999);與 J· Tsuji， Palladiunj Reagents and Catalysts-Innovations in Organic Synthesis，John Wiley &amp; Sons: New York，1995 o 反應圖2 R〇Tet. Lett., 42 7213-7216 (2001); AJ Suzuki, Organomet. Chem.? 576: 147-168 (1999); AF Littke, J. Amer. Chem. Soc. 5 89248.doc -51-200418454 122: 4020-4028 (2000); N. Miyaura et al., Chem. Rev., 95: 2457-2483 (1995); H. Horie et al., J. Mater. Chem., 11: 1063-1071 ( 2001); C. Dai et al. J. Amer. Chem. Soc.? 123: 2719-2724 (2001); F. Diederich et al.? Metal-catalyzed Cross-Coupling Reactions, Wiley-VCH; Weinheim, 1998; A. Mohanakrishnan et al., Syn. Lett, 7: 1097-1099 (1999); BHLipshutz et al., Org. Lett, 3: 1869-1872 (2001); BH Lipshutz et al., Tet. Lett, 40 : 197-200 (1999); with J. Tsuji, Palladiunj Reagents and Catalysts-Innovations in Organic Synthesis, John Wiley &amp; Sons: New York, 1995 o Reaction Figure 2 R.

«3 ，1. NaCivI, 丫‘ (15) M3U &quot; ^ Η〇2〇^Λ 乂、/巳r bh3 R3«3 ， 1. NaCivI, ya‘ (15) M3U &quot; ^ Η〇2〇 ^ Λ 乂, / 巳 r bh3 R3

B「 R2 、X^Y，〜Z、R2 (17)B "R2, X ^ Y, ~ Z, R2 (17)

XX

(16) R2 H〇〆 (17)(16) R2 H〇〆 (17)

TBDMSCI B「反應圖1 τ TBDMSO〆 、X 丫 'R2 tbdmso (18)TBDMSCI B "Reaction diagram 1 τ TBDMSO〆, X y 'R2 tbdmso (18)

(19) hnr4r5 (19) 1.脫畛保護拳 (5) 2· TsCI，驗 l| I x八丫 /乂、(19) hnr4r5 (19) 1. Protective fist (5) 2. TsCI, test l | I x 八 丫 / 乂 、

、x 丫， r2 (8) r2 r6, X ya, r2 (8) r2 r6

Ts〇 、r2Ts〇, r2

R5R4N 89248.doc -52- (20) 200418454 或者，式（8)中 X、X1、Y、Y，、Z、Zf、R2、R3、尺4與 r5 如式（I)之定義，且116為芳基或雜芳基之化合物可依反應圖2 製備。式（1 3)之醋可經還原劑如（但不限於）：氫化鐘處理 ’產生式（14)醇。式（14)醇可經亞硫醯氣處理，產生式（15) 氣化物。式（15)氯化物可經氰化鈉或氰化鉀處理，產生之 可經酸水溶液處理，產生式（16)酸。式（16)酸可經還原劑如 (但不限於）：乙硼烷或甲硼烷THF複合物處理，產生式（17) 醇。式（17)醇可經羥基保護試劑如（但不限於）：第三丁基二 甲石夕院4氯處理。受保護之式（18)化合物可依反應圖1進行 ’產生式（19)化合物。式（19)化合物可採用習此相關技藝之 人士已知之方法脫除保護基，然後以續醯氣如（但不限於） •甲&amp;醯氯或對甲苯續醯氯處理，產生式（2〇)續酸酯。式（2〇) 磺酸酯可經式（5)胺處理，產生式（8)化合物。 反應圖3R5R4N 89248.doc -52- (20) 200418454 Alternatively, X, X1, Y, Y ,, Z, Zf, R2, R3, ruler 4 and r5 in formula (8) are as defined in formula (I), and 116 is Aryl or heteroaryl compounds can be prepared according to Reaction Scheme 2. The vinegar of formula (1 3) may be subjected to a reducing agent such as (but not limited to): hydrogenation bell treatment 'to produce an alcohol of formula (14). The alcohol of formula (14) may be treated with thionine gas to produce a gaseous compound of formula (15). The chloride of formula (15) can be treated with sodium cyanide or potassium cyanide, and the produced can be treated with an aqueous acid solution to produce an acid of formula (16). The acid of formula (16) may be treated with a reducing agent such as (but not limited to): diborane or borane THF complex to produce an alcohol of formula (17). The alcohol of formula (17) may be treated with a hydroxy-protecting agent such as (but not limited to): tertiary butyl dimethylformate and 4 chlorine. The protected compound of formula (18) can be carried out according to Reaction Scheme 1 to produce a compound of formula (19). The compound of formula (19) can be removed by a method known to those skilled in the related art, and then treated with a tritium gas such as (but not limited to) • methyl &amp; tritium chloride or p-toluene tritium chloride to produce the formula (2 O) Continuing acid esters. The sulfonate of formula (20) can be treated with an amine of formula (5) to produce a compound of formula (8). Reaction Figure 3

式（26)中 X、X，、γ、γ，、z、z, R2、R3、R4與 R5如式（I) (疋我且R6為万基或雜芳基之化合物可依反應圖3製備-。In formula (26), X, X, γ, γ, z, z, R2, R3, R4 and R5 are as shown in formula (I). preparation-.

89248.doc -53 - 200418454 物。式（24)溴化物可經式（5)胺處理，產生式（25)化合物。式 (25)化合物可依反應圖1處理，產生式（26)化合物。 反應圖489248.doc -53-200418454. The bromide of formula (24) can be treated with an amine of formula (5) to produce a compound of formula (25). The compound of formula (25) can be processed according to the reaction scheme 1 to produce a compound of formula (26). Reaction Figure 4

(28)(28)

式（34)中Y、Y’、Z’、R2、R4與R5如式（I)之定義，且116為 芳基或雜芳基之化合物可依反應圖4製備。式（28)之雖滿酮 可經鹼如（但不限於）：二異丙基胺化鋰與溴乙酸乙酯處理， 產生式（29)酯。式（29)酯可經第三丁基胺甲硼烷處理，然後 以驗性水溶液如（但不限於）：氫氧化麵之水溶液處理，產生 式（3 0)羥基酸。式（30)羥基酸可經強酸如（但不限於）：濃硫 酸，於溶劑如：甲醇中加熱處理，產生式（31)酯。式（31)酯 可經還原劑如（但不限於）：氫化4$銘處理，產生式（3 2)醇。 式（32)醇可經臭氧處理後，以二甲硫及氫氧化銨處理，產生 89248.doc -54- 200418454 式（33)異喳啉式（33)異4啉可依反應圖丨與2處理，產生式 (34)化合物。 反應圖5The compounds of formula (34) in which Y, Y ', Z', R2, R4 and R5 are as defined in formula (I), and 116 is an aryl group or a heteroaryl group can be prepared according to FIG. 4. Although the ketone of formula (28) can be treated with a base such as (but not limited to): lithium diisopropylamide and ethyl bromoacetate to produce an ester of formula (29). The ester of formula (29) can be treated with tert-butylamine borane and then treated with a test aqueous solution such as (but not limited to): an aqueous solution of a hydroxide surface to produce a hydroxy acid of formula (30). The hydroxy acid of formula (30) may be subjected to a strong acid such as (but not limited to) concentrated sulfuric acid, and heated in a solvent such as methanol to produce an ester of formula (31). The ester of formula (31) may be treated with a reducing agent such as (but not limited to): hydrogenation of 4 $ to produce an alcohol of formula (32). Alcohol of formula (32) can be treated with dimethyl sulfide and ammonium hydroxide after ozone treatment to produce 89248.doc -54- 200418454 Processing yielded a compound of formula (34). Reaction Figure 5

Ν〇2 hnr4r5 (5) K2C03i dmfΝ〇2 hnr4r5 (5) K2C03i dmf

Br (38)Br (38)

(39) (40)(39) (40)

式（42)中r2、r3、r4、心與心如式⑴之定義且^為 -[CdsKRwiq-或一鍵結之化合物可依反應圖5製備。由 1-(2-溴乙基）_4_硝基苯經式（5)胺處理，產生式⑽胺。式 (37)胺可經鈀/碳於氫蒙氣下處理，產生苯胺，其可再經氮 保護試#]如（但不限於）：三甲基乙喊處理’產生式（38)受 保叙笨胺。式（38)受保護之苯胺可經有機輯劑如（但不 89248.doc -55 - 200418454 限於）··正丁基鋰、第二丁基鋰或第三丁基鋰及N，N-二甲基 甲醯胺處理，產生式（39)醛。式（39)醛之苯胺可採用習此相 關技藝之人士已知之方法脫除保護基，如（但不限於）··於鹽 酸水溶液中加熱，產生式（40)醛。式（40)醛可經式（41)酮與 鹼如（但不限於）：乙醇鉀處理，產生式（42)化合物。 式（44)中Ri、R3、R4、R5與R6如式（I)之定義且L2為 -[C(R18)(R19)]q-或一键結之化合物可依反應圖5之說明製備 。式（40)醛可經式（43)酮與鹼如（但不限於）乙醇钾處理，產 生式（44)牝合物。 式（41)與（43)化合物可自商品購得或採用習此相關技藝 之人士已知之方法合成。 反應圖6The compound r2, r3, r4, heart and heart in formula (42) are as defined in formula 且 and ^ is-[CdsKRwiq- or a bonded compound can be prepared according to reaction FIG. 5. Treatment of 1- (2-bromoethyl) _4-nitrobenzene with an amine of formula (5) yields amidine of formula. The amine of formula (37) can be treated with palladium / carbon under hydrogen atmosphere to produce aniline, which can be tested by nitrogen protection #] Such as (but not limited to): trimethylethane is treated. 'Production formula (38) is insured Sulfamine. Protected aniline of formula (38) can be modified by organic agents such as (but not limited to 89248.doc -55-200418454) ... n-butyllithium, second butyllithium or third butyllithium and N, N-di Treatment with methylformamide produces an aldehyde of formula (39). The aniline of the aldehyde of formula (39) can be removed by a method known to those skilled in the related art, such as (but not limited to) · heating in an aqueous hydrochloric acid solution to produce an aldehyde of formula (40). The aldehyde of formula (40) can be treated with a ketone of formula (41) and a base such as (but not limited to): potassium ethoxide to produce a compound of formula (42). Compounds of Ri, R3, R4, R5 and R6 in formula (44) are as defined in formula (I) and L2 is-[C (R18) (R19)] q- or one-bonded compound can be prepared according to the description of reaction Figure 5 . The aldehyde of formula (40) may be treated with a ketone of formula (43) and a base such as (but not limited to) potassium ethoxide to produce a conjugate of formula (44). Compounds of formulae (41) and (43) can be purchased from commercial sources or synthesized using methods known to those skilled in the art. Reaction Figure 6

(50) 89248.doc -56- 200418454 且Re為芳基或雜芳基之(50) 89248.doc -56- 200418454 and Re is an aryl or heteroaryl group

式（50)中R4與Rs為如式⑴之定義， 淋基）甲醇。（7-甲氧〒基-3^奎啉基）甲醇可經氯化劑如（但 不限於）：亞硫醯氯處理，產生3_(氯甲基）_7_甲氧_2_甲基喹 啉。3-(氯甲基）-7-甲氧-2-甲基喹啉經氰化鈉或氰化鉀處理 ，產生（I甲氧-2-甲基-3-p奎琳基）乙腈。（7_甲氧-2-甲基_3 喳啉基）乙腈可經酸如（但不限於）：冰醋酸與濃硫酸，於水 與丨，心二嘮烷中加熱處理，產生（7-甲氧-2-甲基-3-喹啉基） 乙酸。（7-甲氧-2-甲基-3-喹啉基）乙酸可經還原劑如（但不限 於）：Β#6、甲硼烷-THF複合物或甲硼烷-吡啶複合物處理 ，產生2-(7-甲氧-2-甲基-3-峻琳基）乙醇。2-(7-甲氧-2-甲基 -3-4 p林基）乙醇可經甲續氯與驗如（但不限於三乙胺或 二異丙基胺處理，產生甲磺酸2-(7-甲氧-2-甲基-3-喹啉基） 乙酯。甲磺酸2-(7-甲氧-2-甲基-3-喹啉基）乙酯可經式（5)胺 處理，產生式（47)胺。式（47)胺可經BBr3處理，產生式（48) 羥基化合物。式（48)羥基化合物可經三氟甲磺酸酐或三氟甲 磺醯氯處理，產生式（49)三氟甲磺酸酯。式（49)三氟甲磺酸 酯可依反應圖1所述，經式（7)二羥硼酸處理，產生式（50)化 合物。 89248.doc -57- 200418454 反應圖7R4 and Rs in formula (50) are as defined in formula (i), lyl) methanol. (7-methoxyfluorenyl-3 ^ quinolinyl) methanol may be treated with a chlorinating agent such as (but not limited to): thionyl chloride to produce 3_ (chloromethyl) _7_methoxy_2_methylquine Morpholine. 3- (chloromethyl) -7-methoxy-2-methylquinoline is treated with sodium cyanide or potassium cyanide to produce (I methoxy-2-methyl-3-p quinolinyl) acetonitrile. (7_methoxy-2-methyl_3 fluorinyl) acetonitrile can be treated with an acid such as (but not limited to): glacial acetic acid and concentrated sulfuric acid in water and 丨, dioxane to produce (7- (Methoxy-2-methyl-3-quinolinyl) acetic acid. (7-methoxy-2-methyl-3-quinolinyl) acetic acid may be treated with a reducing agent such as (but not limited to): B # 6, a borane-THF complex or a borane-pyridine complex, This produces 2- (7-methoxy-2-methyl-3-junlinyl) ethanol. 2- (7-methoxy-2-methyl-3-4 p-Linyl) ethanol can be treated with methyl chloride and tested (but not limited to triethylamine or diisopropylamine to produce methanesulfonic acid 2- (7-methoxy-2-methyl-3-quinolinyl) ethyl ester. 2- (7-methoxy-2-methyl-3-quinolinyl) ethyl methanesulfonate can be obtained via formula (5) Amine treatment produces an amine of formula (47). The amine of formula (47) can be treated with BBr3 to produce a hydroxy compound of formula (48). The hydroxy compound of formula (48) can be treated with trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride, The trifluoromethanesulfonate of formula (49) is produced. The trifluoromethanesulfonate of formula (49) can be treated with dihydroxyboronic acid of formula (7) as shown in Reaction Figure 1 to produce a compound of formula (50). -57- 200418454 Reaction Figure 7

式（53)中R^Rs如式⑴定義且R6為芳基或雜芳基之丨，5_ 茶咬可依反應圖7所述製備。3,7-二溴-π，〗]茬啶係依见W·In Formula (53), R ^ Rs is as defined in Formula (I) and R6 is an aryl or heteroaryl group. The 5_ tea bite can be prepared according to the reaction shown in FIG. 7. 3,7-dibromo-π,]] stilbene is based on W ·

Paudler，J· 〇rg· Chem·，33:1384 (1968)所述製備，其可經（2- 乙氧乙烯基）三丁基錫烷、鹵化物來源如（但不限於）：四乙 基銨化氯、與鈀來源如（但不限於）：二氯雙（三苯基膦）鈀（π) ’於溶劑如（但不限於）：N，N•二甲基甲醯胺中加熱（約50。〇 至約150°C )處理，產生3-溴-7-[2-乙氧乙烯基]-1，5-吡啶。3-溴-7-[2-乙氧乙晞基]— L5 —莕咬可經酸如（但不限於甲酸， 於約0°C至約60t：下，於溶劑如（但不限於）：1，2-二氯乙烷 中處理，產生（7-溴-1，5-莕啶-3-基）乙醛。或者，3-溴-7-[2-乙氧乙烯基]-1，5-莕啶於溶劑如（但不限於）：四氫呋喃中， 可經酸水溶液如（但不限於）：鹽酸，於約〇°C至約60°C下處 理，產生（7-溴-1，5-苯啶-3-基）乙醛。（7-溴-1，5-莕啶-3-基） 乙醛可經式（5)胺，於還原性胺化條件下如（但不限於）：三 乙驢氧基氫·化鈉，與酸如（但不限於）：乙酸，於溶劑如（但 89248.doc -58- 200418454 不限於）：1，2-二氯乙燒中，於約〇°C至約50°C下處現，產生 式（52)胺。式（52)胺可經式⑺二羥硼酸、鈀來源如（但不限 於）：參（二亞苯甲基丙酮）二鈀（〇)、配位體如（但不限於）： 二（弟二丁基）騰與驗如（但不限於）·氣化4甲’於落劑如（# 不限於）：四氫吱喃中，於約20°C至約80°C下處理，產生式 (53)1，5-莕啶。 反應圖8 〇MsPaudler, J. Org. Chem., 33: 1384 (1968), which can be prepared from (2-ethoxyvinyl) tributylstannane, halide sources such as (but not limited to): tetraethylammonium Chlorine and palladium sources such as (but not limited to): dichlorobis (triphenylphosphine) palladium (π) 'in a solvent such as (but not limited to): N, N • dimethylformamide heating (about 50 (0 to about 150 ° C) treatment to produce 3-bromo-7- [2-ethoxyvinyl] -1,5-pyridine. 3-Bromo-7- [2-ethoxyethenyl] —L5—Bite can be treated with acids such as (but not limited to formic acid, at about 0 ° C to about 60t: below, in solvents such as (but not limited to): Treatment in 1,2-dichloroethane to produce (7-bromo-1,5-pyridin-3-yl) acetaldehyde. Alternatively, 3-bromo-7- [2-ethoxyvinyl] -1, 5-Pyridine in a solvent such as (but not limited to): tetrahydrofuran can be treated with an aqueous acid solution such as (but not limited to): hydrochloric acid at about 0 ° C to about 60 ° C to produce (7-bromo-1, 5-Benzidin-3-yl) acetaldehyde. (7-Bromo-1,5-pyridin-3-yl) Acetaldehyde can be passed through an amine of formula (5) under reductive amination conditions such as (but not limited to) ): Triethylammonium oxyhydrogen · sodium, and acids such as (but not limited to): acetic acid, in solvents such as (but 89248.doc -58- 200418454 not limited to): 1,2-dichloroethane, in When present at about 0 ° C to about 50 ° C, an amine of the formula (52) is produced. The amine of the formula (52) can be passed through the formula dihydroxyboronic acid and palladium sources such as (but not limited to): ) Dipalladium (〇), ligands such as (but not limited to): Di (dibutyl) Teng and test such as (but not limited to) · gasification of 4A 'in the agent such as # Is not limited to): the tetrahydro-thiopyran squeak, to about 80 ° C treated at about 20 ° C, to produce formula (53) Scheme 8 1,5 Nymphoides 〇Ms piperidine.

R4R5R4R5

hnr4r5 (5)hnr4r5 (5)

式（60)中R4與為如式⑴定義且&amp;為芳基或雜芳基之嗜 啉可依反應圖8製備。式（5)胺可與甲磺酸3_丁炔基酯，於室 脈下彳見拌約1小時，然後於約5〇°c下加熱約24小時。使混合 物~卻至主溫，過濾。濾液經乙腈稀釋，產生〇. 1 Μ式（55) 块〇谷液，即用於下一個步驟。5_溴_2_碘苯基胺係依 Sakamoto 述於 Chem· Pharm BuU，35:1823 (198 乃之方法製 備，其可經式（55)炔、鈀（η)來源如（但不限於）·· pd(ph3p)2Cl2 89248.doc -59- 200418454R4 in formula (60) and phosphine which is as defined in formula (2) and &amp; is aryl or heteroaryl can be prepared according to the reaction shown in FIG. 8. The amine of formula (5) can be mixed with 3-butynyl mesylate under the veins for about 1 hour, and then heated at about 50 ° C for about 24 hours. Allow the mixture to reach main temperature and filter. The filtrate was diluted with acetonitrile to produce a 0.1 M block of formula (55), which was used in the next step. 5_Bromo_2_iodophenylamine is prepared according to the method described by Sakamoto in Chem. Pharm BuU, 35: 1823 (198), which can be derived from formula (55) alkyne and palladium (η) such as (but not limited to) ·· pd (ph3p) 2Cl2 89248.doc -59- 200418454

、CuI與鹼如（但不限於）：三乙胺，於有機溶劑如（但不限於） :dmf中，於約Me至約8〇r下處理，產生式（叫炔。式（56) 块可經酸水溶液如（但不限於）：HC1水溶液，於亞硝酸納之 存在下，於約Ot至約loot下處理，產生式（57)羥基噌啉。 式（57)羥基噌啉可依反應圖丨所述，經式（7)二羥硼酸處理， 產生式（58)羥基噌啉。式（58)羥基噌啉可經苯基雙（三氟 甲磺醯亞胺）與鹼如（但不限於）··二異丙基乙基胺，於有機 溶劑如（但不限於）：L2 —二氯乙烷中，於約25t至約仞它下 處理，產，生式（59)三氟甲磺酸酯。式（59)三氟甲磺酸酯可經 催化性飽來源如（但不限於）：乙與氨供體如（但不限 於）：甲酸’於約饥至約MTC下處理，產生式（6〇)嗜啉。 反應圖9, CuI and a base such as (but not limited to): triethylamine, in an organic solvent such as (but not limited to): dmf, treated at about Me to about 80r to produce a formula (called alkyne. Formula (56)) It can be treated with an aqueous acid solution such as (but not limited to): an aqueous HC1 solution in the presence of sodium nitrite at about Ot to about loot to produce a hydroxyxanthroline of the formula (57). As shown in Figure 丨, treatment with dihydroxyboronic acid of formula (7) produces hydroxyxanthroline of formula (58). The hydroxyxanthroline of formula (58) can be treated with phenylbis (trifluoromethanesulfinoimide) and a base such as (but Not limited to ... Diisopropylethylamine, in an organic solvent such as (but not limited to): L2-dichloroethane, treated at about 25t to about 30 ° C, producing, formula (59) trifluoro Methanesulfonate. Formula (59) trifluoromethanesulfonate can be catalyzed by sources such as (but not limited to): B and ammonia donors (but not limited to): formic acid 'at about hunger to about MTC To produce a phosphine of formula (60). Reaction Figure 9

(CF3S〇2)2〇(CF3S〇2) 2〇

TfOTfO

HOHO

(Et)4N+CI- Pd(Ph3P)2CI2(Et) 4N + CI- Pd (Ph3P) 2CI2

(um)2BR6 (7)(um) 2BR6 (7)

R5R4NR5R4N

R5R4NR5R4N

反應圖7 ,, (60) 式（6〇)中1與115如式⑴定義且 亦可依反應圖9製備。7氣3 、， 6、、、方土 $，、、方基炙&quot;1 ;Ht Γ, 備 林醇係依H.E.Baumgart :一，6:333 (1969)所述製備，其可經三氟甲解 或二氟甲磺酸酐與鹼如一 如(但不限於)··二氯甲垸中，於二二心或❹，於溶 1 4 0 c或室溫下處理，產 89248.doc -60- 200418454 7-氯-3-旧啉基二氟甲磺酸酯。7_氯_3_噌啉基三氟甲磺酸酯 可、’二（2-乙氧乙缔基）三丁基錫垸、鹵化物來源如（但不限於） •四乙基銨化氯，與鈀來源如（但不限於）：二氯雙（三苯基 膦）鈀（II) ’於落劑如（但不限於）：N，N_:甲基甲醯胺中，於 約50°C至約150t下處理，產生7_氯_3_(2_乙氧乙烯基）噌啉 。7-氣-3-(2-乙氧乙烯基）噌啉可依反應圖7所述處理，產生 式（62)胺。式（62)胺可經式（7)二羥硼酸、鈀來源如（但不限 於）.一氯（二•第三丁基亞膦酸μ巴（π)二聚體）或參（二亞苯甲 基丙酮）寻鈀（〇)'三（第三丁基）膦與鹼如（但不限於）：氟化铯 ，於溶劑如（但不限於）：二呤烷中，於約3〇。〇至約i2〇t： 下處理’產生式（6 0) ^曾琳。 反應圖107, (60) 1 and 115 in formula (60) are defined as in formula (2) and can also be prepared according to reaction figure 9. 7 gas 3 ,, 6 ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, and ability of the preparations of HEBaumgart: 1, 6: 333 (1969) Formic acid or difluoromethanesulfonic anhydride and base are like (but not limited to) ... Dichloromethane, in dioxin or hydrazone, dissolve in 1 40 ° C or at room temperature, yield 89248.doc -60 -200418454 7-chloro-3-oldolinyl difluoromethanesulfonate. 7_chloro_3_fluorinyl trifluoromethanesulfonate, 'di (2-ethoxyethylen) tributyltin sulfonium, halide sources such as (but not limited to) • Tetraethylammonium chloride, and Sources of palladium such as (but not limited to): dichlorobis (triphenylphosphine) palladium (II) 'in the formulation such as (but not limited to): N, N_: methylformamide, at about 50 ° C to Treatment at about 150t produces 7_chloro_3_ (2_ethoxyvinyl) pyridin. 7-Ga-3- (2-ethoxyvinyl) phosphonium can be treated as described in Reaction Figure 7 to produce an amine of formula (62). An amine of formula (62) can be obtained via dihydroxyboronic acid of formula (7), a source of palladium such as (but not limited to). Benzylacetone) palladium (0) 'tris (third butyl) phosphine and base such as (but not limited to): cesium fluoride in a solvent such as (but not limited to): dipurinane, at about 30% . 〇 to about i2〇t: The following processing 'production formula (60) ^ Zeng Lin. Reaction Figure 10

CICI

〇Tf(OH)2BR6 (7)〇Tf (OH) 2BR6 (7)

(Et)4N+CI- (64) + 〇〜巳：〇—/ ^(Ph3P)2CI2(Et) 4N + CI- (64) + 〇 ~ 巳: 〇— / ^ (Ph3P) 2CI2

式（67)中R4與R5為如式⑴定義且1為芳基或雜芳基之噌 啉可依反應圖10製備。由依反應圖9製備之7_氯_3_噌啉基三 氟曱磺酸酯經式（7)二羥硼酸、鈀來源如（但不限於）：參（二 亞苯甲基丙酮）二鈀（0)、三環己基膦（或三苯基膦或三（第三 89248.doc -61 - 200418454 丁基）膦）與鹼如（但不限於）：氟化鉀，於溶劑如（但不限於） :四氫吱喃中，於约赃至約航下處理，產生式（64)氣化 物。式（64)氣化物可經2_(2_乙氧基_乙烯基卜七宄大^四甲基 -Π，3,2]二氧硼戊環（依c· Μ· v〇gels述於c⑽ (2000) 1，51之方法製備）、鈀來源如（但不限於）：肆（二亞苯 甲，基丙酮）二鈀（0)、三（第三丁基）膦，或此二者改用二氣（二 -罘三丁基亞膦酸）鈀（11)二聚體與鹼如：氟化铯替代，於溶 劑如（但不限於）·· 号燒中，於約赃至約^代下處 理，產4式（65)醚。式（65)醚可依反應圖7所述處理，產生 式（67)噌啉。 反應圖11 (71)R4 and R5 in formula (67) are as defined in formula (1), and 1 is an aryl or heteroaryl oxoline can be prepared according to reaction FIG. 10. The 7_chloro_3_fluorinyltrifluorophosphonium sulfonate prepared according to FIG. 9 via dihydroxyboronic acid of formula (7), and the source of palladium such as (but not limited to): (diphenylene acetone) dipalladium (0), tricyclohexylphosphine (or triphenylphosphine or tris (three 89248.doc -61-200418454butyl) phosphine) and a base such as (but not limited to): potassium fluoride in a solvent such as (but not (Limited to): In tetrahydro squeaking, it is processed from about to about to produce formula (64) gas. The gaseous compound of formula (64) can be passed through 2_ (2_ethoxy_vinylbutafluorene) tetramethyl-Π, 3,2] dioxolane (described in c⑽M · v〇gels) (2000) 1,51), palladium sources such as (but not limited to): (diphenylene, acetone) dipalladium (0), tri (third butyl) phosphine, or both Replace with digas (di-fluorene tributyl phosphinic acid) palladium (11) dimer and base such as: cesium fluoride, in a solvent such as (but not limited to) No. sintering, from about to about ^ Substitute the treatment to produce an ether of formula (65). The ether of formula (65) can be treated as described in Reaction Figure 7 to produce a hydrazone of formula (67). Reaction Figure 11 (71)

AeOHAeOH

Ms〇Ms〇

R5R4rvT v ^ &quot;MO (70) 2 H2, Pd/C MeR5R4rvT v ^ &quot; MO (70) 2 H2, Pd / C Me

RsR〆、厂、叫RsR〆, factory, call

B「CH2CBr2CHO RsR4NB 「CH2CBr2CHO RsR4N

Br (〇H)2BR6 (7)Br (〇H) 2BR6 (7)

R5R4NT v v、N) (73) 式（73)中I與Rs如式（I)之宕羞 、疋我且R0為方基或雜芳基之!琳可依反應圖11所述製備。？ M姑盆—甘衣w 2-(3-硝基冬基）乙醇，〇1⑽·27·6’可經曱磺酿氯（或甲苯項酿氯）與驗如（但不限方 :三乙胺，於溶劑μ但不限於)：二氯爾處理，產生磺酸2-(3_硝基苯基）乙酯。 T S斅2-(3-硝基奉基）乙酯可式（5)胺與鹼如（但不限於）·石卢妒乂 、λ、、士 )蛟鉍鉀，於溶劑如（但不限； 89248.doc -62- 200418454 ••乙腈中處理，產生式（70)胺。式（70)胺可經氫，使用鈀來源 如·（但不限於）··免/碳，於溶劑如（但不限於）··甲醇、乙醇 或乙酸乙醋中處理，產生式（71)苯胺。式（71)苯胺可經2,2,3-二 /臭丙酸依 S. W. Tinsley，J· Amer. Chem. Soc. 77: 4175_4176 (1955)所述處理，產生式（72)峻4。式（72)峻琳可經式（7)二 經硼酸處理，並依反應圖1所述處理，產生式（73)喳啉。 反應圖12R5R4NT v v, N) (73) I and Rs in formula (73) are as shown in formula (I), and R0 is square or heteroaryl! Lin can be prepared according to the reaction shown in FIG. ? M Gupen—Ganyi w 2- (3-Nitrotolyl) ethanol, 〇1⑽ · 27 · 6 'can be made by sulfonium chloride (or toluene chloride) and the test results (but not limited to: triethyl Amine in solvent μ but not limited to): Dichlorole treatment to produce 2- (3-nitrophenyl) ethyl sulfonate. TS 斅 2- (3-nitropentyl) ethyl ester can be an amine of formula (5) and a base such as (but not limited to) Shi Luyu 乂, λ ,, Shi) 蛟 bismuth potassium in a solvent such as (but not limited to) 89248.doc -62- 200418454 •• Acetonitrile treatment to produce an amine of the formula (70). The amine of the formula (70) can be treated with hydrogen, using palladium sources such as (but not limited to) free / carbon, in solvents such as ( (But not limited to) ·· Methanol, ethanol, or ethyl acetate to produce aniline of formula (71). Aniline of formula (71) can be subjected to 2,2,3-di / propanoic acid according to SW Tinsley, J. Amer. Chem Soc. 77: 4175_4176 (1955), the formula (72) Jun 4. Equation (72) Jun Lin can be treated with boric acid by formula (7), and processed according to the reaction shown in Figure 1, resulting in formula ( 73) Porphyrin Reaction scheme 12

(8〇) 式（80)中I與&amp;如式⑴定義且心為芳基或雜芳基之莕啶 可依反應圖12所述製備。3-溴-1-(苯氧羰基）吡啶鏆化氯可 經式（75)格林納試劑，依D. c〇mins et ah，L Het. chem. 1239-1243 (1983)所述處理，產生式（76)化合物。式（76)化合 物可經鹼如（但不限於）：二異丙基胺化鋰與N，N-二甲基甲醯 胺’依Numata et al，Synthesis，1999, 306-31 1 所述之方法處 理’產生式（77)化合物。式乃化合物可經3_丁炔_丨_醇、CuI 鹼如（但不限於）··三乙胺，與鈀來源如（但不限於） Pd(PPh3)2Ch，於落劑如：（但不限於）：N，N_二甲基甲醯胺 中處理’產生式（78)決。式（78)炔可經氨，於約8(rc下，於 89248.doc 200418454 溶劑如（但不限於）：乙醇中處理，產生式（79)莕啶。式（79) 奈啶可依反應圖1所述處理，產生式（8〇)苯啶。 反應圖13(80) The pyridines of I and &amp; as defined in formula (80), as defined in formula (80), which are aryl or heteroaryl, can be prepared as described in the reaction shown in FIG. 12. 3-Bromo-1- (phenoxycarbonyl) pyridinium chloride can be produced by the Grignard reagent of formula (75) according to D. comins et ah, L Het. Chem. 1239-1243 (1983) to produce Compound of formula (76). The compound of formula (76) may be subjected to a base such as (but not limited to): lithium diisopropylamide and N, N-dimethylformamide as described in Numata et al, Synthesis, 1999, 306-31 1 Method treatment 'produces a compound of formula (77). Compounds of the formula can be treated with 3-butynyl alcohol, CuI bases such as (but not limited to) triethylamine, and sources of palladium such as (but not limited to) Pd (PPh3) 2Ch, such as (but Not limited to): Treatment in N, N-dimethylformamide produces formula (78). The alkyne of formula (78) can be treated with ammonia at about 8 (rc, at 89248.doc 200418454) in a solvent such as (but not limited to): ethanol to produce pyridine of formula (79). Naphthalidine can be reacted according to formula (79) The treatment described in Figure 1 produces benzopyridine of formula (80). Reaction Scheme 13

(82) (83) 3-丁炔-1-醇 Pd(Ph3P)2CI2 Cul, Et3N, DMF (83) tBuNH2(82) (83) 3-butyn-1-ol Pd (Ph3P) 2CI2 Cul, Et3N, DMF (83) tBuNH2

Br (85)Br (85)

， 反應圖1 Y, Reaction Figure 1 Y

(85)-^ r4r5n--WU (86) 式（86)中R4與R5如式⑴定義且以6為芳基或雜芳基之莕啶 依反應圖13所述製備。6-溴-2-吡啶甲醛可經N-碘琥珀醯亞 胺於硫酸與乙酸中處理，產生6-溴-3-琪-2-p比淀甲酸與6_ /臭-5-碘-2^比啶甲趁。6-溴-3-硪-2-p比啶甲醛可經第三丁基胺 ，於溶劑如（但不限於）：THF中處理，產生亞胺（84)。亞胺 (84)可經3_ 丁炔醇、CuI、鹼如（但不限於）··三乙胺或二 異丙基胺、與鈀來源如（但不限於）：Pd(pph3)2Cl2,於溶劑 如（但不限於）：N，N_二甲基甲醯胺中處理，產生式（8勹醇1 式（85)醇可依反應圖i處理，產生式（86)萘啶。 反應圖14(85)-^ r4r5n--WU (86) In the formula (86), R4 and R5 are as defined in formula (2), and pyridine with 6 as aryl or heteroaryl is prepared according to the reaction shown in FIG. 13. 6-bromo-2-pyridinecarboxaldehyde can be treated with N-iodosuccinimide in sulfuric acid and acetic acid to produce 6-bromo-3-ki-2-p ratio formic acid and 6_ / odor-5-iodine-2 ^ Take advantage of pyridine. 6-bromo-3-fluorene-2-p-pyridinecarboxaldehyde can be treated with tertiary butylamine in a solvent such as (but not limited to): THF to produce imine (84). Imine (84) can be passed through 3-butynyl alcohol, CuI, bases such as (but not limited to) ... triethylamine or diisopropylamine, and palladium sources such as (but not limited to): Pd (pph3) 2Cl2, in Solvents such as (but not limited to): treatment in N, N-dimethylformamide to produce the formula (8 勹 alcohol 1 formula (85) alcohol can be processed according to the reaction diagram i to produce formula (86) naphthyridine. Reaction diagram 14

^~r6 (88) (84)^ ~ r6 (88) (84)

反應圖1Reaction Figure 1

HOHO

(90)(90)

Re r4r5nRe r4r5n

R6 89248.doc -64- (91) 200418454 式（91)中I與&amp;如式⑴定義且&amp;為芳基或雜芳基之萘啶 可依反應圖14所述製備。依反應圖13製備之式（84)亞胺可經 式（88)炔、CuI、鹼如（但不限於）：三乙胺或二異丙基胺，與 鈀來源如（但不限於）：Pd(PPh3)2Ch，於溶劑如（但不限於） ·· N，N-二曱基曱酿胺中處理，產生式（89)茶★。式（89)茶咬 可經烷基鋰試劑如（但不限於）··甲基鋰、正丁基鋰、第二丁 基鋰或第三丁基鋰，與環氧乙烷，於溶劑如(但不限於)· ，或乙时處理，產生式㈣醇。式（9Q)醇可依反應圖玉 所述處理^產生式（91)莕啶。 反應圖15R6 89248.doc -64- (91) 200418454 In formula (91), I and &amp; are defined as in formula VII and &amp; is naphthyridine of &lt; aryl or heteroaryl &gt; The imine of formula (84) prepared according to reaction FIG. 13 may be via formula (88) alkyne, CuI, base such as (but not limited to): triethylamine or diisopropylamine, and source of palladium such as (but not limited to): Pd (PPh3) 2Ch is treated in a solvent such as, but not limited to, N, N-dimethylfluorenylamine to produce tea of formula (89). Formula (89) tea bites can be passed through an alkyl lithium reagent such as (but not limited to) methyl methyl, n-butyl lithium, second butyl lithium or third butyl lithium, and ethylene oxide in a solvent such as (But not limited to) ·, or B-time treatment to produce formula methanol. The alcohol of formula (9Q) can be treated as described in the reaction scheme to produce pyridine of formula (91). Reaction Figure 15

式（95)中114與r5如式⑴定義— （） ,_ . 6為万基或雜芳基之 淋可依反應圖15所述製備。2 广、 醯亞胺，於乙酸盥菸歒击士 以甲酉曰可經比溴域 。一甲…可經還原劑如(二甲:: 89248.doc -65- 200418454 鈉或氫化鋰鋁’於溶劑如(但不限於)：丁册、乙醇或其混合 物中處理，產生d2•蹲苯基）〒醇。（5H蛾苯基）甲醇 可&amp;氧化劑如（但不限於）：吡啶鑕氯鉻酸鹽、吡啶鏆二鉻酸 鹽、Mn〇2、過酸如：間氣過苯甲酸或依史溫（Swern)條件 (dms〇/ci(c〇2)ci/TEa)處理，產生5备2_碘苯甲醛。：溴 /、苯甲醛可經第二丁基胺，於溶劑如（但不限於）： 中處理，產生N-[(5H琪苯基）亞γ基（第三丁基）胺。 [(5廣2-石典苯基）亞甲基第三丁基）胺可經式⑽）块 、如、举如（但不限於）··三乙胺或二異丙基胺，與免來源 如（但不限於）：Pd(PPh3)2Cl2，於溶劑如（但不限於）：Ν，Ν_ 二甲基甲祕巾處理，產生式（93)異―式（93)異心林可經 喊鍾試劑如（但秘於）：、正了油、第二丁基麵 或弟二丁基41，與環氧乙燒，於溶劑如（但不限於）：聊或 醚中處ί里產生式（94)醇。式（Μ)醇可依反應圖工所述處 理’產生式（95)異喳啉。 反應圖16114 and r5 in formula (95) are as defined in formula — — (), —. 6 is a tenyl or heteroaryl group can be prepared according to the reaction shown in FIG. 15. 2 Cantonese, imine, and acetic acid in tobacco smoke. The formaldehyde can be compared to the bromine domain. One forma… Can be treated with a reducing agent such as (dimethyl :: 89248.doc -65- 200418454 sodium or lithium aluminum hydride 'in a solvent such as (but not limited to): butane, ethanol or a mixture thereof to produce d2 Group) methanol. (5H moth phenyl) methanol can be &amp; oxidants such as (but not limited to): pyridinium chlorochromate, pyridinium dichromate, MnO2, peracids such as methane perbenzoic acid or Esven ( Swern) conditions (dms0 / ci (co2) ci / TEa), yielding 5 prepared 2-iodobenzaldehyde. : Bromine /, benzaldehyde can be treated with a second butylamine in a solvent such as (but not limited to): to produce N-[(5H Qiphenyl) γ-idene (third butyl) amine. [(5-Guang 2-Shidian Phenyl) methylene tert-butyl) amine can be obtained by formula (i), such as, but not limited to, triethylamine or diisopropylamine, and Sources such as (but not limited to): Pd (PPh3) 2Cl2, treated with solvents such as (but not limited to): Ν, Ν_dimethylformate, resulting in formula (93) iso-formula (93) Clock reagents such as (but secretly) :, normal oil, second butyl noodles or dibutyl 41, and ethylene oxide, in solvents such as (but not limited to): Liao or ether in the formula (94) Alcohol. The alcohol of formula (M) can be treated as described in the reaction mapper 'to produce isofluorinate of formula (95). Reaction Figure 16

⑺舞 h2s〇N4BSAcOH⑺ 舞 h2s〇N4BSAcOH

CQ2Me還原劑 BrCQ2Me reducing agent Br

OH Br 氧化劑OH Br oxidant

Br 反應圖1 ^ 與 反應圖2 NBr reaction diagram 1 ^ and reaction diagram 2 N

1/ Pd(Ph3P)2CI2 Cul, Et3N, DMF1 / Pd (Ph3P) 2CI2 Cul, Et3N, DMF

^ R5R4N^ R5R4N

=-CH2CH2〇H= -CH2CH2〇H

89248.doc -66- 200418454 式（34a)異4啉為化合物（34)之次族群，其中χ、γ，與z,均 為蚊原子，例如：CH，以與心如式⑴之定義且心為芳基或 雖方基’（3 4a)次族群化合物可依反應圖16所述製備。2_碘 苯甲酸甲酯可經N_溴琥珀醯亞胺，於乙酸與硫酸中處理， 產生5-溴-2-碘苯甲酸甲酯。5-溴_2-碘苯甲酸甲酯可經還原 训如（但不限於）：氫硼化鈉或氫化鋰鋁，於溶劑如（但不限 於）· THF、乙醇或其混合物中處理，產生（5_溴_2•碘苯基） 甲醇。（5-溴-2-碘苯基）甲醇可經氧化劑如（但不限於广吡啶 麵氯鉻酸^鹽、吡啶鍇二鉻酸鹽、Mn〇2、過酸如··間氯過苯 甲酸或依史溫（Swern)條件（DMs〇/c1(c〇2)c1/tea)處理，產 生5-溴碘苯甲醛。5_溴-2_碘苯甲醛可經第三丁基胺，於溶 劑如（但不限於）：THF中處mNm琪苯基）亞 甲基]N-(第二丁基）胺。冬2_读苯基）亞甲基]養（第89248.doc -66- 200418454 The formula (34a) iso4line is a sub-group of compound (34), where χ, γ, and z are all mosquito atoms, for example: CH, with the definition of the heart as in formula 且 and the heart Compounds that are aryl or alkenyl '(3 4a) subgroups can be prepared as described in reaction FIG. 16. Methyl 2-iodobenzoate can be treated with N-bromosuccinimide in acetic acid and sulfuric acid to produce methyl 5-bromo-2-iodobenzoate. 5-Bromo_2-iodobenzoic acid methyl ester can be reduced, such as (but not limited to): sodium borohydride or lithium aluminum hydride, in a solvent such as (but not limited to) · THF, ethanol or mixtures thereof to produce (5_bromo_2 • iodophenyl) methanol. (5-Bromo-2-iodophenyl) methanol can be subjected to oxidizing agents such as (but not limited to) pyridinium chlorochromic acid ^ salt, pyridinium dichromate, Mn02, peracids such as m-chloroperbenzoic acid Or according to Swern conditions (DMs0 / c1 (c0) c1 / tea), 5-bromoiodobenzaldehyde can be produced. 5-Bromo-2_iodobenzaldehyde can be treated with tertiary butylamine in Solvents such as (but not limited to): mNmkiphenyl) methylene] N- (second butyl) amine in THF. Winter 2_ read phenyl) methylene]] (the first

二丁基）胺可經块：丁-3-炔-1-醇、CuI 鹼如（但不限於）： 三乙胺或二異丙基胺，與鈀來源如（但不限於）：pd(pph3)2ci2 ，於溶劑如（但不限於广N，N-二甲A甲驢胺中處理，產生異 +林。2-幾乙基異七林反應圖1所述處理，產生式（34a)異,奎Dibutyl) amine can pass through: but-3-yn-1-ol, CuI base such as (but not limited to): triethylamine or diisopropylamine, and palladium sources such as (but not limited to): pd ( pph3) 2ci2, treated in a solvent such as (but not limited to, N, N-dimethyl A medonylamine, to produce iso + forest. The reaction described in Figure 1 of 2-chit-iso-isochiral forest produces formula (34a) Iso

89248.doc 67- 200418454 反應圖1789248.doc 67- 200418454 Reaction Figure 17

HN03i Ac2〇 h2so4 (100)HN03i Ac2〇 h2so4 (100)

NH N02NH N02

R5R4NR5R4N

(101)(101)

式（105)中R4與R5如式⑴定義，且1為芳基、雜芳基、雜 環或環烷基之喹淋應圖17製備。依反應圖5所述製備之式 (37)胺可經鈀/碳，於氫蒙氣下處理，產生之苯胺再經乙酸 酐，於溶劑如：硫酸與水之混合物中處理，產生式（1〇〇)乙 酉盛胺。式（100)乙醯胺可採用習此相關技藝之人士已知之條 件進行硝化反應如（但不限於）：使用硝酸，於硫酸中，於乙 酸奸之存在下進行，產生式（101)乙醯胺。式乙醯胺可 採用 Grehen，L，et· al，Acta Chem. Scand· Ser. B· 41，1，18-23 說明之方法，轉化成Boc保護之硝基苯胺，其係由乙酸胺與 二碳酸二-第三丁酯，於4-二甲胺基吡啶之存在下反應，然 後經2-二乙胺基二乙胺處理，產生Bocs護之硝基苯胺，其 89248.doc -68- 200418454 再經跑/碳，於氫蒙氣下處理，產生式（1〇2)苯胺。式（_ 苯版可與式（103)乙醯溴反應，產生式（1〇4)胺。式（1〇句胺可 經酸如：三氟乙酸加熱處理，產生式（1〇5)喳噚啉。處理式 (104)胺可產生式（1〇6)二氫喹喝啉。式（1〇6)二氫喳吟啉可經 氧化劑如：硝酸銀氧化，產生式（1〇5)喳噚啉。 反應圖1 8Rin and R5 in formula (105) are as defined in formula (1), and quinoline in which 1 is aryl, heteroaryl, heterocyclic or cycloalkyl should be prepared as shown in FIG. The amine of formula (37) prepared according to the reaction shown in Figure 5 can be treated with palladium / carbon under hydrogen atmosphere, and the aniline produced can be treated with acetic anhydride in a solvent such as sulfuric acid and water to produce formula (1 〇〇) Acetylamine. Acetamide of formula (100) can be subjected to a nitration reaction using conditions known to those skilled in the art, such as (but not limited to): using nitric acid in sulfuric acid in the presence of acetic acid to produce acetamidine of formula (101) amine. Acetylamine can be converted into Boc-protected nitroaniline by the method described in Grehen, L, et al, Acta Chem. Scand. Ser. B. 41, 1, 18-23. Di-tertiary butyl carbonate, reacted in the presence of 4-dimethylaminopyridine, and then treated with 2-diethylaminodiethylamine to produce Bocs-protected nitroaniline, 89248.doc -68- 200418454 After running / carbon, it was treated with hydrogen gas to produce aniline of formula (102). The formula (_ benzene plate can be reacted with acetamidine of formula (103) to produce an amine of formula (104). The amine of formula (10) can be heated by an acid such as trifluoroacetic acid to produce formula (105) Fluoroline. Treatment of the amine of formula (104) can produce dihydroquinoline of formula (106). Dihydroquinoline of formula (106) can be oxidized by an oxidant such as silver nitrate to produce formula (105) Porphyrin Reaction Scheme 1 8

另一種產生式（105)中I與&amp;如式（I)定義，且]^6為芳基或 雜芳基之喹喝啉於反應圖18。依反應圖17製備之式（1 〇2)苯 胺可與 &gt;臭乙故鹽反應’產生式（110)苯胺。式（11〇)苯胺可經 酸如（但不限於）：三氟乙酸加熱處理，產生式（m)二氫峰 17号琳。式（111)二氫峻17号琳可使用氧化劑如（但不限於）：硝 酸銀氧化，產生式（112)喹嘮啉。式（112)喹噚啉可經三氟^ 績酸肝，於驗如：2,6-二甲基？比淀之存在下，於溶劑如：二 氣甲燒中處理，產生式（113)三氟甲橫酸酯。式（113)三氟甲 磺酸酯可經式（7)二羥硼酸，依反應圖1所述處理，產生式 89248.doc -69- 200418454 (105)喳啰啉。 反應圖19Another production of I and &amp; in formula (105) is as defined in formula (I), and quinoline which is aryl or heteroaryl is shown in reaction FIG. 18. The aniline of formula (102) prepared according to reaction FIG. 17 can be reacted with &gt; ethyl ethyl salt &apos; to produce aniline of formula (110). Aniline of formula (11) can be heat-treated with an acid such as (but not limited to): trifluoroacetic acid to produce a dihydrogen peak of formula (m) Lin 17. Formula (111) Dihydrojun No. 17 can be oxidized using an oxidizing agent such as (but not limited to): silver nitrate to produce quinoxaline of formula (112). The quinoxaline of formula (112) can be treated with trifluoro ^ acid, such as: 2,6-dimethyl? In the presence of Bidudo, it is treated in a solvent such as: dimethyl methane to produce a trifluoromethane horizontal ester of formula (113). The trifluoromethanesulfonate of formula (113) can be treated with dihydroxyboronic acid of formula (7) according to the reaction shown in Fig. 1 to produce the formula 89248.doc -69- 200418454 (105) perylene. Scheme 19

R5R4NR5R4N

(40) Λ (121) R5R4n(40) Λ (121) R5R4n

NH4OH (122)NH4OH (122)

(123) 式（123)中R4與R5如式⑴定義且心為芳基、雜芳基、雜環 或環烷基之喹唑啉可依反應圖19製備。依反應圖5製備之式 (40)苯胺可經式（121)醯基氯，於鹼如：吡啶之存在下，於 溶劑如、二氯甲烷中處理，產生式（122)醯胺。式（122)醯胺 了、、二氣來源如·氫氧化按水落液處理及加熱，產生式（12 3) p奎4唑。 反應圖20 r5r4n(123) A quinazoline in which R4 and R5 in formula (123) are as defined in formula (I) and the aryl group is heteroaryl, heterocyclic or cycloalkyl can be prepared according to the reaction shown in FIG. 19. Aniline of formula (40) prepared according to Reaction Figure 5 can be treated with fluorenyl chloride of formula (121) in the presence of a base such as pyridine in a solvent such as dichloromethane to produce amine of formula (122). Formula (122) sulfonamide, and two gas sources, such as · Hydroxide, are treated with water and heated to produce formula (12 3) p-Quiazole. Reaction diagram 20 r5r4n

(40) Η 尿素(40) Η Urea

(130) (130) 三氟甲 磺酸酐(130) (130) Trifluoromethanesulfonic anhydride

R5R4NR5R4N

(131) (〇H)2BR6 r6(131) (〇H) 2BR6 r6

(131) ^ 卿〜XXI (123) 式（123)中114與115如式（I)定義且R6為芳基或雜芳基之喹唑 4亦可依反應圖20製備。依反應圖5製備之式（40)苯胺可依 Troeger，et. al. .Prakt. Chem. 117，1927, 181所述，經尿素處 89248.doc -70- 200418454 理與加熱，產生式（130)邊吐淋酮。式（130)峻吐4酮可經三 氟甲磺酸酐，於鹼如：2,6-二甲基吡啶之存在下，於溶劑如 ••二氣甲燒中處理，產生通式（13 1)三氟甲續酸酯。式（13 1) 三氟甲磺酸酯可經通式（7)二經硼酸，依反應圖1所述處理， 產生式（123)峻17号琳。 反應圖2 1(131) ^ XXI ~ (123) In the formula (123), 114 and 115 are as defined in the formula (I) and R6 is an aryl group or a heteroaryl group. The quinazole 4 can also be prepared according to reaction FIG. The aniline of formula (40) prepared according to Reaction Figure 5 can be described by Troeger, et. Al.. Prakt. Chem. 117, 1927, 181, through the urea section 89248.doc -70- 200418454 to produce formula (130 ) Sprinkling ketone. The formula (130) Juntuo 4 ketone can be treated with trifluoromethanesulfonic anhydride in the presence of a base such as: 2,6-dimethylpyridine in a solvent such as • digas methane to produce the general formula (13 1 ) Trifluoroformate. Formula (13 1) trifluoromethanesulfonate can be treated with boric acid of general formula (7) and treated as described in Reaction Figure 1 to produce formula (123) Jun 17 Lin. Reaction diagram 2 1

(138)(138)

H2 Pt/C THFH2 Pt / C THF

式（144)與（145)中Y、Y，、Z’、r2、以與化如式⑴定義與 R6為芳基或雜芳基之化合物可依反應圖2丨所述製備。式 (138)硝基苯可經還原劑如（但不限於）：鉑/碳，於氫蒙氣下 處理產生式（139) —胺基苯。式（139)二胺基苯可經2-氧代 丙醛處理，產生式（140)與（141)溴化物之混合物。式（14〇) 89248.doc -71 - 200418454 與（141)溴化物可經甲醛與式（5)胺處理，產生式（142)與 (143)胺基溴化物之混合物。式（142)與（143)之胺基溴化物依 反應圖1所述處理，產生式（丨44)與（145)化合物。 反應圖22Compounds of Y, Y, Z ', r2 in the formulae (144) and (145) as defined in the formula (1) and R6 is an aryl or heteroaryl group can be prepared according to the reaction shown in Figure 2 丨. Nitrobenzene of formula (138) can be treated with a reducing agent such as (but not limited to): platinum / carbon and treated under a hydrogen blanket to produce formula (139) -aminobenzene. Diaminobenzene of formula (139) can be treated with 2-oxopropanal to produce a mixture of bromides of formula (140) and (141). Formula (14) 89248.doc -71-200418454 and (141) bromide can be treated with formaldehyde and amine of formula (5) to produce a mixture of amine bromide of formula (142) and (143). The amine bromides of formulae (142) and (143) are treated as shown in Figure 1 to produce compounds of formulae (44) and (145). Reaction Figure 22

1) NaN02 H2S04 (147)1) NaN02 H2S04 (147)

(148)(148)

SnCI2 濃.HCISnCI2 concentrated.

(149) 2) aq ΚΙ(149) 2) aq KI

式（154)中Y、Y’、z’、R2、114與1^5如式⑴定義且為芳基 或雜芳基之化合物可依反應圖22所述製備。式（147)化合物 係購自商品或可使用相關技藝已知之方式製備，其可經 NaN〇2與酸如（但不限於）··濃硫酸處理後，以幻處理，產生 式（148)碘化合物。式（148)碘化合物可經SnCi2與酸如（但不 限於）：濃HCi處理，產生式（149)化合物。式（149)化合物可 經丁-3-炔小醇、碘化亞銅（1)、鹼如（但不限於）··三乙胺， 及金屬觸媒如（但不限於）；PdC12(PPh3)2處理，產生式（15〇) 炔。式（150)炔可經NaNCh與酸如（但不限於）：6ΜΗ(：ι處理 ’產生式（151)化合物。式（151)化合物可經p〇cl3處理，產 89248.doc -72- 200418454 生式（152)氯化物。式（152)氯化物可經式（7)二羥硼酸，依反 應圖1所述處理，產生式（153)化合物。式（153)化合物可經 式（5)胺處理，產生式（154)化合物。 反應圖23 巳γ 7' 丫、R2 (149) h2nCompounds of Y, Y ', z', R2, 114 and 1 ^ 5 in formula (154), as defined in formula (I), and which are aryl or heteroaryl, can be prepared as described in Reaction Scheme 22. The compound of formula (147) is commercially available or can be prepared in a manner known in the relevant art. It can be treated with NaNO2 and an acid such as (but not limited to) concentrated sulfuric acid, and then treated with magic to produce the iodine of formula (148). Compounds. The iodine compound of formula (148) may be treated with SnCi2 and an acid such as (but not limited to): concentrated HCi to produce a compound of formula (149). Compounds of formula (149) can be treated with but-3-ynol, cuprous iodide (1), bases such as (but not limited to) · triethylamine, and metal catalysts such as (but not limited to); PdC12 (PPh3 ) 2 treatment to produce acetylene of formula (15〇). The alkyne of formula (150) can be treated with NaNCh and an acid such as (but not limited to): 6MΗ (: ι treatment) to produce a compound of formula (151). The compound of formula (151) can be treated with pCl3, yield 89248.doc -72- 200418454 The formula (152) chloride. The formula (152) chloride can be treated with dihydroxyboronic acid of formula (7) as described in Reaction Figure 1 to produce a compound of formula (153). The compound of formula (153) can be processed by formula (5) Amine treatment gave compound of formula (154). Scheme 23 巳 γ 7 'γ, R2 (149) h2n

NR4R5 Pd(Ph3P)2Cl2 Cul，鹼 (55)NR4R5 Pd (Ph3P) 2Cl2 Cul, base (55)

R5R4NR5R4N

(157)(157)

NaN02 6M HCI (157)-^ R5R4N^NaN02 6M HCI (157)-^ R5R4N ^

NN

Br 、丫•〜二 R2 PdCI2(PPh3)2 〇H (158)Br, Ah • ~ 2 R2 PdCI2 (PPh3) 2 〇H (158)

R5R4NR5R4N

OH (159) (159) (〇H)2BR6 ⑺ 燒基i化物 驗 R5R4nOH (159) (159) (〇H) 2BR6 yttrium-based compound R5R4n

(16Q)0烷基(16Q) O alkyl

(159) P〇C·^ R5R4N(159) POC R5R4N

式（159_161)中丫、丫，、2：，、112、114與1如式（1)定義且]^6為 芳基或雜芳基之化合物可依反應圖23製備。式（149)化合物 可經式（55)胺、碘化亞銅（1)、鹼如（但不限於）：三乙胺，及 金屬觸媒如（但不限於）；PdC12(PPh3)2處理，產生式（157)炔 。式（157)炔可經NaN02與酸如（但不限於）：6M HC1處理， 產生式（15 8)化合物。式（15 8)化合物可經式（7)二羥硼酸，依 反應圖1所述處理’產生式（159)化合物。式（159)化合物可 經燒基鹵化物如（但不限於）：碘甲烷或碘乙烷與鹼如（但不 限於）·二乙胺處理’產生式（160)化合物。式（159)化合物可 經磷醞氯處理，產生式（161)氯化物。亦可使用磷醯溴，產 生相應之溴化物。 89248.doc -73 - 200418454 反應圖24Compounds in formula (159_161) where y, y, 2, 2 :, 112, 114, and 1 are as defined in formula (1) and] ^ 6 is aryl or heteroaryl can be prepared according to reaction FIG. Compounds of formula (149) can be treated with amines of formula (55), cuprous iodide (1), bases such as (but not limited to): triethylamine, and metal catalysts such as (but not limited to); PdC12 (PPh3) 2 To produce an alkyne of formula (157). The alkyne of formula (157) can be treated with NaN02 and an acid such as (but not limited to): 6M HC1 to produce a compound of formula (15 8). The compound of formula (15 8) can be treated with dihydroxyboronic acid of formula (7) according to the reaction shown in Figure 1 'to produce a compound of formula (159). The compound of formula (159) may be treated with a halogenated halide such as (but not limited to): methyl iodide or iodoethane and a base such as (but not limited to) diethylamine to produce a compound of formula (160). Compounds of formula (159) can be treated with phosphorus and chlorine to produce chlorides of formula (161). Phosphonium bromide can also be used to produce the corresponding bromide. 89248.doc -73-200418454 Reaction Figure 24

0-保護基0-protecting group

(163)(163)

MsCl 鹼MsCl base

r2 Re 1)脫除保護基 2) POCI3 r2 - (165) (〇H)2BR6 (7)r2 Re 1) removal of protective group 2) POCI3 r2-(165) (〇H) 2BR6 (7)

PdCI2(PPh3)2 r4r5n N^C〇3PdCI2 (PPh3) 2 r4r5n N ^ C〇3

OPG (166)OPG (166)

R4R5NR4R5N

(161) 烷基σ R4R5n(161) alkyl σ R4R5n

Re R2 r6 (161)Re R2 r6 (161)

烷基SHAlkyl SH

R4R5NR4R5N

(161)(161)

NaCNNaCN

R4R5NR4R5N

r6 (161)r6 (161)

另一種製備式（160-161)化合物之方法及式（167-169)化合 物之方法（其中Y、Y’、Zf、R2、R4與R5如式（I)定義且R6為关 基或雜芳基）說明於反應圖24中。通式（151)化合物可經習此 相關技藝之人士已知用於保護羥基之試劑如（但不限於）：第 -74- 89248.doc 200418454 三丁基二甲矽烷基氯或苯甲基溴，與鹼如（但不限於）：碳酸 氫鈉或咪唑處理，產生式（163)中PG為羥基保護基之化合物 。式（163)化合物可經甲磺醯氯（或甲苯磺醯氯）與鹼如（但不 限於）：二異丙基胺或二乙胺處理，產生式（164)續酸酯。式 (164)磺酸酯可經式（5)胺處理，產生式（165)化合物。式（1 65) 化合物可經式（7)二羥硼酸，依反應圖1所述處理，產生式 (166)化合物。式（166)化合物之羥基保護基可採用習此相關 技蟄之人士已知之方法脫離，如（但不限於）：以氟離子、酸 處理’或，使用金屬觸媒（H2與Pd/C)氫化後，以磷驢氯處理， 產生式（161)氣化物。亦可使用磷醯溴，產生相應之溴化物 。式（161)氯化物可經親核物如（但不限於）烷醇鹽、烷基氫 硫化物、烷基格林納試劑或氰化鈉處理，產生式（i67_i69) 化合物。 本發明亦係有關製備式（I)化合物Another method for preparing a compound of formula (160-161) and a compound of formula (167-169) (where Y, Y ', Zf, R2, R4, and R5 are as defined in formula (I) and R6 is a guanyl or heteroaromatic (Base) is illustrated in Reaction Figure 24. Compounds of general formula (151) may be known to those skilled in the art for protecting reagents such as (but not limited to): -74- 89248.doc 200418454 tributylsilyl chloride or benzyl bromide Treatment with a base such as (but not limited to): sodium bicarbonate or imidazole to produce a compound in which PG is a hydroxyl protecting group in formula (163). The compound of formula (163) may be treated with methanesulfonyl chloride (or tosylsulfonium chloride) and a base such as (but not limited to): diisopropylamine or diethylamine to produce a continuous acid ester of formula (164). The sulfonate of formula (164) can be treated with an amine of formula (5) to produce a compound of formula (165). The compound of formula (1 65) can be treated with dihydroxyboronic acid of formula (7) as described in Reaction Figure 1 to produce a compound of formula (166). The hydroxyl protecting group of the compound of formula (166) can be removed by methods known to those skilled in the art, such as (but not limited to): treatment with fluoride ion, acid 'or using metal catalysts (H2 and Pd / C) After hydrogenation, it is treated with phosphorus donkey chloride to produce a gaseous formula (161). Phosphonium bromide can also be used to produce the corresponding bromide. The chloride of formula (161) may be treated with a nucleophile such as (but not limited to) an alkoxide, an alkyl hydrosulfide, an alkyl Grignard reagent, or sodium cyanide to produce a compound of formula (i67_i69). The invention also relates to the preparation of compounds of formula (I)

或其醫藥上可垃a、 要又 &lt; 鹽類、酯類、醯胺類或前藥之方法， 其中 R1為L2R6，其中、為 、R3、R3^R3b為氫 一鍵結，R6為3(2H)-嗒畊酮-2-基；r2 ;; n為2 ; R16與Rl7 89248.doc -75 - 200418454 每次出現時分別為氫；R4與R5共同形成式（a)甲基吡咯啶基 環，其中R7、R8、119與R10中之一為甲基，其餘三個取代基 為氫；Y與Yf為CH ;與X、Xf、Z與Z’為C。該方法包括下列 步驟： (a)提供化合物（II):Or its pharmacologically acceptable method, salt, ester, ammonium, or prodrug, wherein R1 is L2R6, wherein, R3, R3 ^ R3b are hydrogen-bonded, and R6 is 3 (2H) -dacrotonone-2-yl; r2 ;; n is 2; R16 and R17 89248.doc -75-200418454 are hydrogen at each occurrence; R4 and R5 together form the methyl pyrrolidine of formula (a) A basic ring in which one of R7, R8, 119, and R10 is a methyl group, and the remaining three substituents are hydrogen; Y and Yf are CH; and X, Xf, Z, and Z 'are C. The method includes the following steps: (a) providing compound (II):

⑻㈣合物⑼經叫酬原，產生化合物_: ·The compound is called primogen, which produces compound _: ·

(c)由式（III)化合物經3(2H)-嗒畊酮、銅粉與鹼處理，產生 化合物（IV):(c) The compound of formula (III) is treated with 3 (2H) -dacrotonone, copper powder and alkali to produce compound (IV):

(d)活化化合物（IV)之羥基；及由所得化合物與甲基吡咯 淀反應，產生式（I)化合物。 化合物（11)6-溴-莕-2-基-乙酸[CAS 3271-06-5]可依多種已 知方法製備 M?ljW:Jonesetal.，J.Amer.Chem.Soc.，70:2843-2 848 (1948)。化合物（II)可經甲硼烷-THF處理，最好使用約 3至4當量，同時保持反應在0°C以下。化合物（III)可與3(2H)- 89248.doc -76- 200418454 嗒畊酮依W〇00247 19實例62之方法，使用約1當量銅粉與約 3當量鹼反應。較佳鹼為K2C〇3。化合物（IV)可經甲磺醯氯 或甲苯續驢氯，最好於驗例如：三乙胺之存在下處理而活 化。所得化合物可與胺例如：甲基p比洛淀，及更特定言之 2-甲基吡咯啶反應，產生式（I)範圍内之化合物。 本發明化合物與中間物可採用習此有機合成技藝之人士 已知之方法純化及單離。用於純化及單離化合物之常用方 法實例包括（但不限於）：於固體擔體上（如：矽膠、蓉土、 或經烷A烷基衍化之矽石）進行層析法、於高溫或低溫下， 可視需要使用活性碳前處理進行再結晶、薄層層析法，於 多種不同壓力下蒸餾，於真空'下昇華，及研磨法，其說明 於例如:&quot;Vogel's Textbook of Practical Organic Chemistry’’ 第 5版（1989)，Furniss，Hannaford，Smith，與 Tatchell著，英國 Longman Scientific &amp; Technical 出版(Essex CM20 2JE, England) 〇 本發明化合物具有至少一個鹼性氮，因此該化合物可經 酸處理，形成所需鹽類。例如：化合物可經酸，於高於或 低於室溫下處理，產生所需鹽類，其可沉澱，冷卻後過濾 收集。適合該反應之酸實例包括（但不限於）酒石酸、乳酸、 琥轴酸、及爲桃酸、阿卓乳酸、曱績酸、乙績酸、甲苯績 酸、莕磺酸、碳酸、富馬酸、葡糖酸、乙酸、丙酸、水楊 酸、鹽酸、氫溴酸、磷酸、硫酸、檸檬酸、或羥丁酸、樟 腦績酸、蘋果酸、苯乙酸、天冬胺酸、麵胺酸，等等。 本發明組合物 本發明亦提供醫藥組合物，其包含醫療有效量式（I)化合 89248.doc -77- 200418454 物與醫藥上可接受之載劑組合。組合物 私而 α 4、 匕δ本毛明化合 :二”種無毒性醫藥上可接受之載劑共同調配。醫 =物：調配成口服用固體或液體形式、供非 射用或經直腸投藥用。 :文所使用之術語”醫藥上可接受之載劑，，指無毒性惰性 肢、丰固體歧體填料、稀釋劑、包埋材料或任何型能 …辅劑。有些可作為醫藥上可接受之載劑之材料實： :糖如.乳糖、葡萄糖與薦糖；殿粉如：玉米殿粉 =:纖維素與其衍生物如·ι甲基纖維素鋼、乙基纖 、’.素人纖維素乙酸酿；黃耆膠粉末；麥芽；明膠；滑石； 可可奶油與栓劑蠟；油類如：花生油、棉籽油：葵;:、、ι 芝麻油、橄棍油、玉米油與大豆油；二醇類，如：丙二醇 :醋類如：油酸乙酿與月桂酸乙酿；洋菜；緩衝劑如：氫 乳化鎂與氫氧化铭；藻酸；無熱原水；等張性生理食鹽水 :t格氏液（Ringed s〇luti〇n);乙醇與磷酸鹽緩衝液及其他 卜母f生相各性满滑劑如：月桂基硫酸酿納與硬脂酸錢，及 煮色劑、釋出劑、包衣劑、甜味劑、調味劑、及香料、防 腐劑與抗氧化劑’亦卩依習此調配技藝之人士之判斷含在 組合物中。 本發明醫藥組合物可投與人類與其他哺乳動物，其係經 口、直腸、非經腸式、腦池内、陰道内、腹膜内、局部(呈 物末、油霄或滴劑）、頰内投藥或呈經口或鼻用之噴液。未 又所使用之術語’，非經腸式”指投藥·方式包括靜脈内、肌内 、腹胰内、胸骨内、皮下、關節内注射與輸液。 89248.doc -78- 200418454 非經腸式注At !?] Μ: 醬樂組合物包括醫藥上可接受之A ® 7jc 性或非水性浣诂 A 4 饮又心…、固水 /、n懸浮液或乳液與供再組成無菌 /王''用）谷液或白矣、、士、 劑、稀釋冽、二Γ广辨菌粉末。合適之水性與非水性載 Θ /谷劑或媒劑實例包括水、乙醇、多元醇(丙- 醉、聚乙醇、甘、、占 Μ — ν ~ : /由，寺寺，與其合適之混合物）、植物油（如 見油）與'/王射用有機酿類如：油酸乙醋，或其合適混人 物。組合物可藉由例如：使用包衣如： 4 各、、 、田权子大小，及利用界面活性劑等，保持適(d) activating the hydroxyl group of compound (IV); and reacting the obtained compound with methylpyrrole to produce a compound of formula (I). Compound (11) 6-bromo-fluoren-2-yl-acetic acid [CAS 3271-06-5] can be prepared by a variety of known methods. MjlW: Jonesetal., J.Amer.Chem.Soc., 70: 2843- 2 848 (1948). Compound (II) can be treated with borane-THF, preferably about 3 to 4 equivalents, while keeping the reaction below 0 ° C. Compound (III) can be reacted with 3 (2H)-89248.doc -76- 200418454 dacrodone according to the method of WO247 19 Example 62, using about 1 equivalent of copper powder and about 3 equivalents of base. The preferred base is K2CO3. The compound (IV) can be activated by mesylate chloride or toluene chloride, preferably treated in the presence of, for example, triethylamine. The resulting compound may be reacted with an amine such as methyl p-bilodine, and more specifically 2-methylpyrrolidine to produce a compound within the range of formula (I). The compounds and intermediates of the present invention can be purified and isolated using methods known to those skilled in the art of organic synthesis. Examples of common methods for purifying and isolating compounds include (but are not limited to): chromatography on a solid support (such as silica gel, serenite, or alkane-derived silica), At low temperature, if necessary, use activated carbon pretreatment for recrystallization, thin-layer chromatography, distillation under a variety of pressures, sublimation under vacuum, and grinding, which are described in, for example: &quot; Vogel's Textbook of Practical Organic Chemistry '' 5th edition (1989), Furniss, Hannaford, Smith, and Tatchell, published by Longman Scientific &amp; Technical (Essex CM20 2JE, England). The compound of the present invention has at least one basic nitrogen, so the compound can Process to form the desired salt. For example, compounds can be treated with acid at higher or lower than room temperature to produce the desired salts, which can be precipitated and collected by filtration after cooling. Examples of acids suitable for this reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid, and tauric acid, azo lactic acid, acetic acid, acetic acid, toluic acid, sulfonic acid, carbonic acid, fumaric acid , Gluconic acid, acetic acid, propionic acid, salicylic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, or hydroxybutyric acid, camphor acid, malic acid, phenylacetic acid, aspartic acid, facial amino acid ,and many more. Compositions of the invention The invention also provides pharmaceutical compositions comprising a medically effective amount of a compound of formula (I) 89248.doc -77- 200418454 in combination with a pharmaceutically acceptable carrier. The composition is privately α 4 and δ δ Ben Maoming combination: two "non-toxic pharmaceutically acceptable carriers are formulated together. Medicine = substance: formulated into solid or liquid form for oral use, non-radial or rectal administration Use: The term "pharmaceutically acceptable carrier" as used herein refers to non-toxic inert limbs, solid solid fillers, diluents, embedding materials, or any type of ... adjuvant. Some of the materials that can be used as pharmaceutically acceptable carriers are: sugars such as lactose, glucose, and recommended sugars; house powders such as: corn house powders = cellulose and its derivatives such as methyl cellulose steel, ethyl Fiber, '. Plain cellulose acetate brewing; tragacanth powder; malt; gelatin; talc; cocoa butter and suppository wax; oils such as: peanut oil, cottonseed oil: sunflower;:,, ι sesame oil, olive oil, corn Oil and soybean oil; glycols such as: propylene glycol: vinegars such as: oleic acid and lauric acid; agar; buffers such as hydrogen emulsified magnesium and hydroxide; alginic acid; pyrogen-free water; etc. Tonic saline solution: Ringer's solution (Ringed solutin); ethanol and phosphate buffer solution and other bio-active ingredients such as: lauryl sulfate and stearic acid, And coloring agents, release agents, coating agents, sweeteners, flavoring agents, and spices, preservatives and antioxidants are also included in the composition according to the judgment of those who are skilled in this formulation. The pharmaceutical composition of the present invention can be administered to humans and other mammals, and is administered orally, rectally, parenterally, intracranially, intravaginally, intraperitoneally, topically (in the form of powder, oil, or drops), or intrabuccally. Administration or oral or nasal spray. The term "parenteral" is used to refer to administration methods including intravenous, intramuscular, abdominal pancreatic, intrasternal, subcutaneous, intra-articular injection and infusion. 89248.doc -78- 200418454 Parenteral Note At !?] Μ: Sauce composition includes pharmaceutically acceptable A ® 7jc sex or non-aqueous raccoon A 4 drink and heart ..., solid water /, n suspension or emulsion and reconstituted sterile / king ' 'Used' cereals or baijiu, Shishi, agent, dilute diarrhea, Di Γ broad-spectrum bacteria powder. Suitable examples of aqueous and non-aqueous loading Θ / cereals or vehicles include water, ethanol, polyol (propyl alcohol , Polyethanol, Gan, Zhan M — ν ~: / Yu, Sisi, and its suitable mixture), vegetable oil (such as see oil) and '/ Wang She organic brewing such as ethyl oleate, or its suitable Mixed characters. The composition can be maintained by, for example, using coatings such as:

咼、成動性，。 舁：政劑。可藉由多種抗細菌劑與抗黴菌劑例&amp;:對氧苯 甲H鼠丁醇、苯紛、山梨酸，等等防止微生物之作用 U可包括等張性劑例如：糖類、氯化鋼，等等。可採用 I、犮吸收〈試劑例如：單硬脂酸鋁與明膠來延長注射劑型 之吸收性。咼, into action.舁: Political agent. A variety of antibacterial and antimycotic agents can be used &amp;: paraben Benzyl alcohol, Benzene, sorbic acid, etc. to prevent the action of microorganisms U can include isotonic agents such as: sugars, chlorinated steel ,and many more. I, osmium absorption reagents such as aluminum monostearate and gelatin can be used to prolong the absorption of the injection form.

有時候，為了延長藥物之效用，經常需延緩皮下或肌内 :射：藥物之吸收性。此點可使用水溶性差之結⑽^ /貝、心浮液達成。藥物之吸收速率取決於其溶解速率 ’後者則依結晶大小與結晶形狀而異。或者，㈣物溶解 或懸浮於油性媒劑中，延緩非經腸式投藥劑型之吸收。 Θ懸/予液中除了活性化合物外，尚可包含懸浮劑例如··乙 ^基化兴硬脂醇、聚氧乙烯山梨糖醇與山梨糖醇酐酯、截 曰曰纖維素、偏氫氧化銘、惠土、洋菜、黃者膠與其混合物。 若需要時及需要更有效分佈時，本發明化合物可加至緩 89248.doc -79- 200418454 釋或定點傳送系絲+ , H无中，如··聚合母質 其可經過殺菌，例如·妹、M /、U小球。 ·、、二過可隔離細菌之濾器 呈殺菌固體組成形式 # 4或+加 风小式又殺囷劑，其可於臨 水或一些其他無菌注射用介質中。 μ無因 注射用儲積型之製丰 ι法4使樂物於生物可降解之聚合物如 •聚丙X酯-聚乙交酯φ ,忐 -物之比論“ 母質。依據藥物與聚 二物《比例與所使用之特定聚合物性質而$，可 釋出之速率。其他生物可降解之聚合物實例包 與聚，&quot;峨注射用調配物之製法亦為使藥：包= 可與m組織相容之微脂粒或微乳液中。 注射用调配物可私尚 · _ 、、工過叙困例如·經過可隔離細菌之濾 =過攄或添加呈殺菌固體組成形式之殺菌劑，其可於臨^ 前方溶解或句散於無菌水或—些其他無菌注射用介質中。 注射用製劑例如：無菌注射用水性或油性懸浮液可依相 篇已知之方式使用合適勻散劑或濕化劑與懸浮劑調配 。無菌注射用製劑亦可為含於無毒性非經腸式可接受之稀 釋劑或溶劑中之無菌注射用溶液、懸浮液或乳液，如：u_ 丁二醇溶液。可使用之可接受之媒劑與溶劑為水、林格式 /合液、U.S.P.與等張性氣化納溶液。此外，無菌之固定油類 常用為溶劑懸浮介質。此目的可使用任何品牌之固定油類 ，包括合成之單或二_甘油酯。此外，脂肪酸如：油酸亦可 用於製備注射劑。 、 口服用固體劑型包括：膠囊、錠劑、丸劑、粉劑與粒劑 此等固體劑型中，由一種或多種本發明化合物混合至少 89248.doc -80- 200418454 一種醫藥上可接受之惰性載劑如：檸檬酸納或鱗酸二㈣/ )填料或補充劑如：殿粉、乳糖、絲、葡萄糖、甘霖 ㈣與水楊酸；b)、结合劑如：叛甲基纖維素、藻酸鹽、明 膠、聚乙埽t各相、薦糖與金合歡膠；c)保濕劑如：甘 t;d)崩解劑如：洋菜、碳_、馬鈴薯或樹薯殿粉、藻 鉍、某些矽酸鹽與碳酸鈉；e)延滯溶解劑如：石蠟；⑽速 :收劑如.四級銨化合物；g)濕化劑如：鯨蠟醇與單硬脂 酸甘油酯；h)吸收劑如：高嶺土與％土 ；與丨)潤滑劑如： 仴石心酸鈣、硬脂酸鎂、聚乙二醇固體、月桂基硫酸 酉曰.·内舁其/比合物。若為膠囊、鍵劑與丸劑時，劑型中亦 可包含緩衝劑。 亦可使用項似型怨之固體組成作為使用乳糖及高分子量 聚乙二醇之軟性與硬性明膠囊之填料。 叙劑、糖衣錠、膠囊、丸劑與粒劑之固體劑型可使用包 衣及外殼製備，如：腸溶性包衣與製藥技藝已知之其他包 衣。其可視需要包含不透明劑，亦可為延至僅在腸道中釋 出或偏向在某一部份勝道中釋出之組合物。適用於延緩活 性劑釋出之物質實例包括聚合物與蠟類。 經直腸或陰道投藥之組合物為栓劑較佳，其製法為混合 本發明化合物與於室溫下呈固態，但於體溫下卻呈液態之 合適之典刺激性載劑如：可可奶油、聚乙二醇或栓劑用蠘 ’因此將會於直腸或陰道中融化釋出活性化合物。 - 口服用液體劑型包括醫藥上可接受之乳液、微乳液、溶 液、懸浮液、糖漿與池劑。液體劑型中除了活性化合物外 89248.doc -81 - 200418454 ，尚可包含相關技藝上常用之惰性稀釋劑如，例如：水或 ’、他’合劑、落解劑與乳化劑如：6醇、異丙基醇、碳酸乙 醋、乙酸乙酷、苯甲醇、苯甲酸苯甲醋、丙二醇、1?3-丁二 鮮、二甲基甲醯胺、油類（特定言之棉籽油、花生油’、玉米 油取胚芽油、橄欖油、1麻油與芝麻油)、甘油、四氫糠醇 、聚乙二醇與山梨糖醇酐之脂肪酸酯類，與其混合物。 服用組合物中除了惰性稀釋劑外尚包含辅劑如：濕化 劑、乳化劑與懸浮劑、甜味劑、調味劑與香料。 毛凡化口物之局邵或穿皮式投藥劑型包括油膏、糊劑 1霜^洗液、凝膠、粉劑、溶液、喷液、吸入劑或貼布 、由所而 &lt; 本發明化合物於無菌條件下與醫藥上可接受之 、技任何而要《防腐劑或緩衝劑依需要混合。眼用調配 耳滴戶，《1 3艮用藥霄、粉劑與溶液亦包括在本發明範圍 内。 油膏、糊劑、乳霜與凝膠中除了本發明活性化合物外， η包含動物性與植物性脂防、油、虫致、石犧、殿粉、黃 耆膠、纖維素衍生物、聚乙二醇、石夕嗣、息土、碎酸、滑 石與氧化鋅，或其混合物。 粉劑與噴液中除了本發明化合物外，尚可包含乳糖、滑 石、枝、風乳化鋁、碎酸舞與聚酿胺粉末，或此等物質 ^混合物。噴液中亦可包含習知之推進劑如：氯氣碳氯化 物。 本發明化合物亦可呈微脂粒形式投藥。如同相關技藝已 、者微月“:通书订生自磷脂或其他脂質。微脂粒係由單 89248.doc -82- 200418454 層或多層層壓之水合液晶勻散於水性介質中形成。任何無 毒性生理上可接受且可代謝之脂質均可用㈣成微脂粒。 呈微脂粒之組合物巾除了本發明化合物外，尚可包含安定 劑、防腐冑’等等。較佳液體為天然與合成之磷脂及鱗脂 基膽鹼（卵磷脂），其可分開使用或組合使用。 形成微脂粒之方法係相關技藝已知者。參見例如： Prescott, Ed., Methods m Cell Bi〇l〇gy? v〇lume χιγ? Academic press，New York，Νγ，（1976)，p 33以後。 ， 本發明，化合物之局部投藥用劑型包括粉劑、嘴液、油膏 與吸入劑。由活性化合物於無菌條件下與醫藥上可接受之 載劑及任何需要之防腐劑、緩衝劑或推進劑依需要混合。 眼用調配物、眼用藥膏、粉劑與溶液亦包括在本發明^圍 内。亦包括含有本發明化合物之水性液體組合物。 本發明化合物可呈無機酸或有機酸所衍生之醫藥上可接 受之鹽類、酯類或醯胺類使用。本文所使用之術語，，醫藥上 可接受之鹽類、酯類與醯胺類”指在完整之醫學判斷下，適 用於與人體或較低等動物之組織接觸，而沒有不當毒性、 刺激、過敏反應，等等，且符合合理之效益/危險比例，並 可有效用於所需目的之式（I)化合物之羧酸鹽、胺基酸加成 鹽類、兩性離子S旨類與酸胺類。 本文所使用之術語”醫藥上可接受之鹽類，，指彼等鹽類係 在完整之醫學判斷下’適用於與人體或較低等動物之組鐵 接觸’而沒有不當毒性、刺激、過敏反應，等等，且符人 合理之效益/危險比例。醫藥上可接受之鹽係相關技藝已知 89248.doc -83- 200418454 者。該等鹽類可於本發明化合物之最終單離與純化法期間 於原位合成，或另外由游離鹼官能基與合適之有機酸反靡 製成。 代表性酸加成鹽包括（但不限於）：乙酸鹽、己二酸鹽、薄 酸鹽、檸檬酸、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、硫酸 氫鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、二葡糖酸鹽、甘 油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、富馬酸鹽、鹽酸Sometimes, in order to prolong the effectiveness of a drug, it is often necessary to delay the subcutaneous or intramuscular: Shot: Absorption of the drug. This point can be achieved by using poorly water-soluble crustaceans / shellfish and heart floaters. The absorption rate of a drug depends on its dissolution rate. The latter varies depending on the crystal size and crystal shape. Alternatively, the mash is dissolved or suspended in an oily vehicle to delay the absorption of parenteral dosage forms. In addition to the active compounds in the Θ suspension / preparative, it may contain suspending agents such as ethyl ethyl stearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, cellulose, meta-hydroxide Ming, Huitu, agar, yellow gum and its mixture. If needed and when more effective distribution is needed, the compound of the present invention can be added to the release of 89248.doc -79- 200418454 or fixed-point delivery system, +, H is not neutral, such as · polymer matrix which can be sterilized, for example , M /, U small ball. · 、 Secondary filter that can isolate bacteria. It is in the form of sterilized solids. # 4 or + air-cooled small type insecticide, which can be used in water or some other sterile injection media. μ non-causative storage method for injection-type storage method 4 makes fun animals biodegradable polymers such as • polypropylene X ester-polyglycolide φ, plutonium-property ratio "parent material. According to the drug and poly two "Proportion and the specific polymer properties used, and the rate of release. Other examples of biodegradable polymers include poly and poly," the preparation method of formulations for injection injection is also to make the drug: 包 = 可 与m tissue-compatible microlipids or microemulsions. Formulations for injection can be kept private, such as after passing through a filter that can isolate bacteria = pass or add a fungicide in the form of a bactericidal solid composition, It can be dissolved or dispersed in sterile water or some other sterile injectable medium in front of it. Preparations for injection, such as sterile injectable aqueous or oily suspensions, can be used with suitable dispersing agents or humidified in a manner known in this article. Formulations and suspensions. Sterile injection preparations can also be sterile injectable solutions, suspensions or emulsions contained in non-toxic parenterally acceptable diluents or solvents, such as: u_ butanediol solution. Can be used The acceptable vehicle and solvent are water, Format / mix solution, USP and isotonic gasification sodium solution. In addition, sterile fixed oils are often used as solvent suspension media. For this purpose, any brand of fixed oils can be used, including synthetic mono- or diglycerides. In addition Fatty acids such as: oleic acid can also be used to prepare injections. Solid dosage forms for oral use include: capsules, tablets, pills, powders, and granules. In these solid dosage forms, at least 89248.doc -80 is mixed with one or more compounds of the present invention. -200418454 A pharmaceutically acceptable inert carrier such as: sodium citrate or diphosphonic acid /) fillers or supplements such as: dian powder, lactose, silk, glucose, glycinol and salicylic acid; b), binding agents Such as: methylcellulose, alginate, gelatin, polyethylene acetate, saccharose and acacia gum; c) humectant such as: Gant; d) disintegrator such as: agar, carbon, etc. Potato or cassava powder, algal bismuth, certain silicates and sodium carbonate; e) delaying dissolving agents such as: paraffin; ⑽speed: collectors such as quaternary ammonium compounds; g) wetting agents such as: whale wax Alcohol and glyceryl monostearate; h) absorbents such as: kaolin and% soil; and 丨) Lubricants such as: calcium vermiculite, magnesium stearate, polyethylene glycol solids, lauryl sulphate, etc., and its ratio. For capsules, bonds and pills, the dosage form can also contain Buffering agent. It can also be used as a filler for soft and hard gelatin capsules using lactose and high molecular weight polyethylene glycol. Solid dosage forms of narcotics, dragees, capsules, pills and granules can be coated And shell preparation, such as: enteric coating and other coatings known in the pharmaceutical technology. It can include opaque agent if necessary, or it can be extended to release in the intestinal tract or biased to release in a certain part of the path Examples of substances suitable for delaying the release of active agents include polymers and waxes. Rectal or vaginal compositions are preferred as suppositories, which are prepared by mixing the compound of the present invention with a solid at room temperature, but at body temperature. Suitable liquid irritating carriers, such as cocoa butter, polyethylene glycol or suppositories, are in liquid form and will therefore melt in the rectum or vagina to release the active compound. -Liquid dosage forms for oral use include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and pools. In addition to active compounds, the liquid dosage form 89248.doc -81-200418454 can also contain inert diluents commonly used in related technologies, such as: water or ', other' mixtures, disintegrants and emulsifiers such as: 6 alcohol, iso Propyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid benzoate, propylene glycol, 1-butanediamine, dimethylformamide, oils (specifically cottonseed oil, peanut oil ', Corn oil is obtained from germ oil, olive oil, 1 sesame oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, fatty acid esters of polyethylene glycol and sorbitan, and mixtures thereof. In addition to inert diluents, adjuvants such as: wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances are included in the composition. The local or transdermal dosage forms of Mao Fanhua mouth products include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches, and the invention &lt; the present invention The compounds are mixed under sterile conditions with pharmaceutically acceptable, technically acceptable preservatives or buffers as needed. Ophthalmic formulation Ear drops households, "13, medicines, powders and solutions are also included in the scope of the present invention. In addition to the active compounds of the present invention in ointments, pastes, creams, and gels, η includes animal and vegetable lipids, oils, insects, stone sacrifices, powder, tragacanth gum, cellulose derivatives, polymer Ethylene glycol, Shixiyan, polydip, broken acid, talc and zinc oxide, or mixtures thereof. In addition to the compounds of the present invention, the powders and sprays may also contain lactose, talc, twigs, wind-emulsified aluminum, crushed acid and polyamine powder, or mixtures thereof. The spray liquid may also contain conventional propellants such as: chlorocarbon chloride. The compounds of the present invention can also be administered in the form of microlipids. As the relevant technique has been, "Zhuyue": Tongshu is regenerated from phospholipids or other lipids. Microlipids are formed by single 89248.doc -82- 200418454 layer or multilayer laminated hydrated liquid crystal dispersed in an aqueous medium. Any Non-toxic, physiologically acceptable and metabolizable lipids can be used to form lipid particles. In addition to the compounds of the present invention, the composition of the lipid particles may also include stabilizers, preservatives, and the like. The preferred liquid is natural It can be used separately or in combination with synthetic phospholipids and squidylcholine (lecithin). Methods for forming microlipids are known in related art. See, for example: Prescott, Ed., Methods m Cell Bi〇l 〇gy? V〇lume χγ? Academic press, New York, Nγ, (1976), p 33 and later. In the present invention, the topical pharmaceutical dosage forms of the compounds include powders, mouth liquids, ointments and inhalants. Aseptic conditions are mixed with a pharmaceutically acceptable carrier and any required preservatives, buffers or propellants as needed. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also included within the scope of the present invention. Also included contain An aqueous liquid composition of a compound of the present invention. The compound of the present invention can be used as a pharmaceutically acceptable salt, ester or amidine derived from an inorganic or organic acid. As used herein, the term, pharmaceutically acceptable “Salts, esters, and amidines” means that, under complete medical judgment, they are suitable for contact with human or lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and meet reasonable benefits / Dangerous proportions and carboxylic acid salts, amino acid addition salts, zwitterions, and acid amines of the compounds of formula (I) which can be effectively used for the required purpose. The term "pharmaceutically acceptable salts" as used herein means that their salts are 'suitable for contact with humans or lower-group animals' irons' under complete medical judgment without undue toxicity, irritation, or allergies Reactions, etc., and meet reasonable human benefit / danger ratios. Pharmaceutically acceptable salts are known in the relevant arts 89248.doc -83- 200418454. These salts can be used for the final isolation and purification of the compounds of the present invention Synthesized in situ during the process, or otherwise made from free base functional groups and suitable organic acids. Representative acid addition salts include (but are not limited to): acetate, adipic acid, thin acid, lemon Acid, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphor, camphorsulfonate, digluconate, glyceryl phosphate, hemisulfate, heptane Acid, caproate, fumarate, hydrochloric acid

鹽、氫溴酸鹽、氫碘酸鹽、2-羥基乙磺酸鹽、乳酸鹽、馬 來酸鹽N甲磺酸鹽、菸酸鹽、2_莕磺酸鹽、草酸鹽、雙羥 茶酸鹽、果酸鹽、過硫酸鹽、3_苯基丙酸鹽、苦味酸鹽^ 特戊酸鹽、丙酸鹽、琥珀酸鹽、酒石酸鹽、硫代氰酸鹽、 磷酸鹽、麩胺酸鹽、碳酸氫鹽、對甲苯磺酸鹽與十一：烷 酸鹽。本發明化合物之較佳鹽類為酒石酸鹽與鹽酸鹽。 含有驗性氮之基團可經四級化，其係使用如：低碳教 基齒化物如：甲基、乙基、丙基、與丁基氯化物、溴化Salt, hydrobromide, hydroiodate, 2-hydroxyethanesulfonate, lactate, maleate N mesylate, nicotinate, 2-amidinesulfonate, oxalate, dihydroxy Theanine, citrate, persulfate, 3-phenylpropionate, picrate ^ Tvalproate, propionate, succinate, tartrate, thiocyanate, phosphate, bran Amines, bicarbonates, p-toluenesulfonates and eleven: alkanoates. Preferred salts of the compounds of the present invention are tartrate and hydrochloride. Groups containing qualitative nitrogen can be quaternized, and they are used, for example, low-carbon radicals such as methyl, ethyl, propyl, and butyl chloride, bromide

與碘化物；二烷基硫酸酯如：二甲基、二乙基、二丁基 二戊基硫酸酉旨；長鏈齒化物如：癸基、繼、肉豆養 與硬脂基氯化物、溴化物與破化物；芳基燒基自化物如 苯甲基與苯乙基漠化物’等等。藉以得到水或油可溶解 可勻散之產物。 可用於形成醫藥上可接受之酸加成鹽類之酸實例包捂裊 機酸如1酸、幻㈣、錢料酸，有機酸如：草酸·:、 馬來酸、琥珀酸與檸檬酸。 驗加成鹽類可料發明化合物之最終單離與純化法期間 89248.doc -84 - 200418454 万、f位氣備，其係由含羧酸之部份基團與合適鹼如：醫藥 =可接文《金屬陽離子之氫氧化物、碳酸鹽或碳酸氫鹽， 或:、虱或有機-級、二級或三級胺反應。醫藥上可接受之 鹽類包括（但不限於）··以鹼金屬或鹼土金屬為主之陽離子如 :鐘、納、卸、避、鎂與銘之鹽類，等等，及無毒性四級 氨與胺陽離子包括：銨、四甲基銨、w乙基銨、甲基胺、 安—τ基胺、二乙基胺、二乙基胺、乙基胺等等 、其他通料形成驗加成鹽類之代表性有機胺類包括乙二 胺、乙气胺、二乙醇胺、六氫吡啶與六氫吡畊。 本文所使用纟術語，，醫藥上可接受之醋類”指本發明化合 物:可於活體内水解之酿類，且包括彼等容易於人體内降 解:下母化合物或其鹽類之酉旨類。醫藥上可接受之本發明 無毒性酉旨類包括Cl_至c6垸基酿類與C5-至c7環垸基酉旨類，但 以C1·至C4烷基酿類較佳。式⑴化合物之酉旨類可依據常用之 、製備例如·此等酯類可藉由含有羥基之化合物與酸 ^垸基羧酸（如：乙酸）反應，或與酸及芳基羧酸（如：苯甲 酸)反應：而附接在羥基上。若化合物含有羧酸基團時，醫 樂上可接受之酯類係由含有羧酸基團之化合物與鹼如：三 乙胺及烷基卣化物、烷基三氟甲磺酸酯(例如:甲基碘、苯甲 基埃、環戊基句反應製得。其製法亦可由化合物與酸（如： 鹽酸）及燒基幾酸（如：乙酸），或與酸及芳基叛酸（如：苯甲 酸）反應。 本文所使用之術語”醫藥上可接受之醯胺，，指由氨、一級 匕至㈣基胺類與二級C1_K6二燒基胺類衍生之本發明之 89248.doc -85 - 200418454 該胺亦可呈含有一個氮With iodide; dialkyl sulfates such as: dimethyl, diethyl, dibutyl dipentyl sulfate; long chain tooth compounds such as: decyl, relay, bean bean and stearyl chloride, Bromides and broken compounds; aryl alkyl compounds such as benzyl and phenethyl deserts' and so on. Thereby, water or oil can be dissolved and dispersed product. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include organic acids such as 1 acid, phantom acid, and acid acids, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. During the final isolation and purification of the compounds of the invention which can be added to the salt, the final isolation and purification method 89248.doc -84-200418454 million, f-position gas preparation, which consists of a carboxylic acid-containing group and a suitable base such as: Following the article "Hydroxide, carbonate or bicarbonate of metal cations, or: Lice or organic-grade, secondary or tertiary amine reactions. Pharmaceutically acceptable salts include (but are not limited to) ... cations mainly composed of alkali metals or alkaline earth metals such as: bell, sodium, unloading, avoiding, magnesium and Ming salts, etc., and non-toxic grade IV Ammonia and amine cations include: ammonium, tetramethylammonium, wethylammonium, methylamine, an-tauylamine, diethylamine, diethylamine, ethylamine, etc. Representative organic amines that form salts include ethylenediamine, ethylamine, diethanolamine, hexahydropyridine, and hexahydropyrine. As used herein, the term "pharmaceutically acceptable vinegar" refers to compounds of the present invention: brews that can be hydrolyzed in vivo, and include those that are easily degraded in the human body: subclasses of the parent compound or its salts The non-toxic compounds of the present invention that are pharmaceutically acceptable include Cl- to c6 methyl groups and C5- to c7 cyclomethyl groups, but C1 · to C4 alkyl groups are preferred. Compounds of formula ⑴ The esters can be prepared according to the commonly used ones. For example, these esters can be reacted with a compound containing a hydroxyl group with an acid carboxylic acid such as acetic acid, or with an acid and an aryl carboxylic acid such as benzoic acid. ) Reaction: and attached to the hydroxyl group. If the compound contains a carboxylic acid group, medically acceptable esters are composed of a compound containing a carboxylic acid group and a base such as triethylamine and alkyl halides, alkanes Trifluoromethanesulfonate (for example: methyl iodide, benzyl ene, cyclopentyl). The preparation method can also be made from compounds and acids (such as: hydrochloric acid) and carbamic acid (such as: acetic acid), Or with acids and aryl benzates (eg, benzoic acid). The term "pharmaceutically acceptable" as used herein Amine refers to 89248.doc -85-200418454 of the present invention which is derived from ammonia, primary amines to fluorenylamines and secondary C1_K6 dialkylamines. The amine may also contain a nitrogen

播毒性醢胺。若使用二級胺類時， 原子之5-或6-員雜環。以衍生自氨、 Ci-至C2二級·胺之聽胺較佳。式（工、 知方法製備。醫藥上可接受之醉脸 R劑如··二環己基碳化二 二垸基胺例如··與甲基胺 亞胺或窺r基二咪唑，及烷基胺、二 、二乙基胺、六氫吡啶反應。其製法亦可由化合物與酸如 :硫酸及烷基羧酸如：乙酸，或與酸及芳基羧酸如：苯甲 酸，於脫水條件下，添加分子篩進行反應。組合物可包含 本發明化合物之醫藥上可接受之前藥型。 本文所使用之術語’’醫藥上可接受之前藥，，或”前藥，，代表 彼等在完整之醫學判斷下，適用於與人體或較低等動物之 組織接觸，而沒有不當毒性、刺激、過敏反應，等等，且 符合合理之效益/危險比例，.並可有效用於所需目的之本發 明化合物之前藥。本發明之前藥很容易於活體内轉化成式 (I)之母化合物’例如·於血液中水解。較詳細之討論說明 於 T· Higuchi 與 V· Stella 之 Pro-drugs as Novel Delivery Systems，V· 14 of the A. C. S. Symposium Series及 Edward Β·Sowing toxic amidine. When using secondary amines, 5- or 6-membered heterocycles of atoms. Preferred are amines derived from ammonia, Ci- to C2 secondary amines. Formula (produced by known methods). Pharmaceutically acceptable drunk R agents such as dicyclohexylcarbodiamidine amines such as with methylamine imine or p-diimidazole, and alkylamines, 2, diethylamine, hexahydropyridine reaction. The preparation method can also be made from compounds with acids such as sulfuric acid and alkyl carboxylic acids such as acetic acid, or with acids and aryl carboxylic acids such as benzoic acid. A molecular sieve reacts. The composition may comprise a pharmaceutically acceptable prior drug form of a compound of the present invention. The term `` pharmaceutically acceptable prodrug, or "prodrug," as used herein, represents them under the complete medical judgment , Suitable for contact with human or lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and in accordance with a reasonable benefit / danger ratio, and can be effectively used for the compounds of the present invention before the desired purpose The prodrug of the present invention can be easily converted into the parent compound of formula (I) in vivo, for example, hydrolyzed in blood. A more detailed discussion is described in Pro-drugs as Novel Delivery Systems by T. Higuchi and V. Stella, V · 14 of the A. C. S. Symposium Series and Edward Β ·

Roche, ed.? Bioreversible Carriers in Drug Design, American Pharmaceutical Association與 Pergamon Press (1987)，其揭示 内容已以引用之方式完全併入本文中。 -86- 89248.doc 200418454 本發明包括化學合成或於活體内經生物轉形成式⑴化合 物之醫藥活性化合物。 本發明方法 本發明化合物與組合物適用於調節組織胺_3受體之效應 。特定言之本發明化合物與組合物可用於治療與預防受組 織胺-3受體調節之病變。典型地，此等病變可因選擇性調 節哺乳動物體内組織胺_3受體而緩和，較佳為投與本發明 化合物或組合物，其可單獨投藥或與作為療程之一部份之 另一種活1性劑組合投藥。 本發明化合物包括（但不限於）彼等對組織胺_3受體具有 親和性之化合物，其明確說明於實例中。作為組織胺_3受 體配位體之本發明化合物適用於治療及預防疾病或病症如 •急性心肌梗塞、阿茲海默氏症、氣喘、注意力缺乏之過 動異常、兩極化病變、認知功能障礙、精神病之認知能力 缺陷、記憶力缺陷、學習力缺陷、癡呆、皮膚癌瘤、嗑藥 、糖尿病、II型糖尿病、抑鬱症、癲癇、胃腸病變、發炎、 胰島素抗性症候群、噴射遲滯、髓質甲狀腺癌瘤、黑色素 瘤、梅尼爾氏症（Meniere’s disease)、代謝症候群、中度認 知受損、偏頭痛、情緒與注意力改變、動暈症、發作性睡 眠、神經性發炎、肥胖、強迫觀念與強迫行為性異常、疼 痛、巴金森氏症、多囊性卵巢症候群、精神分裂症、精神 分裂症之認知力缺陷、發作、敗血性休克、χ症候群、妥瑞 特氏（Toureue’s)症候群、眩暈與睡眠障礙。 包括（但不限於）彼等明確說明於實例中之本發明化合物 89248.doc - 87 - 200418454 於治療敗血性休克與心血管病變，特定言之急性心肌梗塞 上之能力可於下列文獻中證實：Imamura et al.，Circ.Res.， 78:475-481 (1996); Imamura et. al·，Circ.Res·，78 : 863-869 (1996); R. Levi 與 N. C. E. Smith, n 組織胺 H3-受體：於心肌 絕血中之新領域（Histamine H3-receptors: A new frontier in myocardial ischemia)’’，J. Pharm. Exp. Ther·，292 · 825-830 (2000);與 Hatta，E.，K. Yasuda與 R. Levi，，，組織胺 H3-受體之 活化作用在人體拖延之心肌絕血模式中抑制載劑所媒介之 正腎上氣素釋出（Activation of histamine H3-receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocradial ischemia)1*, J.Pharm. Exp. Ther., 283 ： 494-500 (1997)。 包括（但不限於）彼等明確說明於實例中之本發明化合物 於治療睡眠障礙，特定言之發作性睡眠上之能力可於下列 文獻中證實：Lin et al.，Brain Res·，523:325-330 (1990); Monti，et al.，Neuropsychopharmacology 15:3 1-35 (1996); Sakai，et al·，Life Sci·，48:2397-2404 (1991); Mazurkiewicz-Kwilecki與 Nsonwah，Can. J. Physiol. Pharmacol.5 67:75-78 (1989); P. Panula, et al.? Neuroscience 44:465-481 (1998); Wada，et al.，Trends in Neuroscience 14:415 (1991);與 Monti， et al·，Eur· J. Pharmacol· 205:283(1991)。 包括（但不限於）彼等明確說明於實例中之本發明化合刼 於治療認知與記憶過程障礙上之能力可於下列文獻中證實 :Mazurkiewicz-Kwilecki與Nsonwah，Can. J. Physiol. Pharmacol.， 89248.doc -88- 200418454 67:75-78 (1989); Ρ· Panula，et al·，Neuroscience，82:993-997 (1997); Haas, et al., Behav. Brain Res., 66 · 41-44 (1995); De Almeida與 Izquierdo, Arch. Int. Pharmacodyn.5 283:1 93- 1 98 (1986) ; Kamei et al.? Psychopharmacology, 102:312-318 (1990); Karnei 與 Sakata，Jpn. J. Pharmacol·，57:437-482 (1991); Schwartz et ah，Psychopharmacology，The fourth Generation of Progress. Bloom與 Kupfer編輯，Raven Press，New York， (1995) 397 ;與 Wada，et al·，Trends in Neurosci·，14:415 (1991)。， 包括（但不限於）彼等明確說明於實例中之本發明化合物 於治療注意力缺陷過動異常（ADHD)上之能力可於下列文 獻中證實：Shaywitz et al·，Psychopharmacology, 82:73-77(1984); Dumery 與 Blozovski，Exp. Brain Res·，67:61-69 (1987) ; Tedford et al.5 J. Pharmacol. Exp. Ther.? 275:598-604 (1995); Tedford et al·，Soc. Neurosci. Abstr·，22:22 (1996); 與 Fox，et al·，Behav· Brain Res·，13 1:151-161 (2002)。 包括（但不限於）彼等明確說明於實例中之本發明化合物 於治療發作，特定言之癲癇上之能力可於下列文獻中證實 :Yokoyama，et al·，Eur. J. Pharmacol., 234:129 (1993); Yokoyama與 Iinuma，CNS Drugs 5:321 (1996); Onodera et al.， Prog. Neurobiol·，42:685 (1994); R. Leurs，R. C. Vollinga與 H. Timmerman, n組織胺H3-受體之配位體之醫學化學及醫 療潛力（The medicinal chemistry and therapeutic potential of ligands of the histamine H3 receptor)M,Progress in Drug 89248.doc -89- 200418454Roche, ed.? Bioreversible Carriers in Drug Design, American Pharmaceutical Association, and Pergamon Press (1987), the disclosures of which are fully incorporated herein by reference. -86- 89248.doc 200418454 The present invention includes a pharmaceutically active compound that is chemically synthesized or biotransformed in vivo into a compound of formula (I). Methods of the invention The compounds and compositions of the invention are suitable for modulating the effect of the histamine-3 receptor. In particular, the compounds and compositions of the present invention are useful in the treatment and prevention of lesions regulated by the histamine-3 receptor. Typically, these lesions can be alleviated by the selective modulation of histamine-3 receptors in mammals. It is preferred to administer the compound or composition of the present invention, which can be administered alone or as part of a course of treatment. A combination of live sex drugs. The compounds of the present invention include, but are not limited to, compounds which have an affinity for the histamine-3 receptor, which are explicitly illustrated in the examples. The compounds of the present invention as histamine_3 receptor ligands are suitable for the treatment and prevention of diseases or conditions such as: • acute myocardial infarction, Alzheimer ’s disease, asthma, hyperactivity disorder due to lack of attention, bipolar disorder, cognition Dysfunction, cognitive impairment in mental illness, memory deficit, learning deficit, dementia, skin cancer, peony, diabetes, type II diabetes, depression, epilepsy, gastrointestinal disease, inflammation, insulin resistance syndrome, jet retardation, spinal cord Thyroid cancer, melanoma, Meniere's disease, metabolic syndrome, moderate cognitive impairment, migraine, mood and attention changes, motion sickness, narcolepsy, neurological inflammation, obesity, Obsessions and obsessive-compulsive abnormalities, pain, Parkinson's disease, polycystic ovary syndrome, schizophrenia, cognitive deficits in schizophrenia, seizures, septic shock, χ syndrome, Toureue's syndrome Dizziness and sleep disorders. Including, but not limited to, the ability of the compounds of the present invention 89248.doc-87-200418454, specifically illustrated in the examples, to treat septic shock and cardiovascular disease, specifically acute myocardial infarction, can be demonstrated in the following documents: Imamura et al., Circ. Res., 78: 475-481 (1996); Imamura et. Al., Circ.Res., 78: 863-869 (1996); R. Levi and NCE Smith, n Histamine H3 -Receptors: Histamine H3-receptors: A new frontier in myocardial ischemia '', J. Pharm. Exp. Ther ·, 292 · 825-830 (2000); and Hatta, E ., K. Yasuda and R. Levi ,,, Histamine H3-receptor activation inhibits vehicle-mediated release of adrenaline in delayed myocardial hemostasis in the human body (Activation of histamine H3-receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocradial ischemia) 1 *, J. Pharm. Exp. Ther., 283: 494-500 (1997). Including, but not limited to, the ability of the compounds of the present invention explicitly described in the examples to treat sleep disorders, and in particular paroxysmal sleep can be demonstrated in the following literature: Lin et al., Brain Res., 523: 325 -330 (1990); Monti, et al., Neuropsychopharmacology 15: 3 1-35 (1996); Sakai, et al., Life Sci., 48: 2397-2404 (1991); Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol. 5 67: 75-78 (1989); P. Panula, et al.? Neuroscience 44: 465-481 (1998); Wada, et al., Trends in Neuroscience 14: 415 (1991); And Monti, et al., Eur. J. Pharmacol. 205: 283 (1991). Including (but not limited to) their ability to combine the present invention explicitly described in the examples to treat cognitive and memory process disorders can be demonstrated in the following literature: Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol., 89248.doc -88- 200418454 67: 75-78 (1989); P. Panula, et al., Neuroscience, 82: 993-997 (1997); Haas, et al., Behav. Brain Res., 66 · 41 -44 (1995); De Almeida and Izquierdo, Arch. Int. Pharmacodyn. 5 283: 1 93- 1 98 (1986); Kamei et al.? Psychopharmacology, 102: 312-318 (1990); Karnei and Sakata, Jpn J. Pharmacol., 57: 437-482 (1991); Schwartz et ah, Psychopharmacology, The fourth Generation of Progress. Edited by Bloom and Kupfer, Raven Press, New York, (1995) 397; and Wada, et al., Trends in Neurosci., 14: 415 (1991). , Including (but not limited to) their ability to treat attention deficit hyperactivity disorder (ADHD), as explicitly illustrated in the examples, can be demonstrated in the following literature: Shaywitz et al., Psychopharmacology, 82: 73- 77 (1984); Dumery and Blozovski, Exp. Brain Res., 67: 61-69 (1987); Tedford et al. 5 J. Pharmacol. Exp. Ther.? 275: 598-604 (1995); Tedford et al ·, Soc. Neurosci. Abstr ·, 22:22 (1996); and Fox, et al ·, Behav · Brain Res ·, 13 1: 151-161 (2002). Including (but not limited to) their ability to treat seizures, specifically epilepsy, which are explicitly illustrated in the examples, can be demonstrated in the following literatures: Yokoyama, et al., Eur. J. Pharmacol., 234: 129 (1993); Yokoyama and Iinuma, CNS Drugs 5: 321 (1996); Onodera et al., Prog. Neurobiol., 42: 685 (1994); R. Leurs, RC Vollinga and H. Timmerman, n Histamine H3 -The medicinal chemistry and therapeutic potential of ligands of the histamine H3 receptor M, Progress in Drug 89248.doc -89- 200418454

Research 45:170-165，（1995); Leurs與 Timmerman，Prog.Drug Res·，39:127 (1992);組織胺 H3-受體（The histamine H3 receptor)，Leurs與Timmerman編輯，Elsevier Science，Amsterdam， The Netherlands (1998) ; H. Yokoyama 與 K.Iinuma，” 組織胺 與發作：與癲癇治療法之相關性（Histamine and Seizures: Implications for the treatment of epilepsy)’’，CNS Drugs，5(5) :321-330 (1995);與 K. Hurukami，H. Yokoyama, K. Onodera， K. Iinuma與丁· Watanabe，，，AQ-0145，一種新發展之組織胺 H3-擷抗劑，降低小白鼠受電擊誘發痙攣之發作感受性（A newly developed histamine H3 antagonist，decreased seizure susceptibility of electrically induced convulsions in mice)’’， Meth. Find. Exp. Clin. Pharmacol·，17(C):70-73 (1995)。 包括（但不限於）彼等明確說明於實例中之本發明化合物 於治療動暈症、阿茲海默氏症與巴金森氏症上之能力可於 下列文獻中證實：Onodera，et al.，Prog. Neurobiol·，42:685 (1994); Leurs與 Timmerman，Prog· Drug Res.，39:127(1992) ;與組織胺 Η3_ 受體（The histamune H3 receptor)，Leurs 與 Timmerman編輯，Elsevier Science，Amsterdam，The Netherlands (1998)。 包括（但不限於）彼等明確說明於實例中之本發明化合物 於治療發作性睡眠、精神分裂症、抑鬱症與癡呆上之能力 可於下列文獻中證實：R. Leurs，R. C. Vollinga與H. Timmerman，π組織胺H3-受體之配位體之醫學化學及醫療潛 力(The medicinal chemistry and therapeutic potential of 89248.doc -90- 200418454 ligands of the histamine H3 receptor)”，Progress in Drug Research 45:170-165 (1995);組織胺 H3_ 受體（The histamine H3 receptor)，Leurs 與 Timmerman 編輯，Elsevier Science， Amsterdam，The Netherlands (1998);與 Perez-Garcia C，et. al.5及Psychopharmacology (Beri) 142(2):215-20 (Feb，1999)。 包括（但不限於）彼等明確說明於實例中之本發明化合物 於治療睡眠障礙、認知功能障礙、情緒與注意力改變、眩 暈與動暈症，及治療精神病之認知力缺陷上之能力可於下列 文獻中證，實：Schwartz，Physiol· Review 71:1-51 (1991) 〇 包括（但不限於）彼等明確說明於實例中之本發明化合物 於治療中度認知力受損、學習力缺陷與癡呆上之能力可於 下列文獻中證實：C. E. Tedford，”組織胺H3-受體：新藥物之 目標（The histamune H3 receptor: a target for new drugs)’’，the Pharmacochemistry Library，vol· 30 (1998)，R· Leurs與 H· Timmerman編輯，Elsevier (New York)，p. 269與其中包含之 參考文獻。 包括（但不限於）彼等明確說明於實例中之本發明化合物 於治療肥胖上之能力可於下列文獻中證實：Leurs，et a1·， Trends in Pharm· Sci·，19:177-183 (1998); Ε· Itoh，Μ·Research 45: 170-165, (1995); Leurs and Timmerman, Prog. Drug Res., 39: 127 (1992); The histamine H3 receptor, edited by Leurs and Timmerman, Elsevier Science, Amsterdam , The Netherlands (1998); H. Yokoyama and K. Iinuma, "Histamine and Seizures: Implications for the treatment of epilepsy", CNS Drugs, 5 (5) : 321-330 (1995); with K. Hurukami, H. Yokoyama, K. Onodera, K. Iinuma and Ding Watanabe ,,, AQ-0145, a newly developed histamine H3-receptor that reduces mice A newly developed histamine H3 antagonist (decreased seizure susceptibility of electrically induced convulsions in mice) '', Meth. Find. Exp. Clin. Pharmacol., 17 (C): 70-73 (1995) Including (but not limited to) their ability to treat motion sickness, Alzheimer's disease and Parkinson's disease as explicitly illustrated in the examples of the compounds of the present invention can be demonstrated in the following literature: Onodera, et al. , Prog. Neuro Biol., 42: 685 (1994); Leurs and Timmerman, Prog. Drug Res., 39: 127 (1992); and the histamine H3 receptor, edited by Leurs and Timmerman, Elsevier Science, Amsterdam, The Netherlands (1998). The ability of the compounds of the present invention including, but not limited to, the examples explicitly described in the treatment of narcolepsy, schizophrenia, depression and dementia can be demonstrated in the following literature: R. Leurs , RC Vollinga and H. Timmerman, The medicinal chemistry and therapeutic potential of 89248.doc -90- 200418454 ligands of the histamine H3 receptor ", Progress in Drug Research 45: 170-165 (1995); The histamine H3 receptor, edited by Leurs and Timmerman, Elsevier Science, Amsterdam, The Netherlands (1998); and Perez-Garcia C, et. al. 5 and Psychopharmacology (Beri) 142 (2): 215-20 (Feb, 1999). Including (but not limited to) their ability to treat sleep disorders, cognitive dysfunction, mood and attention changes, dizziness and motion sickness, and cognitive deficits in the treatment of psychiatric disorders, as clearly illustrated in the examples Evidence from the following: Schwartz, Physiol. Review 71: 1-51 (1991). Including (but not limited to) the compounds of the present invention, which are specifically illustrated in the examples, for the treatment of moderate cognitive impairment and learning deficits. The ability to fight dementia can be confirmed in the following literature: CE Tedford, "The histamune H3 receptor: a target for new drugs", the Pharmacochemistry Library, vol. 30 ( 1998), edited by R. Leurs and H. Timmerman, Elsevier (New York), p. 269 and the references contained therein. Including (but not limited to) the compounds of the present invention which are explicitly illustrated in the examples for the treatment of obesity Capabilities can be demonstrated in the following literatures: Leurs, et a1 ·, Trends in Pharm · Sci ·, 19: 177-183 (1998); E · Itoh, M ·

Fujimiay，與A. 普醯胺，一種組織胺H3-受體擴抗劑 ，可在大老鼠上強力抑制肽γγ-所謗發之食物攝取 (Thioperamide, A histamune H3 receptor antagonist，powerfully suppresses peptide YY-induced food intake in rats)’’ Biol. Psych·，45(4) : 475-481 (1999) ; S· I. Yates，et al·，n新穎之 89248.doc -91 - 200418454 組織胺H3-受體擷抗劑，GT-2394於Sprague-Dawley大老鼠 上對食物攝取及體重增加上之效應（Effects 〇f a novel histamine H3 receptor antagonist, GT-2394, on food intake and weight gain in Sprague-Dawley rats,” Abstracts，Society for Neuroscience，102.10 : 219 (2〇〇〇年 11月），與 C. Bjenning， et al.，，f周邊投與希普赛吩可於Sprague-Dawley大老鼠上提 高下丘腦中組織胺濃度及強力減少食物攝取（PeriPherally administered ciproxifan elevates hypothalamic histamine levels and potently reduces food intake in the Sprague Dawley rat)” Abstracts，International Sendai Histamine Symposium， Sendai，Japan，#P39 (November，2000) 0 包括（但不限於）彼等明確說明於實例中之本發明化合物 於發炎與疼痛上之能力可於下列文獻中證實：Phillips，et al·，Annual Reports in Medicinal Chemistry 33:31-40 (1998) 0 包括（但不限於）彼等明確說明於實例中之本發明化合物 於治療偏頭痛上之能力可於下列文獻中證實：R. Leurs，R. C. Vollinga與Η· Timmerman.，”組織胺H3-受體之配位體之醫 學化學及醫療潛力（The medicinal chemistry and therapeutic potential of ligands of the histamine H3 receptor)n Progress in Drug Research 45:170-165 (1995); Matsubara，et al·，Eur. J· Pharmacol·，224:145 (1992);與 Rouleau，etal·，J· Pharmacol· Exp. Ther.，281:1085 (1997)。 _ 包括（但不限於）彼等明確說明於實例中之本發明化合物 於治療癌症，特定言之黑色素瘤、皮膚癌瘤與髓質甲狀腺 89248.doc -92- 200418454 癌瘤上之能力可於下列文獻中證實：PolishMed. Sci.Mon.， 4(5):747 (1998); Adam Szelag，”組織胺H3-受體於活體外之 增生細胞中增殖作用上之角色（Role of histamune H3 receptors in the proliferation of neoplastic cells in vitro)n Med· Sci. Monit·，4(5):747-755 (1998);與 C· H. Fitzsimons，et al.，’’改變具有H-ras基因之上皮腫瘤細胞株之組織胺受體訊 號（Histamine receptors signalling in epidermal tumor cell lines with H-ras gene alterations)” Inflammation Res·，47 (Suppl 1)‘S50-S51 (1998)。 包括（但不限於）彼等明確說明於實例中之本發明化合物 於治療前庭功能障礙，特定言之梅尼爾氏症上之能力可於 下列文獻中證實：R. Leurs，R. C· Vollinga與H.Timmerman，’’ 組織胺H3-受體之配位體之醫學化學及醫療潛力（The medicinal chemistry and therapeutic potential of ligands of the histamine H3 receptor)*', Progress in Drug Research 45:170-165 (1995)，與 Pan，et al.，Methods and Findings in Experimental與 Chemical Pharmacology 21:771-777(1998)。 包括（但不限於）彼等明確說明於實例中之本發明化合物 於治療氣喘上之能力可於下列文獻中證實·· A. Delaunois A.， et al.，π組織胺H3-受體於自兔子單離且經灌流之肺部中調 節乙酸基膽驗、卡巴辛與P物質之效應（Modulation of acetyl choline, capsaicin and substance P effects by histamune H3 receptor in isolated perfused rabbit lungs)n European Journal of Pharmacology 277(2-3):243-250 (1995);與 Dimitriadou，et 89248.doc -93 - 200418454 al.，”大老鼠肺部與脾臟中組織胺H3_受體之調節作用證實肥 大細胞與c-敏感性神經纖維之間之功能相關性（Functi〇nai relationsh^ between mast cells and C-sensitive nerve fibres evidenced by histamune H3 receptor modulation in rat lung and spleen，” Clinical Science 87⑺：i5i i63 …料）。 g括（i_不限於）彼等明確說明於實例中之本發明化合物 於治療過敏性鼻炎上之能力可於下列文獻中證實：Mew， etai.，pn^essinResp.Researeh31:133(2〇〇i)。 本毛月’化σ物特別適用於治療及預防影響記憶力或認知 力之疾病或病症，例如：阿兹海默氏症、注意力缺乏之過 動-常、精神分裂症、或精神分裂症之認知力缺陷。 本發明醫藥組合物中活w 士 、 化、 肀活性成分芡確實劑量可以變化，以 使活性化合物（群）可針對 π H ϋ m I 疋…者、，且合物與投藥模式達到 所而足有效醬療反應。所 性、投藥途徑、所,、Λ瘅广、、將依特足化合物之活 病史而定炊 嚴重性與所治療患者過去之 病史而疋。然而，習并 、 於為了達到&amp; + ^ *《人士均了解，可採用低 万、為了達到所需醫療效果而需要 漸提高劑量至達到需效果為止。W I開始治療’然後逐 田知用上逑或其他治療法時 純型本發明化合物，劣#山 便用哥潦有效量之一種 上可接受之鹽類、. 、 土式時，可使用其醫藥 可呈醫藥組合物投藥， 杀土。或者，化合物 ^头，其中包含所需 _ 醫藥上可接受之載劑 。物與一種或多種 執^且合。本發明化合 有效量”指化合物用於 所使用術語，，醫療 療…量足以對任何醫學治療 89248.doc -94- 法達成合理之效益/危險比 盥 — …、而咸了解，本發明化合物 母日總劑量將由參與之醫師在完整之醫學判斷 。對任何特定患者之明確醫療有效劑量將依多種因 “决走’包括所治療之病變邱 化合物之活性；所使用之= 所使用特定 斤使用心特疋組合物；患者之年齡、體重 、—般身體健康狀況、性別與飲食；㈣用特定化合物之 投&quot;間、投藥途徑與排泄速率；治療時間長短；與所使 用特疋化合物組合使用或同時使用之藥物；與醫學技藐上 習知之瓤似因素。例如：習此相關技藝之人士均了解：可 採用低於為了達到所需醫療效果而需要之劑量開始治療， 然後逐漸提高劑量至達到需效果為止。 本發明化合物投與人類或較低等動物之每日總劑量為約 勺30 mg/kg/天。供口服時，更佳之劑量可在約㈦ 至約0.1 mg/kg/天之範圍内。若需要時，有效之每日劑量可 分成多個小劑量供投藥用；因此單一劑量組合物可能包含 此等用量或多重之小劑量，以補足每日劑量。 本發明化合物與製法將可參考下列僅供說明且不限制本 無明範圍之貫例進一步了解。 參考實例 參考實例1 金與（2SV2-甲基吡咯啶之舉法 (2R)-2-甲基Ρ比ρ各啶酒石酸鹽之製法為依wmiam Gaffield， et al.述於 Tetrahedron，37:1861-1869 (1981)中之方法，使用 D-酒石酸解析2-甲基吡咯啶，或者依Kairer與Ehrhardt述於 89248.doc -95 - 200418454Fujimiay, together with A. promethamine, a histamine H3-receptor potentiator, potently inhibits the uptake of peptides γγ-induced food in rats (Thioperamide, A histamune H3 receptor antagonist, powerfully suppresses peptide YY- induced food intake in rats) '' Biol. Psych ·, 45 (4): 475-481 (1999); S. I. Yates, et al ·, n novel 89248.doc -91-200418454 Histamine H3- Effects of GT-2394 on food intake and weight gain in Sprague-Dawley rats (Effects 〇fa novel histamine H3 receptor antagonist, GT-2394, on food intake and weight gain in Sprague-Dawley rats, Abstracts, Society for Neuroscience, 102.10: 219 (November 2000), and C. Bjenning, et al., F. Peripheral administration of Hipsaifen can enhance hypothalamus in Sprague-Dawley rats Histamine concentration and potently reduce food intake (PeriPherally administered ciproxifan elevates hypothalamic histamine levels and potently reduces food intake in the Sprague Dawley rat) "Abstracts, International Sendai Histamine Sy mposium, Sendai, Japan, # P39 (November, 2000) 0 Including, but not limited to, the ability of the compounds of the present invention, which are explicitly illustrated in the examples, to be inflammatory and painful, can be demonstrated in the following documents: Phillips, et al. , Annual Reports in Medicinal Chemistry 33: 31-40 (1998) 0 Including, but not limited to, the ability of the compounds of the present invention explicitly described in the examples to treat migraine can be demonstrated in the following documents: R. Leurs, RC Vollinga and T. Timmerman, "The medicinal chemistry and therapeutic potential of ligands of the histamine H3 receptor" n Progress in Drug Research 45: 170-165 (1995); Matsubara, et al., Eur. J. Pharmacol., 224: 145 (1992); and Rouleau, etal., J. Pharmacol. Exp. Ther., 281: 1085 (1997). _ Including, but not limited to, the ability of the compounds of the present invention explicitly described in the examples to treat cancer, specifically melanoma, skin cancer, and medullary thyroid 89248.doc -92- 200418454 cancer tumors, the ability can be in the following Confirmed in the literature: PolishMed. Sci.Mon., 4 (5): 747 (1998); Adam Szelag, "The role of histamine H3-receptors in the proliferation of in vitro proliferating cells (Role of histamune H3 receptors in the proliferation of neoplastic cells in vitro) Med · Sci. Monit ·, 4 (5): 747-755 (1998); and C · H. Fitzsimons, et al., `` Altering epithelial tumors with H-ras gene Histamine receptors signalling in epidermal tumor cell lines with H-ras gene alterations "Inflammation Res., 47 (Suppl 1) 'S50-S51 (1998). Including (but not limited to) their ability to treat vestibular dysfunction, specifically the Menillian's disease, as explicitly described in the examples, can be demonstrated in the following literature: R. Leurs, R. C. Vollinga With H. Timmerman, `` The medicinal chemistry and therapeutic potential of ligands of the histamine H3 receptor * '', Progress in Drug Research 45: 170-165 (1995), and Pan, et al., Methods and Findings in Experimental and Chemical Pharmacology 21: 771-777 (1998). Including (but not limited to) their ability to treat asthma as explicitly described in the examples can be demonstrated in the following documents: A. Delaunois A., et al., Π Histamine H3-receptor Modulation of acetyl choline, capsaicin and substance P effects by histamune H3 receptor in isolated perfused rabbit lungs in rabbit isolated and perfused lungs n European Journal of Pharmacology 277 (2-3): 243-250 (1995); and Dimitriadou, et 89248.doc -93-200418454 al., "The regulation of histamine H3_ receptors in the lungs and spleens of rats confirms that mast cells and c- Functional correlation between sensitive nerve fibers (Functionai relationsh ^ between mast cells and C-sensitive nerve fibres evidenced by histamune H3 receptor modulation in rat lung and spleen, "Clinical Science 87⑺: i5i i63… materials). g (i.e., not limited to) their ability to treat allergic rhinitis as explicitly stated in the examples can be demonstrated in the following documents: Mew, etai., pnessinResp.Researeh31: 133 (2〇〇 i). This hair month's sigma is particularly suitable for the treatment and prevention of diseases or conditions that affect memory or cognition, such as: Alzheimer's disease, attention-deficit hyperactivity-normal, schizophrenia, or schizophrenia Cognitive impairment. The exact dosage of active ingredients, active ingredients, and active ingredients in the pharmaceutical composition of the present invention can be changed, so that the active compound (group) can target π H ϋ m I 疋 ..., and the composition and the mode of administration are sufficient. Effective sauce response. The nature, route of administration, and medicine, will be determined by the history of the disease of the special foot compound, and the severity will depend on the past medical history of the treated patients. However, in order to achieve &amp; + ^ *, everyone understands that it can be used, and in order to achieve the required medical effect, the dose needs to be gradually increased until the desired effect is achieved. WI started treatment 'and then used the compound of the present invention in a pure form when using scutellaria or other treatment methods. Inferior # 山 便 用 哥 上 effective amount of one of the acceptable salts, ... Can be administered as a pharmaceutical composition to kill the soil. Alternatively, the compound contains a desired _ pharmaceutically acceptable carrier. The thing is combined with one or more kinds. The "combined effective amount of the present invention" means that the compound is used in the terminology used. The amount of medical treatment ... is sufficient to achieve a reasonable benefit / danger ratio for any medical treatment 89248.doc -94-and it is understood that the parent compound of the present invention The total daily dose will be determined by the participating physicians in the full medical judgment. The clear medically effective dose for any particular patient will depend on the activity of the compound of the disease to be treated, including the disease to be treated; Specialty composition; patient's age, weight, general physical health status, sex and diet; use of specific compounds &quot; interval, route of administration and excretion rate; duration of treatment; use in combination with the special compound or Concomitant medications; similar factors to those known in medical technology. For example, those who are familiar with this technique know that treatment can be started at a dose lower than required to achieve the desired medical effect, and then gradually increase the dose until the desired effect is achieved. The total daily dose of a compound of the present invention administered to humans or lower animals is about 30 mg / kg / day. When administered orally, a more preferred dose may range from about ㈦ to about 0.1 mg / kg / day. If desired, the effective daily dose may be divided into multiple small doses for administration; therefore, a single dose composition may contain these or multiple small doses to make up the daily dose. The compounds and preparation methods of the present invention will be further understood by referring to the following examples which are for illustration only and do not limit the scope of this ignorance. Reference Example Reference Example 1 The method of gold and (2SV2-methylpyrrolidine) (2R) -2-methyl P ratio piperidine tartrate is prepared according to Wmiam Gaffield, et al. In Tetrahedron, 37: 1861- The method of 1869 (1981) using D-tartaric acid to resolve 2-methylpyrrolidine, or described by Kailer and Ehrhardt in 89248.doc -95-200418454

Helv. Chim. Acta，34: 2202, 2208 (1951)之方法，由 L-脯胺醇 製備。（2R)-2-甲基吡咯啶氫溴酸鹽亦為（2R)-2-甲基吡咯啶 之合適來源，且係採用 Nijhuis，Walter Η· N·，et al·，J·〇rg. Chem·，54(1): 209-216, 214 (1989)所述之方法製備。其他說 明合成（2R)-2-甲基p比嘻淀與其鹽之製法可參見Andres, Jose M·，et al. Eur. J.〇rg. Chem·，9:1719-1726 (2000);與Elworthy， Todd R·; Meyers，A. 1·，Tetrahedron，50(20): 6089-6096(1994)。 (2S)-2-甲基吡咯啶可於本文所提供之實驗製法中替代 (2R)-2-甲，基吡咯啶使用。（2S)-2-甲基吡咯啶可依Kim， Mahn-Joo5 et al.5 Bioorg. Med. Chem. Lett. 6(1):71-76 (1996) 中說明之方法製備。 參考實例2 二羥硼酸與酯試劑之製法 許多種芳基、雜芳基、與雜環二羥硼酸與二羥硼酸酯類 可自商品購得或可依合成有機化學之科學文獻中說明之方 法製得。用於合成式（I)化合物之二羥硼酸與二羥硼酸酯類 試劑之不設限實例示於下表1與下列說明中。 表1 二羥硼酸與二羥硼酸酯類試劑實例 二羥硼酸或二羥硼酸酯類 商品來源，化學摘要編號或參考 文獻 2-嘧啶酮-5-二羥硼酸 Matrix Scientific，Columbia，SC， USA 1H-嘧啶-2,4-二酮-5-二羥硼酸 Specs，Fleminglaan，the Netherlands 89248.doc -96- 200418454 吡啶-3-二羥硼酸 1692-25-7，Frontier Scientific， Inc.，Logan, UT，USA 2,4-二甲氧嘧啶-5-二經硼酸 89641-18-9，Frontier Scientific, Inc·，Logan，UT，USA 2-甲氧-5-吡啶二羥硼酸 Digital Specialty Chemicals, Dublin, NH 嘧啶-5-二羥硼酸 S. Gronowitz，et al.，丨On the synthesis of various thienyl-and selenienylpyrimidines，” Chem. Scr. 26(2) ： 305-309 (1986). 嘧啶-5-二羥硼酸，四甲基乙二 醇酯 $ Umemoto, et al.? Angew. Chem. Int. Ed. 40(14) ： 2620-2622 (2001). 式（7a)之二羥硼酸酯類： (ReO)(RfO)B-R6 (7a) 可於反應圖中替代式（7)二羥硼酸進行合成。由式（7a)化合 物中以Re與心代表之取代基可為烷基，或者Re與Rf可共同形 成一環，其本身可再經烷基或芳基取代。合適式（7a)化合物 實例包括（但不限於）.：（CH30)2BPh與（4-氰基甲基苯基）二羥 硼酸四甲基乙二醇酯（CombiBlocks Inc·，San Diego))。式（7) 二羥硼酸與式（7a)二羥硼酸酯可自商品購得或可依習知合 成有機化學之人士已知之方法製得。例如：Takagi et al. (Tetrahedron Letters，43:5649-5651 (2002))製備之式（7a)雜 芳基四甲基乙二醇甲硼烷酯類係使用雜芳香系化合物與雙 (四甲基乙二醇甲硼烷），於IrCl[COD]2-(4,4’-二-第三丁基 -2,2、聯吡啶）之銦觸媒存在下，於辛烷中反應。其他已說明 89248.doc -97- 200418454 之方法為使芳基iS化物與雜芳基il化物經烷基鋰或格林納 試劑轉金屬化，然後經三烷基硼酸酯處理，然後經酸處理 ，產生式（7)與（7a)化合物（Β· T. O’Neill, et al.，Organic Letters， 2:4201 (2000); M. D. Sindkhedkar， et al.，Helv. Chim. Acta, 34: 2202, 2208 (1951), prepared from L-prolinol. (2R) -2-methylpyrrolidine hydrobromide is also a suitable source of (2R) -2-methylpyrrolidine hydrobromide, and Nijhuis, Walter ter · N ·, et al ·, J · 〇rg. Chem., 54 (1): 209-216, 214 (1989). Other instructions for the preparation of (2R) -2-methylp-bihexidine and its salts can be found in Andres, Jose M., et al. Eur. J.〇rg. Chem., 9: 1719-1726 (2000); and Elworthy, Todd R .; Meyers, A. 1.1., Tetrahedron, 50 (20): 6089-6096 (1994). (2S) -2-methylpyrrolidine can be used in place of (2R) -2-methylpyrrolidine in the experimental preparation methods provided herein. (2S) -2-methylpyrrolidine can be prepared according to the method described in Kim, Mahn-Joo5 et al. 5 Bioorg. Med. Chem. Lett. 6 (1): 71-76 (1996). Reference Example 2 Preparation of Dihydroxyboric Acid and Ester Reagents Many kinds of aryl, heteroaryl, and heterocyclic dihydroxyboric acids and dihydroxyborates are commercially available or can be described in accordance with the scientific literature on synthetic organic chemistry be made of. Non-limiting examples of dihydroxyboronic acid and dihydroxyborate reagents used to synthesize compounds of formula (I) are shown in Table 1 below and in the following description. Table 1 Examples of dihydroxyboric acid and dihydroxyborate reagents Dihydroxyboric acid or dihydroxyborate commercial source, chemical abstract number or reference 2-pyrimidinone-5-dihydroxyborate Matrix Scientific, Columbia, SC, USA 1H -Pyrimidine-2,4-dione-5-dihydroxyboronic acid Specs, Fleminglaan, the Netherlands 89248.doc -96- 200418454 Pyridine-3-dihydroxyboronic acid 1692-25-7, Frontier Scientific, Inc., Logan, UT , USA 2,4-Dimethoxypyrimidin-5-diazoboronic acid 89641-18-9, Frontier Scientific, Inc., Logan, UT, USA 2-methoxy-5-pyridine dihydroxyboronic acid Digital Specialty Chemicals, Dublin, NH Pyrimidine-5-dihydroxyboronic acid S. Gronowitz, et al., On the synthesis of various thienyl-and selenienylpyrimidines, "Chem. Scr. 26 (2): 305-309 (1986). Pyrimidine-5-dihydroxy Boric acid, tetramethylglycol ester Umemoto, et al.? Angew. Chem. Int. Ed. 40 (14): 2620-2622 (2001). Dihydroxyborate esters of formula (7a): (ReO) (RfO) B-R6 (7a) can be synthesized in the reaction scheme instead of dihydroxyboronic acid of formula (7). The substituents represented by Re and Xin in the compound of formula (7a) may be alkane Or Re and Rf may form a ring together, which may be substituted by alkyl or aryl. Examples of suitable compounds of formula (7a) include (but are not limited to): (CH30) 2BPh and (4-cyanomethyl) Phenyl) tetramethylglycol dihydroxyborate (CombiBlocks Inc., San Diego)). The dihydroxyboronic acid of formula (7) and the dihydroxyboronic acid ester of formula (7a) are commercially available or can be obtained by conventional methods. It is prepared by a method known to those skilled in synthetic organic chemistry. For example: Takagi et al. (Tetrahedron Letters, 43: 5649-5651 (2002)). Heteroaryltetramethylethylene glycol borane esters of formula (7a) It is based on the use of heteroaromatic compounds with bis (tetramethylethylene glycol borane) and indium contact with IrCl [COD] 2- (4,4'-di-third-butyl-2,2, bipyridine) The reaction is carried out in octane in the presence of a medium. Other methods have been explained 89248.doc -97- 200418454. The aryl iS compound and the heteroaryl il compound are metallized with an alkyl lithium or Grignard reagent, and then passed through trioxane. Boronic acid ester treatment followed by acid treatment to produce compounds of formulae (7) and (7a) (B · T. O'Neill, et al., Organic Letters, 2: 4201 (2000); MD Sindkhedkar et al.,

Tetrahedron, 57:2991 (2001); W. C. Black, et al.Journal of Medicinal Chemistry，42:1274 (1999); Letsinger; Dandegaonker, J.Amer. Chem. Soc.? 81:498-501 (1959); Carroll, F. Ivy, et al. J· Med. Chem·，2229-223 7 (2001)。另一種方法為 Miyaura 反 應，其說^明於 Ishiyama，Tatsuo; Ishida，Kousaku，Miyaura， Nor io，Tetrahedron，9813-9816 (2001)，其中由芳基與雜芳基 鹵化物與雙（四甲基乙二醇甲硼烷）、KOAc及Pd2dba3與參-環己基膦或 PdCl2dppf反應（Ishiyama，et al. Tetrahedron， 9813-9816 (2001))。另一種製備式（7a)化合物之反應說明於 0. Baudoin, et al.? J. Org. Chem.? 65;9268-9271 (2000) j 其中 由芳基與雜芳基鹵化物或三氟甲磺酸酯與二烷氧基甲硼烷 如：四甲基乙二醇甲硼烷，於Et3N與Pd(OAc)2之存在下， 於二吟烷中反應。式（7)與（.7a)中R6為環烷基環之化合物可 由例如：環烯製備（例如··參見H. C· Brown，et al.J. Amer· Chem. Soc.，95:2396-2397 (1973)與乩€：.31*〇\¥11，61&amp;1.，了· Amer.Chem. Soc·，98:1798-1806 (1976))或由環完基格林納 試劑或環烷基鋰中間物製備（參見例如：Graf et al.， Tetrahedron，55:8801-8814 (1999)與 Michailow，et al·，Ιζν· Akad. Nauk SSSR Ser· Khim，76:78 (1959))。 參考實例3 89248.doc •98- 200418454 完型試劑I製法 許多種如：Me3SnR6、Bu3SnR6與R6ZnC1之試劑適用於反 應圖1之史迪爾（SUlle)反應條件，且可自商品購得。然而， 右式中Re為雜芳基、雜環或芳基之試劑無法自商品購得時 ，其可依習此相關技藝之人士可採用之方法之—製備。此 等万法實例包括以鋰自素-金屬交換雜芳基、雜環或芳基鹵 化物，然後經 Me3SnCl (Li，et al· J· Med· Chem. 1996, 39, 1846)、Bu3SnCl、ZnCl2、4B(OCH3)3(〇，Neill，etal.〇rg.Lett· 2000, 2, 4201; Sindkhedkar，et al· Tet. 2001，57, 2991)處理， 及依Knochel，et al· J. 〇rg· Chem. 2000, 65, 4618-4634所述 ’以鎮-鹵素-金屬交換異丙基鎂化氯，然後經Me3SnCl、 BusSnCl、或ZnCh處理。雜芳基鹵化物與三氟甲磺酸酯可 依 A· 0· Koren，et al. J. Med· Chem· 1998, 41，3690所述，經 三甲基錫燒基鈉處理，產生Me3SnR6。雜芳基鹵化物與三氟 甲磺酸酯可依 W. C. Black，et al. J. Med.Chem. 1999，42, 1274所述，經六甲基二錫烷處理，產生Me3SnR6。 實例 實例1 4-(6-{2」J(2RV2-甲基-1_吡咯啶某乙基I — ?·-革其丨苽基氰Tetrahedron, 57: 2991 (2001); WC Black, et al. Journal of Medicinal Chemistry, 42: 1274 (1999); Letsinger; Dandegaonker, J. Amer. Chem. Soc.? 81: 498-501 (1959); Carroll , F. Ivy, et al. J. Med. Chem., 2229-223 7 (2001). Another method is the Miyaura reaction, which is described in Ishiyama, Tatsuo; Ishida, Kousaku, Miyaura, Nor io, Tetrahedron, 9813-9816 (2001), which consists of aryl and heteroaryl halides and bis (tetramethyl) Ethylene glycol borane), KOAc and Pd2dba3 are reacted with p-cyclohexylphosphine or PdCl2dppf (Ishiyama, et al. Tetrahedron, 9813-9816 (2001)). Another reaction for the preparation of a compound of formula (7a) is illustrated in Baudoin, et al.? J. Org. Chem.? 65; 9268-9271 (2000) j where aryl and heteroaryl halides or trifluoromethyl A sulfonate and a dialkoxyborane such as tetramethylethylene glycol borane are reacted in dioxane in the presence of Et3N and Pd (OAc) 2. Compounds of formula (7) and (.7a) in which R6 is a cycloalkyl ring can be prepared, for example, from a cycloolefin (for example, see H.C. Brown, et al. J. Amer. Chem. Soc., 95: 2396 -2397 (1973) and 乩 €: .31 * 〇 \ 11, 61 &amp; 1. Amer. Chem. Soc., 98: 1798-1806 (1976)) or by Cyclo-Glenner reagent or ring Preparation of alkyllithium intermediates (see, for example: Graf et al., Tetrahedron, 55: 8801-8814 (1999) and Michailow, et al., Izv. Akad. Nauk SSSR Ser. Khim, 76:78 (1959)). Reference Example 3 89248.doc • 98-200418454 Preparation method of intact reagent I Many kinds of reagents such as: Me3SnR6, Bu3SnR6, and R6ZnC1 are applicable to the reaction conditions of SUlle in FIG. 1 and are commercially available. However, when the reagent in the right formula where Re is heteroaryl, heterocyclic or aryl is not commercially available, it can be prepared according to the method available to those skilled in the art. Examples of such methods include exchanging heteroaryl, heterocyclic, or aryl halides with lithium, and then passing Me3SnCl (Li, et al. J. Med. Chem. 1996, 39, 1846), Bu3SnCl, ZnCl2 , 4B (OCH3) 3 (〇, Neill, etal.〇rg. Lett. 2000, 2, 4201; Sindkhedkar, et al. Tet. 2001, 57, 2991), and according to Knochel, et al. J. 〇rg · Chem. 2000, 65, 4618-4634, 'Isopropylmagnesium chloride exchanged with town-halogen-metal, and then treated with Me3SnCl, BusSnCl, or ZnCh. Heteroaryl halides and trifluoromethanesulfonates can be treated with sodium trimethyltin alkoxide as described in A. Koren, et al. J. Med. Chem. 1998, 41, 3690 to produce Me3SnR6. Heteroaryl halides and triflate can be treated with hexamethyldistannane as described in W. C. Black, et al. J. Med. Chem. 1999, 42, 1274 to produce Me3SnR6. Examples Example 1 4- (6- {2 ″ J (2RV2-methyl-1_pyrrolidine, an ethyl group I-?-Leather

實例1A (6-溴-2-茗某）甲醇 以20分鐘時間，在1·0 Μ氳化鋰鋁之THF攪拌溶液（1〇8 mL ，108 mmol)中滴加 6-溴-2-莕甲酸甲酯（18.9 g，71.3 mmol) 之THF (180 mL)溶液，同時保持反應溫度在-5°C以下。當添 -99- 89248.doc 200418454 加完畢時，反應混合物於-1 〇°C下攪拌1小時，然後依序滴 加蒸餾水（4 mL)、2N Na2C〇3水溶液（4 mL)與蒸餾水（12 mL) 中止反應。於室溫下攪拌1 5分鐘後，過濾反應混合物。濾 塊經乙酸乙酯（3 X 100 mL)洗滌，合併之濾液脫水（硫酸鎂） 與過濾。濾液減壓濃縮，產生白色固體。於40T：下真空乾 燥一夜，產生產物（16.84 g，收率 99%)。M.p. 149.9-151.6°C 。4 NMR (CDC13，300 MHz) δ 7·99 (d，J=2 Hz，1H)， 7.79-7.67 (m，3H)，7.55 (dd，J=2，12 Hz，1H)，7.52 (dd，J=2, 12 Hz，1尽)，4.85 (s，2H)。MS (DCI-NH3)[M]+ 236。Example 1A (6-bromo-2-fluorene) methanol was added dropwise to a 1.0 M lithium aluminide THF stirred solution (108 mL, 108 mmol) over a period of 20 minutes. A solution of methyl formate (18.9 g, 71.3 mmol) in THF (180 mL) while keeping the reaction temperature below -5 ° C. When the addition of -99- 89248.doc 200418454 was completed, the reaction mixture was stirred at -10 ° C for 1 hour, and then distilled water (4 mL), 2N Na2CO3 aqueous solution (4 mL) and distilled water (12 mL) Stop the reaction. After stirring at room temperature for 15 minutes, the reaction mixture was filtered. The filter block was washed with ethyl acetate (3 X 100 mL), and the combined filtrate was dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure to give a white solid. Drying under vacuum at 40T overnight gave the product (16.84 g, 99% yield). M.p. 149.9-151.6 ° C. 4 NMR (CDC13, 300 MHz) δ 7.99 (d, J = 2 Hz, 1H), 7.79-7.67 (m, 3H), 7.55 (dd, J = 2, 12 Hz, 1H), 7.52 (dd, J = 2, 12 Hz, 1 end), 4.85 (s, 2H). MS (DCI-NH3) [M] + 236.

實例IB 2-溴-6-(氣甲基）荽 取含實例1A之產物（30.5 g，129 mmol)之二4燒（320 mL) 攪拌溶液於無水氮蒙氣下冷卻至-1 〇°C。一次添加全量無水 ZnCl2固體（514 mg，3.77 mmol，0.03當量）後，滴力口亞石危酸 氯（19.3 mL，264 mmol，2.0當量）。使反應混合物回升至 室溫，然後再攪拌2小時。此反應混合物減壓濃縮，殘質分 溶於二氯甲烷與飽和NaHC〇3水溶液（500 mL)之間。有機層 經鹽水（2 X 100 mL)洗滌，脫水（硫酸鎂），與過濾。漉液減 壓濃縮，產生白色固體。於40°C下真空乾燥一夜，產生產 物（32.6 g，收率 99%)。Μ·ρ· 133.l-134.rC。4 NMR (CDC13, 300 MHz) δ 8.00 (d，J=2 Hz，1H)，7.81-7.67 (m，3H)，7.56 (dd, J=2，12 Hz，1H)，7.54 (dd，J=2，12 Hz，1H)，4.73 (s，2H) 。MS (DCI-NH3) [M] + 254。Example IB 2-Bromo-6- (gas methyl) 荽 Take the product of Example 1A (30.5 g, 129 mmol) bis (4 mL) (320 mL) and stir the solution to -10 ° C under anhydrous nitrogen. . After adding the entire amount of anhydrous ZnCl2 solids (514 mg, 3.77 mmol, 0.03 equivalent) in one portion, the titanite chlorite acid (19.3 mL, 264 mmol, 2.0 equivalent) was added. The reaction mixture was warmed to room temperature and then stirred for another 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and a saturated aqueous solution of NaHC03 (500 mL). The organic layer was washed with brine (2 X 100 mL), dehydrated (magnesium sulfate), and filtered. The mash was concentrated under reduced pressure to give a white solid. Vacuum drying at 40 ° C overnight yielded the product (32.6 g, 99% yield). M · ρ · 133.1-134.rC. 4 NMR (CDC13, 300 MHz) δ 8.00 (d, J = 2 Hz, 1H), 7.81-7.67 (m, 3H), 7.56 (dd, J = 2, 12 Hz, 1H), 7.54 (dd, J = 2, 12 Hz, 1H), 4.73 (s, 2H). MS (DCI-NH3) [M] + 254.

實例1C 89248.doc -100- 200418454 (6 -溴-2-¾:某）乙時 取含貫例 1B產物（32.2 g，126 mmol)與 NaCN (7.44 g，152 mmol，1.2當量）之乙腈（314 mL)與蒸餾水（32 mL)之混合物 於無水氮蒙氣下，於回流下攪拌2 1小時。反應混合物冷卻 至室溫’然後減壓濃縮。殘質與蒸餾水（314 mL)攪拌45分鐘 。所得白色固體經過濾單離，使用蒸餾水（丨5〇〇 mL)洗滌。 於40C下真空乾燥一夜，產生產物（32.2g，收率97%)。M.p. 119.6-120.6°C。4 NMR (CDC13, 300 ΜΗζ) δ 8.01 (d，J=2 Hz， 1H)，7.817.68 (m，3H)，7.60 (dd，J=2, 12 Hz，1H)，7.41 (dd， J=2, 12 Hz，1H)，3.90 (s，2H)。MS (DCI-NH3) [M+NH4]+ 263 ，[M+NH4 · NH3]+ 280。Example 1C 89248.doc -100- 200418454 (6-Bromo-2-¾: a) acetonitrile containing the product of Example 1B (32.2 g, 126 mmol) and NaCN (7.44 g, 152 mmol, 1.2 equivalents) A mixture of 314 mL) and distilled water (32 mL) was stirred under anhydrous nitrogen for 2 hours under reflux. The reaction mixture was cooled to room temperature 'and then concentrated under reduced pressure. The residue was stirred with distilled water (314 mL) for 45 minutes. The resulting white solid was isolated by filtration and washed with distilled water (500 mL). Drying under vacuum at 40C overnight gave the product (32.2 g, yield 97%). M.p. 119.6-120.6 ° C. 4 NMR (CDC13, 300 MHz) δ 8.01 (d, J = 2 Hz, 1H), 7.817.68 (m, 3H), 7.60 (dd, J = 2, 12 Hz, 1H), 7.41 (dd, J = 2, 12 Hz, 1H), 3.90 (s, 2H). MS (DCI-NH3) [M + NH4] + 263, [M + NH4 · NH3] + 280.

實例ID (6-溴- 2- ¾基）乙酸 取含實例1C產物（29.62 g，120 mmol)之冰醋酸（300 mL) 與蒸餾水（150 mL)攪拌混合物於無水氮蒙氣下冷卻至_15它 。以20分鐘時間滴加添加濃硫酸（12〇 mL，4.32 mo卜36.0 當量），同時保持反應溫度在1 〇。〇以下。反應混合物於回流 下攪拌2小時。冷卻至35°C後，加冰（500 g)至混合物中，續 攪拌45分鐘。所得白色固體經過濾單離，使用蒸餾水（丨5〇〇 mL)洗滌。於40°C下真空乾燥一夜，產生產物（29.57 g，收 率 93°/〇)。1h NMR (CDC13, 300 ΜΗζ) δ 7.99 (d，J=2 Hz，1H)， 7.76-7.64 (m，3H)，7·54 (dd，J=2，12 Hz，1H)，7.44 (dd，J=2, 12 Hz，1H)，3.81 (s，2H)。MS (DCI-NH3)[M+NH4] + 282。Example ID (6-Bromo- 2- ¾yl) acetic acid Take a mixture of glacial acetic acid (300 mL) and distilled water (150 mL) containing the product of Example 1C (29.62 g, 120 mmol) and cool to _15 under anhydrous nitrogen. it. Concentrated sulfuric acid (120 mL, 4.32 mo and 36.0 equivalents) was added dropwise over a period of 20 minutes while maintaining the reaction temperature at 10 °. 〇 or less. The reaction mixture was stirred at reflux for 2 hours. After cooling to 35 ° C, add ice (500 g) to the mixture and continue stirring for 45 minutes. The resulting white solid was isolated by filtration and washed with distilled water (500 mL). Drying under vacuum at 40 ° C overnight yielded the product (29.57 g, yield 93 ° / 0). 1h NMR (CDC13, 300 ΜΗζ) δ 7.99 (d, J = 2 Hz, 1H), 7.76-7.64 (m, 3H), 7.54 (dd, J = 2, 12 Hz, 1H), 7.44 (dd, J = 2, 12 Hz, 1H), 3.81 (s, 2H). MS (DCI-NH3) [M + NH4] + 282.

實例IE 89248.doc -101 - 200418454 2-(6-漠-2-¾:某）λ _ 於無水氮蒙氣下，以15分鐘時間，在含實例1〇產 物（28.6 g，l〇8mm〇l)之無水THF (143 mL)攪拌溶液中滴加 1·0 M BH3-THF 溶液（409 mL，409 mmol，3.8當量），同時保 持反應溫度在0°c以下。當添加完畢時，反應混合物於-15。〇 下攪拌1 5分鐘，然後回升至室溫，再攪拌2小時。反應混合 物隨後冷卻至-l〇°C，使用蒸餾水（1〇4 mL)中止反應。於室 溫下撥拌15分鐘後，反應混合物減壓濃縮。殘質分溶於二 氯甲烷（WOmL)與蒸餾水（200 mL)之間，水層經二氯甲烷（2 xlOOmL)萃取。合併之有機萃液經蒸餾水（3xl〇〇mL)洗滌 ’脫水（1故鎂：）與過濾。滤液減壓濃縮，產生白色固體。於 40 C下真空乾燥一夜，產生產物（26.1 g，收率96%)。M.p. 102.3-103.1°C ° !H NMR (CDC13? 300 MHz) δ 7.98 (d5 J=2 Hz5 1H)，7.74-7.63 (m，3H)，7.53 (dd，J=2, 12 Hz，1H)，7.49 (dd， J=2，12 Hz，1H)，4.00-3.92 (m，2H)，3.02 (t，J=6 Hz，2H)， 1.43-1.35 (t br，J=6 Hz，1H)。MS (DCI_NH3)[M+NH4]+ 268。Example IE 89248.doc -101-200418454 2- (6- Mo-2-¾: XX) λ _ under anhydrous nitrogen, for 15 minutes, containing the product of Example 10 (28.6 g, 108 mm. l) To a stirred solution of anhydrous THF (143 mL) was added dropwise a 1.0 M BH3-THF solution (409 mL, 409 mmol, 3.8 equivalents) while keeping the reaction temperature below 0 ° c. When the addition was complete, the reaction mixture was at -15. Stir for 15 minutes, then return to room temperature and stir for another 2 hours. The reaction mixture was then cooled to -10 ° C and the reaction was quenched with distilled water (104 mL). After stirring for 15 minutes at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (WOmL) and distilled water (200 mL), and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic extracts were washed with distilled water (3 x 100 mL), and dehydrated (1 mg :) and filtered. The filtrate was concentrated under reduced pressure to give a white solid. Drying under vacuum at 40 C overnight gave the product (26.1 g, yield 96%). Mp 102.3-103.1 ° C °! H NMR (CDC13? 300 MHz) δ 7.98 (d5 J = 2 Hz5 1H), 7.74-7.63 (m, 3H), 7.53 (dd, J = 2, 12 Hz, 1H), 7.49 (dd, J = 2, 12 Hz, 1H), 4.00-3.92 (m, 2H), 3.02 (t, J = 6 Hz, 2H), 1.43-1.35 (t br, J = 6 Hz, 1H). MS (DCI_NH3) [M + NH4] + 268.

實例IF 與乙基）-2-篇基1笨基氰 取含貫例1E產物（〇·6〇 g，2.39 mmol)、4-氰基苯基二輕硼 酸（0·42 g，2.87 mmo卜 1.2 當量）、PdCl2(PPh3)2 (34 mg， 0.048 mmo 卜 0.020 當量）與 κ3ρ〇4 H20 (1.38g，7.17 mmo 卜 3·0當量）之異丙醇（4〇 mL)與蒸餾水（15 mL)混合物於651：及 無水於氮蒙氣下攪拌丨5小時。反應混合物冷卻至溫度，然 後減壓濃縮。殘質分溶於乙酸乙酯與鹽水之間。水層經乙 89248.doc -102- 200418454 酸乙醋洗滌，合併之有機萃液經飽和NH4C1水溶液洗滌，脫 水（硫酸鎂）與過濾。濾液減壓濃縮，殘質經管柱層析法純化 (7 · 3己纪/乙酸乙酯）。取含產物之溶離份合併，減恩濃縮 ’產生灰白色固體產物（〇·59 g，收率90%)。4 NMR (CDC13, 300 MHz) δ 8.04 (d，J=2 Hz, 1H)，7.93-7.68 (m，8H)，7.44 (dd，J-2，12 Hz，1H)，3.98 (t，J=6 Hz，2H)，3.07 (t，&gt;6 Hz， 2H)。MS (DCI-NH3)[M+NH4]+291，[M+NH4 ·ΝΗ3] + 308。Example IF and Ethyl) -2-benzyl 1benzyl cyanide contains the product of Example 1E (0.60 g, 2.39 mmol), 4-cyanophenyl diphenylboronic acid (0.42 g, 2.87 mm) 1.2 equivalent), PdCl2 (PPh3) 2 (34 mg, 0.048 mmo, 0.020 equivalent) and κ3ρ〇4 H20 (1.38g, 7.17 mmo, 3.00 equivalent) isopropanol (40 mL) and distilled water (15 mL ) The mixture was stirred at 651 ° C under anhydrous nitrogen for 5 hours. The reaction mixture was cooled to a temperature and then concentrated under reduced pressure. The residue was dissolved between ethyl acetate and brine. The aqueous layer was washed with ethyl acetate 89248.doc -102- 200418454, and the combined organic extracts were washed with saturated aqueous NH4C1 solution, dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (7.3 Hz / ethyl acetate). The product-containing fractions were combined and concentrated to give off-white solid product (0.59 g, yield 90%). 4 NMR (CDC13, 300 MHz) δ 8.04 (d, J = 2 Hz, 1H), 7.93-7.68 (m, 8H), 7.44 (dd, J-2, 12 Hz, 1H), 3.98 (t, J = 6 Hz, 2H), 3.07 (t, &gt; 6 Hz, 2H). MS (DCI-NH3) [M + NH4] +291, [M + NH4 · ΝΗ3] + 308.

實例1G k甲基苯確酸2-氰基茉基）-2-:某1 λ酯 取含實例IF產物（0·48 g，1·76 mmol)、對甲苯續醯氯（0.37 g ’ 1·93 mmol，1·1 當量）與吡啶（3,0 mL，37.1 mmol，21.1 當 量）之無水二氣甲烷（20 mL)混合物於室溫與無水氮蒙氣下 稅拌3天。反應混合物減壓濃縮。殘質分溶於乙酸乙g旨與1 〇% 擰檬酸水溶液之間。水層經乙酸乙酯洗滌，合併之有機萃 液經飽和NaHC03水溶液洗滌，脫水（硫酸鎂）與過濾。濾液 減壓濃縮，殘質經管柱層析法純化（6 ·· 4二氣曱燒/己燒）。 取含產物之溶離份合併，減壓濃縮，產生白色固體產物（〇.3〇 g，收率 40%)。4 NMR (CDC13, 300 ΜΗζ) δ 8.01 (d，J=2 Hz， 1H)，7.86-7.75 (m，6H)，7.72-7.56 (m，4H)，7.29 (dd，J=2, 12 Hz，1H)，7.17 (d，J=9 Hz，2H)，4.34 (t，J=6 Hz，2H)，3·14 (t， J=6 Hz，2H)，2.36 (s，3H)。MS (DCI_NH3)[M+NH4]十 445 0 實例1H _ 丨2-「（2RV2-甲某-1-p比咯啶基1乙基1-2-¾:某）茉某氨 取含實例1G產物（0·30 g，1 ·08 mmol)、（2R)-2 -甲基p比洛淀 89248.doc -103 - 200418454 (CL30 g ’ 3·52 mm〇卜 5 〇當量）、與碳酸铯（〇·7〇 g ’ 21 mmol ’ 3·0當f )&lt;無水乙清（5 mL)混合物於密封試管中，於50°C 與典水氮冢氣下攪拌2天。反應混合物冷卻至室溫，然後減 壓;辰縮。殘質分溶於乙酸乙酯與飽和Na2c〇3水溶液之間。水 層經乙酸乙醋洗滌，合併之有機萃液經鹽水洗滌，脫水（硫 酸錢）與過遽。濾液減壓濃縮，殘質經管拄層析法純化（95 • 5 ·微量之二氯甲烷/甲醇/NH4OH)。取含產物之溶離份合 併’減壓濃縮，產生灰白色固體產物（0.130 g，收率54.4%) 。此固體溶於甲醇中，與一當量^酒石酸攪拌。減壓排除溶 劑’產生產物之酒石酸鹽之白色固體。M.p. 157.4-158. It 。1H NMR (酒石酸鹽，CD3〇D，300 MHz) δ 8.20 (d，J=2 Hz， 1H)，8·01-7·93 (m，4H)，7·88-7·81 (m，4H)，7·53 (dd，J=2，12 Hz，1H)，4.40 (s，2H)，3.81-3.63 (m，2H)，3.63-3.50 (m，1H)， 3.40-3.20 (m, 4H)? 2.40-2.27 (m5 1H)5 2.18-2.04 (m, 2H), 1.85-1.70 (m，1H)，1.47 (d，J=6 Hz，3H)。MS (DCI-NH3) [M+H]+ 341。 實例2Example 1G k-methylbenzoic acid 2-cyanamosyl) -2-: A 1 λ ester containing the product of Example IF (0.48 g, 1.76 mmol), p-toluene chloride (0.37 g '1 • A mixture of 93 mmol, 1.1 equivalents) and pyridine (3,0 mL, 37.1 mmol, 21.1 equivalents) in anhydrous digas methane (20 mL) was stirred at room temperature under anhydrous nitrogen for 3 days. The reaction mixture was concentrated under reduced pressure. The residue is dissolved between ethyl acetate and 10% aqueous citric acid solution. The aqueous layer was washed with ethyl acetate, and the combined organic extracts were washed with saturated aqueous NaHC03 solution, dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (6 ·· 4 digassing / hexane). The product-containing fractions were combined and concentrated under reduced pressure to give a white solid product (0.30 g, yield 40%). 4 NMR (CDC13, 300 MHz) δ 8.01 (d, J = 2 Hz, 1H), 7.86-7.75 (m, 6H), 7.72-7.56 (m, 4H), 7.29 (dd, J = 2, 12 Hz, 1H), 7.17 (d, J = 9 Hz, 2H), 4.34 (t, J = 6 Hz, 2H), 3.14 (t, J = 6 Hz, 2H), 2.36 (s, 3H). MS (DCI_NH3) [M + NH4] Ten 445 0 Example 1H _ 丨 2-"(2RV2-methyl-1-1-p than pyridyl 1ethyl1-2-¾: some) Molybdenum ammonia contains Example 1G Product (0 · 30 g, 1.08 mmol), (2R) -2 -methyl p-biloline 89248.doc -103-200418454 (CL30 g '3.52 mm 0.005 equivalent), and cesium carbonate (0.70 g '21 mmol '3.0 f) &lt; The mixture of anhydrous ethyl acetate (5 mL) was placed in a sealed test tube, and stirred at 50 ° C for 2 days under nitrogen and nitrogen gas. The reaction mixture was cooled to Room temperature, then reduced pressure; Chen shrink. The residue was dissolved between ethyl acetate and saturated aqueous Na2co3 solution. The aqueous layer was washed with ethyl acetate, the combined organic extracts were washed with brine, dehydrated (sulfate) and The filtrate was concentrated under reduced pressure, and the residue was purified by tube chromatography (95 • 5 · trace amount of dichloromethane / methanol / NH4OH). The product-containing fractions were combined and concentrated under reduced pressure to give an off-white solid product (0.130 g, yield 54.4%). This solid was dissolved in methanol and stirred with one equivalent of tartaric acid. The solvent was removed under reduced pressure to produce a white solid of tartrate. Mp 157.4-158. It. 1H NMR (tartaric acid , CD3OD, 300 MHz) δ 8.20 (d, J = 2 Hz, 1H), 8.01-7 · 93 (m, 4H), 7.88-7 · 81 (m, 4H), 7.53 (dd, J = 2, 12 Hz, 1H), 4.40 (s, 2H), 3.81-3.63 (m, 2H), 3.63-3.50 (m, 1H), 3.40-3.20 (m, 4H)? 2.40-2.27 (m5 1H) 5 2.18-2.04 (m, 2H), 1.85-1.70 (m, 1H), 1.47 (d, J = 6 Hz, 3H). MS (DCI-NH3) [M + H] + 341. Examples 2

溴-2-S某）乙基1-2-曱某吡咯啶 實例2A 三氟甲磺酸2-(6-溴-2-萁基）乙酯 在0°C之含實例1E產物（1·〇8 g，4,3mmol)與吡啶（0.46 mL ，5.6 mmol，1.3當量）之無水二氣甲烷（40 mL)攪拌溶液中滴 加三氟甲續酸肝（0.87 mL，5.16 mmol，1.2當量）。反應混合 物於0°C下攪拌1小時，然後以冰水（20 mL)處理。單離出有 89248.doc -104- 200418454 機層，脫水（硫酸鎂），過濾。濾液減壓濃縮，產生之油狀物 經矽膠填料使用95 : 5己烷/乙酸乙酯溶離純化。取含產物 之溶離份合併，減壓濃縮，產生灰白色固體產物（1.34 g， 收率 81%)。4 NMR (CDC13, 300 MHz) δ 8.00 (d，J=2 Hz，1H)， 7.77-7.64 (m，3H)，7.56 (dd，J=2，12 Hz，1H)，7.35 (dd，J=2, 12 Hz，1H)，4·73 (t，J=6 Hz，2H)，3.28 (t，J二6 Hz，2H)。MS (DCI-NH3) [M+NH4]+ 400，[M+NH4 · NH3]+ 417 oBromo-2-S, a) ethyl 1--2-pyrrolidine Example 2A 2- (6-bromo-2-fluorenyl) ethyl trifluoromethanesulfonate at 0 ° C, containing the product of Example 1E (1 · 〇8 g, 4,3 mmol) and pyridine (0.46 mL, 5.6 mmol, 1.3 eq.) In a stirred solution of anhydrous digas methane (40 mL) was added dropwise trifluoromethane liver (0.87 mL, 5.16 mmol, 1.2 eq.) . The reaction mixture was stirred at 0 ° C for 1 hour and then treated with ice water (20 mL). There are 89248.doc -104- 200418454 machine layers, dehydrated (magnesium sulfate), and filtered. The filtrate was concentrated under reduced pressure, and the resulting oil was purified by silica gel packing using 95: 5 hexane / ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure to give an off-white solid product (1.34 g, yield 81%). 4 NMR (CDC13, 300 MHz) δ 8.00 (d, J = 2 Hz, 1H), 7.77-7.64 (m, 3H), 7.56 (dd, J = 2, 12 Hz, 1H), 7.35 (dd, J = 2, 12 Hz, 1H), 4.73 (t, J = 6 Hz, 2H), 3.28 (t, J = 6 Hz, 2H). MS (DCI-NH3) [M + NH4] + 400, [M + NH4 · NH3] + 417 o

實例2B 溴-2-苯基）乙某-2-甲基吡咯啶 取含實例2A產物（1.34 g，3_5 mmol)、（2R)-2-甲基吡咯啶 (0.90 g，10.57 mmol，3.0當量）與碳酸铯（3.42 g，1〇.49 mm〇1 ，3.0當量）之乙腈（15 mL)混合物於5〇°c之密封試管中擅拌 1 8小時。反應混合物冷卻至室溫，然後減壓濃縮。殘質分 洛於乙酸乙酯與與蒸餾水之間。有機層經鹽水洗滌，然後 脫水（硫酸鎂）與過濾。濾液減壓濃縮，產生之米色固體溶於 EhO中。所得溶液過濾去除任何不可溶物，然後&amp;Hci (氣 體）處理，過濾收集產生之白色沉澱。此鹽類鹽溶於最少量 水中，添加氫氧化鈉調至pH 14。此鹼性水混合液經玢2〇萃 取。有機層脫水（硫酸鎂），過濾。濾液減壓濃縮，產生游離 鹼產物，為白色固體（0.9〇 g，收率8〇·8%”Μρ· (HC1鹽） 247.3-250.rC。！HNMR (游離驗，cd3〇d，3〇〇mHz)s8〇〇 (d，J-2 Hz，1H)，7.77-7.67 (m，3H)，7.52 (dd，&gt;2, 12 Hz, 1H)， 7.42 (dd，J=2，12 Hz，1H)，3.32-3.23 (m，lH)，3.18-3.03 (m， 1H)，3.03-2.87 (m，2H)，2.48·2·24 (m，3H)，2 〇7_194 (m， 89248.doc -105 - 200418454 1H)，1.86- 1.73 (m，2H)，1.52-1.38 (m，1Η)，1·15 (d，J=6 Hz， 3H)。MS (DCI-NH3) [M+H]+ 318。 iii3-(6-{2JXggl-.2-甲吡各虚基i乙某丨_2_苯某）笨基i乙酮 實例3ΑExample 2B Bromo-2-phenyl) ethoxy-2-methylpyrrolidine The product from Example 2A (1.34 g, 3-5 mmol) and (2R) -2-methylpyrrolidine (0.90 g, 10.57 mmol, 3.0 equivalents) ) And an acetonitrile (15 mL) mixture with cesium carbonate (3.42 g, 10.49 mm, 3.0 equivalents) in a sealed test tube at 50 ° C for 18 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was between ethyl acetate and distilled water. The organic layer was washed with brine, then dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure and the resulting beige solid was dissolved in EhO. The resulting solution was filtered to remove any insoluble matter, and then treated with &amp; Hci (gas), and the white precipitate generated was collected by filtration. This salt is dissolved in a minimum amount of water and adjusted to pH 14 with sodium hydroxide. This alkaline water mixture was extracted through 玢 20. The organic layer was dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure to give a free base product as a white solid (0.90 g, yield 80 · 8% "Mρ · (HC1 salt) 247.3-250.rC. HNMR (free test, cd30d, 30%). 〇mHz) s800 (d, J-2 Hz, 1H), 7.77-7.67 (m, 3H), 7.52 (dd, &gt; 2, 12 Hz, 1H), 7.42 (dd, J = 2, 12 Hz , 1H), 3.32-3.23 (m, 1H), 3.18-3.03 (m, 1H), 3.03-2.87 (m, 2H), 2.48 · 2 · 24 (m, 3H), 2.07_194 (m, 89248. doc -105-200418454 1H), 1.86- 1.73 (m, 2H), 1.52-1.38 (m, 1Η), 1.15 (d, J = 6 Hz, 3H). MS (DCI-NH3) [M + H ] + 318. iii3- (6- {2JXggl-.2-methylpyridinyl group i 2a _2_2 benzene a) benzyl i ethyl ketone Example 3A

Ug_-{6-(2-轉·乙暮H荔基！茉某丨乙酮 取含貫例1Ε產物（0.78 g，3.11 mmol)、3 -乙醯基苯基二羥 硼酸（0.61 g，3.72 mmol，1.2當量）、PdCl2(PPh2)2 (0.044 g ’ 0.062 mmol，〇·〇2當量）與 κ3Ρ〇4Η2〇（1.80 g，9.35 mmol ’ 3當量）之異丙醇（4〇 mL)與蒸餾水（15 mL)混合物於65它與 典水氮蒙氣下攪拌1.5小時。反應混合物冷卻至室溫，然後 減壓濃縮。殘質分溶於乙酸乙酯與鹽水之間。水層經乙酸 乙酉旨洗務’合併之有機萃液經飽和NH4C丨水溶液洗滌，脫 水（硫酸鎂）與過滤。濾液減壓濃縮，殘質經管柱層析法純化 (7 · 3己烷/乙酸乙酯）。取含產物之溶離份合併，減壓濃縮 ，產生灰白色固體產物（0.57 g，收率63%)。4 NMR (CD3〇D， 300 MHz) δ 8.31 (s，1H)，8.05 (s，1H)，8.92-8.98 (m，4H)， 8·72-8·79 (m，2H)，8·54 (t，J=7 Hz，1H)，7·4 (d，J=5.7 Hz, 1H)，3.96 (t，J=5.3 Hz，2H)，3 〇4 (t，拎5 3 Hz，2H)，2 Q &amp; 3H)，2.48 (bs，1H)。MS (DCI-NH3) [M+H]+291 [M+NH4]+3〇8。Ug _- {6- (2-trans. Ettriol H Liyl! Moss 丨 ethyl ketone) contains the product of Example 1E (0.78 g, 3.11 mmol), 3-ethyl ethyl phenyl dihydroxyborate (0.61 g, 3.72 mmol, 1.2 equivalents), PdCl2 (PPh2) 2 (0.044 g '0.062 mmol, 0.02 equivalents) and κ3PO4Η20 (1.80 g, 9.35 mmol' 3 equivalents) in isopropanol (40 mL) and distilled water (15 mL) The mixture was stirred at 65 ° C with nitrogen and nitrogen for 1.5 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved between ethyl acetate and brine. The aqueous layer was subjected to ethyl acetate. Washing 'The combined organic extracts were washed with saturated NH4C 丨 aqueous solution, dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (7.3 hexane / ethyl acetate). The fractions of the product were combined and concentrated under reduced pressure to give an off-white solid product (0.57 g, yield 63%). 4 NMR (CD30D, 300 MHz) δ 8.31 (s, 1H), 8.05 (s, 1H), 8.92 -8.98 (m, 4H), 8.72-8 · 79 (m, 2H), 8.54 (t, J = 7 Hz, 1H), 7.4 (d, J = 5.7 Hz, 1H), 3.96 (t, J = 5.3 Hz, 2H), 3 〇4 (t, 拎 53 Hz, 2H), 2 Q &amp; 3H), 2.48 (bs, 1H). MS (DCI-NH3) [M + H] +291 [M + NH4] +308.

實例3B 乙醯基笨基V2-萁篡l λ巧 - 在 〇°C 之含實例 3Α產物（〇·44 g，！ .49 1^1〇1)與 Et3N (〇.3〇 g ，2·98 mmol，2.0當量）攪拌溶液中，經由針筒滴加甲磺醯 89248.doc -106- 氯（0·24 g，2·09 mmol，1.4當量）。15分鐘後，離開冰浴， 反應混合物於室溫下攪拌1.5小時。反應混合物減壓濃縮。 殘質分溶於鹽水與CI^Cl2之間。水層經CHWh洗滌。合併 之有機萃液脫水（硫酸鎂）及過濾。濾液減壓濃縮，產生灰白 色固體產物（0.547 g，收率 99.6%)。4 NMR (CDC13，300 MHz)3 8.28(s，lH)，8.05(s，lH)，7.87-7.98 (m，4H)，7.72-7·79 (m，2H)，7·55 (t，J=5.6 Hz，1H)，7.38 (d，J=5.6 Hz，1H)， 4.48 (t，J=6 Hz，2H)，3.22 (t，J=6 Hz，2H)，2·86 (s，3H)，2.66 (s，3H)。MS (DCI-NH3)[M+NH4]+ 386。Example 3B Ethylbenzyl V2-pyridine λα- containing the product of Example 3A (0.44 g,! .49 1 ^ 10) and Et3N (0.30 g, 2. · 98 mmol, 2.0 equivalents) was stirred into the solution, and mesylmethane 89248.doc -106- chloride (0.24 g, 2.09 mmol, 1.4 equivalents) was added dropwise via a syringe. After 15 minutes, the ice bath was left and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved between saline and CI ^ Cl2. The aqueous layer was washed with CHWh. The combined organic extracts were dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure to give an off-white solid product (0.547 g, yield 99.6%). 4 NMR (CDC13, 300 MHz) 3 8.28 (s, 1H), 8.05 (s, 1H), 7.87-7.98 (m, 4H), 7.72-7 · 79 (m, 2H), 7.55 (t, J = 5.6 Hz, 1H), 7.38 (d, J = 5.6 Hz, 1H), 4.48 (t, J = 6 Hz, 2H), 3.22 (t, J = 6 Hz, 2H), 2.86 (s, 3H ), 2.66 (s, 3H). MS (DCI-NH3) [M + NH4] + 386.

實例3C 1-「3-(6-{2-「(2幻-2-甲基-1-峨洛淀基1乙基}-2-篇基）苯其1乙两同 取含實例3B產物（0.55 g，1·48 mmol)、（2R)-2-甲基p比略淀 (0.26 g，3·05 mmol，3 當量）與 Cs2C03 (1.16 g，3·56 mmo卜 2當量）之無水乙腈（30 mL)混合物於45°C之密封試管中授掉 18小時。反應混合物冷卻至室溫，然後減壓濃縮。殘質分 溶於乙酸乙酯與2N NaOH水溶液之間。水層經乙酸乙酉旨洗 滌。合併之有機層脫水（硫酸鎂）與過濾。濾液減壓濃縮，殘 質經管柱層析法純化（95: 5:微量之二氯甲烷/甲醇/NH4〇h) 。取含產物之溶離份合併，減壓濃縮，產生灰白色固體產 物（0.115 g，收率22%)。固體溶於醚中，以HC1 (氣體）處理 ，產生HC1 鹽。1H NMR (CD3OD，300 ΜΗζ) δ 8.31 (s ιΗ) 8.10 (s，1Η)，7·99 (s，1Η)，7.96 (s，1Η)，7·89 (s，lH)，7 87 (d J=13.3 Ηζ，1Η)，7.75 (d，J=5.8 Ηζ，1Η)，7·71 (s，ιΗ)，7 58 (t J=6.7Hz，1Η)，7·39 (d，J=5.8 Ηζ，1Η)，3.2-3.28 (m，1Η)， 89248.doc -107- 200418454 3.1- 3.2 (m，1H)，2.9-3.03 (m，2H)，2.67 (s，3H)，2.37-2.47 (m， 2H)，2.26 (q，J=7Hz，1H)，1.94-2.05 (m5 1H)，1.74-1.85 (m， 2H) 1.39-1.52 (m，1H)，1.17 (d，J=6 Hz，3H)。MS (DCI-NH3) [M+H] + 358。 實例4 咯啶某1乙基卜2_荃某）笨某1 -2-丙醇 利用針筒在含實例3C產物（0.68 g，1·91 mmol)之無水THF (10mL)瀑合物中滴加CH3MgC]L (〇% g，7 64 mm〇1，4當量） 。反應混合物於室溫下攪拌18小時。添加K2Hp〇4 (25 mL) 中止反應。反應混合物減壓濃縮。殘質分溶於2N NaOH水 溶液與乙酸乙酯之間。水層經乙酸乙酯洗滌，合併之有機 萃液脫水（硫酸鎂），與過濾。濾液減壓濃縮，殘質經管柱層 析法純化（90: 10: (U二氣甲烷/甲醇/NH4〇H)。取含產物之 溶離份合併，減壓濃縮’產生灰白色固體產物(〇u8g，收 率17%)。固體溶於醚中，以HC1 (氣體）處理，產生hci鹽。 NMR (CD3OD? 300 ΜΗζ&gt; δ 8.05 (s? 1Η)? 7.87-7.9(m? 3Η)? 7.42 (d? J=6 Hz, 1H)5 7.0 (s5 1H)9 7.7 (d? J=5.3 Hz5 1H)? 7.45^ 7·49 (m，1H)，7·42 (S，1H)，7·4 (s，1H)，3·2-3·28 (m，1H)， 3.1- 3.2 (m，1H)，2.9-3.03 (m，2H)，2.37-2.47 (m，2H)，2.26 (q， J=7 Hz? 1H)? 1.94^2.05 (m? 1H)5 1.74^ 1.85 (m, 2H) 1.39-1.52 (m，1H)，1.61 (s，6H)，1.17 (d，Hz，3H)。MS (DCI-NH3) [M+H]+ 374。 實例5 89248.doc -108- 200418454 6-{2-f(2R)-2-甲基-1-吡咯啶某1乙基丨-2-衾某教 取含實例2B產物（100 mg，0.3 14 mmol)、氰化鋅（22 mg， 〇· 1 88 mmol，0.6當量）、Pd2(dba)3 (14 mg，0.016 mmol，0.05 當量）、1，1，-雙（二苯基膦基）二茂絡鐵（21 mg，0.038 mmol ，〇·12當量）之DMF (5 mL)與蒸餾水（0.05 mL)混合物於無水 氮蒙氣與120°C下攪拌24小時。反應混合物冷卻至80°C，以 4 : 1 : 4飽和NH4C1水溶液/NH4OH/水處理，攪拌一夜，同 時冷卻至室溫。混合物經乙酸乙酯萃取。有機層先經4 : 1 :5飽和以h4C1水溶液/NH4〇H/水洗滌後，以鹽水洗滌。有 機層脫水（硫酸鎂），過濾。濾液減壓濃縮，殘質經管柱層析 法純化（97 : 3 :微量之二氣甲烷/甲醇/NH4OH)。取含產物 之溶離份合併，減壓濃縮，殘質溶於Et20。溶液經HC1 (氣 體）處理，混合物減壓濃縮，產生產物之鹽酸鹽白色固體（5 ! mg，收率 43%)。Μ·ρ· 187.4-188.6°C。4 NMR (CD3OD，300 MHz) δ 8.38 (s br5 1H)? 8.03 (d5 J=2 Hz? 1H)3 8.00 (d5 J=2 Hz? 1H)，7·94 (s br，2H)，7.68 (dd，J=2，12 Hz，1H)，7.63 (dd，J=2, 12 Hz，1H)，3.84-3.67 (m，2H)，3.63-3.48 (m，1H)，3.43-3.19 (m，4H)，2.43-2.29 (m，1H)，2·24-2·01 (m，2H)，1.84-1.68 (m， 1H)，1·48 (d，J=7 Hz，3H)。MS (DCI-NH3)[M+H]+ 265。 實例6 甲基-1-吡咯啶基1甲某卜:基）苯某氰 實例6A 一 羥甲基萁某篡聲 取含實例1A產物（〇·119 g，0.50 mmol)、4-氰基苯基二羥 89248.doc -109- 200418454 硼酸（0.088 g，〇·6〇 mm〇l ’ 1 ·2 當量）、pdCl2(PPh3)2 (7 mg， 0.001 mmo 卜 〇·〇20 當量）與 K3p〇4。H20 (288 mg，1.5 mmol ，3.0當量）之異丙醇（l〇 mL)與蒸鶴水（4 mL)混合物於50°C下 ，於無水氮蒙氣下授拌1 ·5小時。反應混合物冷卻至室溫， 然後減壓濃縮。殘質分溶於乙酸乙酯與飽和NH4C1水溶液 之間。有機層脫水（硫酸鎂），過濾。濾液減壓濃縮，殘質經 管柱層析法純化（65 : 35己烷/乙酸乙酯）。取含產物之溶離 份合併，減壓濃縮，產生白色固體產物（95 mg，收率73%) 。Μ·ρ· 174.1-175.5〇C 咕 NMR (CDC13, 300 ΜΗ3) δ 8.06 (d， J=2 Hz，1H)，7.97-7.70 (m，8H)，7·54 (dd，J=2，12 Hz，1H)， 4.90 (dbr，J=6 Hz，2H)，1.78 (tbr，J=6 Hz，1H)。MS (DCI-NH3) [M+NH4]+ 277，[M+NH4.NH3] 294 〇Example 3C 1- "3- (6- {2-" (2-Hydroxy-2-methyl-1-erlotyl 1ethyl) -2-yl) benzene (0.55 g, 1.48 mmol), (2R) -2-methyl p-pyridine (0.26 g, 3.05 mmol, 3 eq.) And Cs2C03 (1.16 g, 3.56 mmo 2 eq.) Anhydrous The acetonitrile (30 mL) mixture was allowed to stand in a sealed test tube at 45 ° C for 18 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved between ethyl acetate and 2N aqueous NaOH solution. The aqueous layer was subjected to acetic acid. Wash with acetic acid. The combined organic layers were dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (95: 5: trace dichloromethane / methanol / NH4oh). The product containing the product was taken. The dissolved fractions were combined and concentrated under reduced pressure to give an off-white solid product (0.115 g, yield 22%). The solid was dissolved in ether and treated with HC1 (gas) to produce the HC1 salt. 1H NMR (CD3OD, 300 ΜΗζ) δ 8.31 (s Η) 8.10 (s, 1Η), 7.99 (s, 1Η), 7.96 (s, 1Η), 7.89 (s, 1H), 7 87 (d J = 13.3 Ηζ, 1Η), 7.75 ( d, J = 5.8 Ηζ, 1Η), 7.71 (s, ιΗ), 7 58 (t J = 6.7Hz, 1Η), 7 39 (d, J = 5.8 Ηζ, 1Η), 3.2-3.28 (m, 1Η), 89248.doc -107- 200418454 3.1- 3.2 (m, 1H), 2.9-3.03 (m, 2H), 2.67 (s, 3H), 2.37-2.47 (m, 2H), 2.26 (q, J = 7Hz, 1H), 1.94-2.05 (m5 1H), 1.74-1.85 (m, 2H) 1.39-1.52 (m, 1H), 1.17 ( d, J = 6 Hz, 3H). MS (DCI-NH3) [M + H] + 358. Example 4 Pyridine 1 ethyl 1 2 2 quan 1) Ben 1 1-2-propanol using a syringe at CH3MgC] L (0% g, 7 64 mm 0, 4 equivalents) was added dropwise to the anhydrous THF (10 mL) waterfall compound containing the product of Example 3C (0.68 g, 1.91 mmol). The reaction mixture was stirred at room temperature. 18 hours. K2Hp04 (25 mL) was added to stop the reaction. The reaction mixture was concentrated under reduced pressure. The residue was dissolved between 2N NaOH aqueous solution and ethyl acetate. The aqueous layer was washed with ethyl acetate, and the combined organic extracts were dehydrated ( Magnesium sulfate), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (90: 10: (U 2 gas methane / methanol / NH 4 0H). The fractions containing the product were combined and concentrated under reduced pressure to give an off-white solid product (0u8g, yield 17%). The solid was dissolved in ether and treated with HC1 (gas) to produce the hci salt. NMR (CD3OD? 300 ΜΗζ &gt; δ 8.05 (s? 1Η)? 7.87-7.9 (m? 3Η)? 7.42 (d? J = 6 Hz, 1H) 5 7.0 (s5 1H) 9 7.7 (d? J = 5.3 Hz5 1H)? 7.45 ^ 7.49 (m, 1H), 7.42 (S, 1H), 7.4 (s, 1H), 3.2-3 · 28 (m, 1H), 3.1- 3.2 (m , 1H), 2.9-3.03 (m, 2H), 2.37-2.47 (m, 2H), 2.26 (q, J = 7 Hz? 1H)? 1.94 ^ 2.05 (m? 1H) 5 1.74 ^ 1.85 (m, 2H ) 1.39-1.52 (m, 1H), 1.61 (s, 6H), 1.17 (d, Hz, 3H). MS (DCI-NH3) [M + H] + 374. Example 5 89248.doc -108- 200418454 6 -{2-f (2R) -2-methyl-1-pyrrolidine, 1 ethyl 丨 -2- 衾, which contains the product of Example 2B (100 mg, 0.3 14 mmol), zinc cyanide (22 mg, 0.18 mmol, 0.6 equivalent), Pd2 (dba) 3 (14 mg, 0.016 mmol, 0.05 equivalent), 1,1, -bis (diphenylphosphino) ferrocene iron (21 mg, 0.038 mmol, 0 · 12 equivalents of a mixture of DMF (5 mL) and distilled water (0.05 mL) under an anhydrous nitrogen atmosphere at 120 ° C and stirred for 24 hours. The reaction mixture was cooled to 80 ° C, and 4: 1: 4 saturated NH4C1 aqueous solution / Treated with NH4OH / water and stirred overnight while cooling to room temperature. The mixture was extracted with ethyl acetate. The organic layer was first subjected to After 4: 1: 5 saturated washing with h4C1 aqueous solution / NH4OH / water, washing with brine. The organic layer was dehydrated (magnesium sulfate), filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (97: 3: A small amount of gas (methane / methanol / NH4OH). The fractions containing the product are combined, concentrated under reduced pressure, and the residue is dissolved in Et20. The solution is treated with HC1 (gas), and the mixture is concentrated under reduced pressure to produce the product as a hydrochloride salt as a white solid (5! Mg, yield 43%). M · ρ · 187.4-188.6 ° C. 4 NMR (CD3OD, 300 MHz) δ 8.38 (s br5 1H)? 8.03 (d5 J = 2 Hz? 1H) 3 8.00 ( d5 J = 2 Hz? 1H), 7.94 (s br, 2H), 7.68 (dd, J = 2, 12 Hz, 1H), 7.63 (dd, J = 2, 12 Hz, 1H), 3.84-3.67 (m, 2H), 3.63-3.48 (m, 1H), 3.43-3.19 (m, 4H), 2.43-2.29 (m, 1H), 2.24-2 · 01 (m, 2H), 1.84-1.68 ( m, 1H), 1.48 (d, J = 7 Hz, 3H). MS (DCI-NH3) [M + H] + 265. Example 6 Methyl-1-pyrrolidinyl 1-methyl: phenyl) benzene cyanide Example 6A Monomethylol sulfonium extracts the product containing Example 1A (0.19 g, 0.50 mmol), 4-cyanobenzene Dihydroxy 89248.doc -109- 200418454 Boric acid (0.088 g, 0.60 mm ′ 1 · 2 equivalents), pdCl2 (PPh3) 2 (7 mg, 0.001 mmo 2 .02 equivalents) and K3p. 4. A mixture of H20 (288 mg, 1.5 mmol, 3.0 eq.) In isopropanol (10 mL) and steamed crane water (4 mL) was stirred at 50 ° C for 1.5 hours under anhydrous nitrogen. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and saturated aqueous NH4C1 solution. The organic layer was dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (65:35 hexane / ethyl acetate). The product-containing fractions were combined and concentrated under reduced pressure to give a white solid product (95 mg, yield 73%). M · ρ · 174.1-175.5 ° C NMR (CDC13, 300 ΜΗ3) δ 8.06 (d, J = 2 Hz, 1H), 7.97-7.70 (m, 8H), 7.54 (dd, J = 2, 12 Hz, 1H), 4.90 (dbr, J = 6 Hz, 2H), 1.78 (tbr, J = 6 Hz, 1H). MS (DCI-NH3) [M + NH4] + 277, [M + NH4.NH3] 294 〇

實例6B 4-[6-(氯甲基）-2-莕基]苯基氰 取含實例 6A產物（90 mg，0.347 mmol)、0.5 M ZnCl2之 THF 溶液（0.21 mL，0.104 mmol，0.3 當量）與亞硫醯氯（0.51 mL ，6·94 mmol，20.0當量）之二，号烷（40 mL)混合物於室溫與無 水氮蒙氣下攪拌3小時。反應混合物減壓濃縮，殘質分溶於 乙酸乙酯與飽和Na2C〇3水溶液之間。有機層脫水（硫酸鎂） 與過濾。濾液減壓濃縮，殘質經管柱層析法純化（95 : 5己 燒/乙酸乙酯）。取含產物之溶離份合併，減壓濃縮，產生白 色固體產物（91 mg，收率 94.4%)。M.p. 147.5-149.2°C。ΓΗ NMR (CDC13, 300 MHz) δ 8.05 (d，J=2 Ηζ，1Η)，7.97-7.90 (m， 2H)，7·89-7.84 (m，lH)，7.84-7.71 (m，5H)，7.57 (dd，J=2, 12 89248.doc -110- 200418454Example 6B 4- [6- (chloromethyl) -2-fluorenyl] phenylcyanide Take the product of Example 6A (90 mg, 0.347 mmol), 0.5 M ZnCl2 in THF (0.21 mL, 0.104 mmol, 0.3 equivalent) Stir with thionyl chloride (0.51 mL, 6.94 mmol, 20.0 eq.), And the alkane (40 mL) mixture was stirred at room temperature under anhydrous nitrogen for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and a saturated aqueous Na2CO3 solution. The organic layer is dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (95: 5 hexane / ethyl acetate). The product-containing fractions were combined and concentrated under reduced pressure to give a white solid product (91 mg, yield 94.4%). M.p. 147.5-149.2 ° C. ΓΗ NMR (CDC13, 300 MHz) δ 8.05 (d, J = 2 Ηζ, 1Η), 7.97-7.90 (m, 2H), 7.89-7.84 (m, 1H), 7.84-7.71 (m, 5H), 7.57 (dd, J = 2, 12 89248.doc -110- 200418454

Hz，1H)，4.78 (s，2H)°MS (DCI-NH3) [M+NH4]+ 295, [M+NH4.NH3]+ 312 °Hz, 1H), 4.78 (s, 2H) ° MS (DCI-NH3) [M + NH4] + 295, [M + NH4.NH3] + 312 °

實例6C ΐ!ί^_{.2-『（2ΙΙ)-2-甲基-1-吡咯啶墓1甲某丨-2·•苯基）笨某氛 取含貫例6B產物（90 mg，0.324 mmol)、（2R)-2-甲基p比p各 啶（138 mg，1.62 mmol，· 5.0 當量）與碳酸铯（317 mg，0.972 mmol，3·0當量）之乙腈（10 mL)混合物於密封試管中，於45°C 下4見掉3小時’然後於立溫下2天。反應混合物減壓濃縮。 殘質分寒於乙酸乙酯與蒸餾水之間。有機層脫水（硫酸鎂） 與過濾。濾液減壓濃縮，殘質經管柱層析法純化（97 : 3 : 微量之二氯甲烷/曱醇/NH4〇H)。取含產物之溶離份合併， 減壓濃縮，殘質溶於EhO中。溶液經HC1 (氣體）處理，過滤 收集沉殿，產生產物之鹽酸鹽，為白色固體（51 mg，收率43%) 。Μ·ρ· 212.6-213.6。。。4 NMR (CD3〇D，300 ΜΗζ) δ 8.29 (d， J = 2 Hz，1H)，8·15_8·06 (m，3H)，7.98 (d，J=9 Hz，2H)，7·93 (dd，J=2，12 Hz，1H)，7.86 (d，J=9 Hz，2Η)，7·67 (dd，J=2，12 Hz，1H)，4.77 (，J=3 Hz，1H)，4.37 (d，J=3 Hz，1H)，3.75-3.61 (m，lH)，3.46-3.30 (m，2H)，2.48-2.35 (m，1H)，2.22-1.92 (m， 2H)，1·86’1·72 (m，1Η)，1·47 (d，J=7 Hz，3H)。MS (DCI-NH3) [M+H]+ 327。 實例7 3-—d{2-「(2尾)二2-甲蓋吡咯喊基1乙某卜革莘、y芊氰-Example 6C ΐ! Ί ^ _ {. 2-[(2ΙΙ) -2-Methyl-1-pyrrolidine tomb 1A, -1, 2-phenyl 0.324 mmol), (2R) -2-methyl p-pyridine (138 mg, 1.62 mmol, · 5.0 equivalents) and acetonitrile (10 mL) in cesium carbonate (317 mg, 0.972 mmol, 3.0 equivalents) In a sealed tube, see 3 hours at 45 ° C and then stand for 2 days at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was separated between ethyl acetate and distilled water. The organic layer is dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (97: 3: trace amount of dichloromethane / methanol / NH4OH). The dissolved fractions containing the product were combined, concentrated under reduced pressure, and the residue was dissolved in EhO. The solution was treated with HC1 (gas) and collected by filtration to produce the hydrochloride salt of the product as a white solid (51 mg, yield 43%). M · ρ · 212.6-213.6. . . 4 NMR (CD3OD, 300 MHz) δ 8.29 (d, J = 2 Hz, 1H), 8.15_8 · 06 (m, 3H), 7.98 (d, J = 9 Hz, 2H), 7.93 ( dd, J = 2, 12 Hz, 1H), 7.86 (d, J = 9 Hz, 2Η), 7.67 (dd, J = 2, 12 Hz, 1H), 4.77 (, J = 3 Hz, 1H) , 4.37 (d, J = 3 Hz, 1H), 3.75-3.61 (m, 1H), 3.46-3.30 (m, 2H), 2.48-2.35 (m, 1H), 2.22-1.92 (m, 2H), 1 86'1 · 72 (m, 1Η), 1.47 (d, J = 7 Hz, 3H). MS (DCI-NH3) [M + H] + 327. Example 7 3--d {2-"(2 tails) bis-2-methylgallidyl 1-ethyl-methyl-branthine, y-cyanine-

實例7A 3.二[6-(2一:裝基）-2-¾:某 1 革筝免 89248.doc -111 - 200418454 標過化合物係依實例3 A之方法製備，但其中改用3 -氰基 豕基一务硼替代3 -乙基苯基二獲硼酸（0.21 g，收率 7.86 (m，3H)，7.76-7.55 (m，4H)，7·43 (dd，J=2，12 Hz，1H)， 3.98 (t，&gt;6 Hz，2H)，3·07 (t，J=6 Hz，2H)。MS (DCI-NH3) [M+NH4]+ 291，[M+NH4.NH3]+ 308。Example 7A 3. 二 [6- (2 一: 装 基) -2-¾: A certain leather compound is free from 89248.doc -111-200418454 The labeled compound was prepared according to the method of Example 3 A, but 3-was used instead. Cyanofluorenyl monovalent boron replaces 3-ethylphenyl diboronic acid (0.21 g, yield 7.86 (m, 3H), 7.76-7.55 (m, 4H), 7.43 (dd, J = 2, 12 Hz, 1H), 3.98 (t, &gt; 6 Hz, 2H), 3.07 (t, J = 6 Hz, 2H). MS (DCI-NH3) [M + NH4] + 291, [M + NH4. NH3] + 308.

實例7B 黃酸2-「6-0-氰基苯某）-2-篇基1乙酯 在〇 C |含實例7A產物（0.21 g，0.768 mmol)與吡啶（0.08 mL ’ 1·〇 mm〇i，13當量）之無水二氣甲烷（15 mL)攪拌溶液 中滴加三氟甲磺酸酐（〇16 mL，〇·922 mmol，1.2當量）。反 應混合物於〇°C下攪拌30分鐘，然後經冰水（2〇 mL)處理。單 離有機層，脫水（MgS04)與過滤。濾液減壓濃縮，產生之油 狀物經管柱層析法純化（95 : 5至7〇 : 3〇己烷/乙酸乙酯）。取 S產物之〉谷離份合併’減壓濃縮，產生產物（6 〇 m g，收率 19%)。4 NMR (CDC13，300 MHz) δ 8.02-7.87 (m，5H)， 7.76-7.55 (m，4H)，7.40 (dd，&gt;2, 12 Hz，1H)，4·80 (t，J=6 Hz， 2H)，3.32 (t，J=6 Hz，2H)。MS (DCI-NH3) [M+NH4；T423。Example 7B 2- "6-0-cyanobenzene" flavonic acid 2-ethyl 1 ethyl group at 0C | Contains the product of Example 7A (0.21 g, 0.768 mmol) and pyridine (0.08 mL '1.0 mm). i, 13 equivalents) to a stirred solution of anhydrous digas methane (15 mL) was added dropwise trifluoromethanesulfonic anhydride (0 16 mL, 0.292 mmol, 1.2 equivalents). The reaction mixture was stirred at 0 ° C for 30 minutes, and then It was treated with ice water (20 mL). The organic layer was separated, dehydrated (MgS04) and filtered. The filtrate was concentrated under reduced pressure, and the resulting oil was purified by column chromatography (95: 5 to 70:30). / Ethyl acetate). Take the product> Segment fractions and combine them under reduced pressure to give the product (60 mg, yield 19%). 4 NMR (CDC13, 300 MHz) δ 8.02-7.87 (m, 5H) , 7.76-7.55 (m, 4H), 7.40 (dd, &gt; 2, 12 Hz, 1H), 4.80 (t, J = 6 Hz, 2H), 3.32 (t, J = 6 Hz, 2H). MS (DCI-NH3) [M + NH4; T423.

實例7C 甲基-1-吡咯啶某1乙基卜2-衮篡、苯甚氰 標題化合物係依實例3C之方法製備，但其中改用實例7B 產物替代實例3B產物（21 mg，收率38%^M.p. 228.5-231.6¾ 。iH NMR (CD3〇D，300 MHz) δ 8·23 (d，J=2 Ηζ，1Η)，8·20-8*18 (m， 1H)， 8.14-8.09 (m， 1H)， 8.04-7.98 (m， 2H)， 89248.doc • 112 - 200418454 7.90-7.85 (m，2H)，7.70-7.65 (m，2H)，7.60(t，J=7Hz，2H)， 7.54 (dd，J二2，12 Hz，1H)，3.81-3.63 (m，2H)，3.60-3.48 (m， 1H)，3.40-3.13 (m，4H)，2.39-2.24 (m，1H)，2.18-2.00 (m， 2Η)，1·82-1·67 (m，1H)，1.46 (d，&gt;7 Hz，3H)。MS (DCI-NH3) [M+H]+ 34 卜 K6-{2-「（2RV2-甲基-1-吡咯啶某1乙基卜2-¾:基）吡啶 取含實例2B產物（50 mg，0.157 mmol)、4-吡啶基二羥领Example 7C Methyl-1-pyrrolidine, a 1-ethyl-2-oxan, benzocyanine title compound was prepared according to the method of Example 3C, but the product of Example 7B was used instead of the product of Example 3B (21 mg, yield 38 % ^ Mp 228.5-231.6¾. IH NMR (CD3OD, 300 MHz) δ 8 · 23 (d, J = 2 Ηζ, 1Η), 8 · 20-8 * 18 (m, 1H), 8.14-8.09 ( m, 1H), 8.04-7.98 (m, 2H), 89248.doc • 112-200418454 7.90-7.85 (m, 2H), 7.70-7.65 (m, 2H), 7.60 (t, J = 7Hz, 2H), 7.54 (dd, J-2, 12 Hz, 1H), 3.81-3.63 (m, 2H), 3.60-3.48 (m, 1H), 3.40-3.13 (m, 4H), 2.39-2.24 (m, 1H), 2.18-2.00 (m, 2Η), 1.82-1 · 67 (m, 1H), 1.46 (d, &gt; 7 Hz, 3H). MS (DCI-NH3) [M + H] + 34 BU K6- {2-"(2RV2-methyl-1-pyrrolidine, 1 ethyl 2- 2-:: yl) pyridine, containing the product of Example 2B (50 mg, 0.157 mmol), 4-pyridyl dihydroxy collar

酸（48 mg^，〇·393 mmo 卜 2·5 當量）、PdCl2(PPh3)2(6 mg，0.008, mmol，〇·〇54當量）與 κ3Ρ〇4 · H20 (181 mg，0.943 mmol，6·&lt;Acid (48 mg ^, 0.393 mmo, 2.5 equivalents), PdCl2 (PPh3) 2 (6 mg, 0.008, mmol, 0.0054 equivalents), and κ3PO4 · H20 (181 mg, 0.943 mmol, 6 &Lt;

當量）之異丙醇（5 mL)與蒸餾水（2 mL)混合物於60°C與無水 於氮冡氣下攪拌1小時。反應混合物冷卻至室溫，然後減壓 农縮。殘質分溶於乙酸乙酯與飽*Na2C〇3水溶液之間。有 機層脫水（硫酸鎂）與過濾。滤液減壓濃縮，殘質經管柱層析 法純化（95 : 5 :微量之二氯甲烷/甲醇/NH4OH)。取含產物 合離伤♦併’減壓濃縮，產生之灰白色固體產物溶於扮2C 中以HC1 (乱骨豊）處學。此混合物減壓濃縮，產生產物之二 鹽酸鹽，為灰白声口； j、、瓦&amp; π _Equivalent) of a mixture of isopropanol (5 mL) and distilled water (2 mL) was stirred at 60 ° C and anhydrous for one hour under nitrogen. The reaction mixture was cooled to room temperature, and then reduced in pressure to shrink. The residue was dissolved between ethyl acetate and a saturated aqueous solution of Na2CO3. The organic layer is dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (95: 5: trace dichloromethane / methanol / NH4OH). The product containing the product was isolated and concentrated under reduced pressure, and the resulting off-white solid product was dissolved in 2C and treated with HC1. This mixture was concentrated under reduced pressure to produce the second hydrochloride salt of the product.

、性固 m(21 mg，收率 34%)。iH NMR (CD3OD? 300 MHz) δ 8 ΟΛ ^ τ ^ )δ MO (d，&gt;6 Ηζ，2Η)，8·63 (d，Ηζ. 1Η), 8.56 (d, J=6 Ηζ,2Η), 8.15.8.05 (m&gt; 3Η), 7.98.y 95 (m 1Η),7.64 (dd, J=2, 12 η2,1Η), 3.86-3.69 (m, 2Η), 3.65-3.5C 3.45-3^9 (m,4H)52 44.2 3〇^ 2H), 1.85-1.70 (ra \V\\ i cn ’ )，h50 (d，J=6 Hz，3H)。MS (DCI-NH3、 [M+H]+ 317。 89248.doc -113 - 200418454 實例9Sexual solid m (21 mg, yield 34%). iH NMR (CD3OD? 300 MHz) δ 8 ΟΛ ^ τ ^) δ MO (d, &gt; 6 Ηζ, 2Η), 8.63 (d, Ηζ. 1Η), 8.56 (d, J = 6 Ηζ, 2Η) , 8.15.8.05 (m &gt; 3Η), 7.98.y 95 (m 1Η), 7.64 (dd, J = 2, 12 η2, 1Η), 3.86-3.69 (m, 2Η), 3.65-3.5C 3.45-3 ^ 9 (m, 4H) 52 44.2 3〇 ^ 2H), 1.85-1.70 (ra \ V \\ i cn '), h50 (d, J = 6 Hz, 3H). MS (DCI-NH3, [M + H] + 317. 89248.doc -113-200418454 Example 9

Ιιίβ-甲基比咯啶基1乙基卜2_苯基）吡啶 標題化合物係依實例8之方法製備，但其中改用3_吡啶基 一經硼酸替代4-p比症基二經硼酸（16 mg，收率26%)。NMR (CD3〇D，300 MHz) δ 9.35-9.32 (m，1H)，9.11-9.06 (m，1H)， 8.89-8.85 (m，lH)，8.41 (d，J=2 Hz，1H)，8·26-8·20 (m，1H)， 8.08 (t，J二9 Hz，2H)，7.98-7.93 (m，2H)，7.62 (dd，J=2, 12 Hz， 1H)，3.86-3.69 (m，2H)，3.65-3.49 (m，1H)，3.45-3.22 (m，4H)， 2.43-2.31“m，1H)，2.23-2.01 (m，2H)，1.86-1.71 (m，1H)， 1.51 (d，J=7 Hz，3H)。MS (DCI-NH3) [M+H]+ 317。 實例10 (j·.-狀本基.)（6-{2-「(2R)-2 -甲基-比味哈基&quot;[乙基}_2-篇:基）甲醇 滴加1 ·7 Μ弟二丁基鐘之戊燒溶液（〇.41 mL，0.69 1 mmol ’ 2.2 當里）至-78 C 之含貫例 2B 產物（loo mg，0.314 mmol) 之無水THF (3 mL)攪拌溶液中。反應混合物於-78它下攪拌 20分鐘後’滴加3-氟苯甲醛（0.04 mL，〇·377 mmol，1.2當量） 至反應混合物中。於-78°C下攪拌10分鐘後，使反應混合物 回升至主丨皿’然後分洛於乙乙酉旨與飽和Na】C Ο 3水溶液之 間。有機層脫水（硫酸鎂）與過濾。濾液減壓濃縮，殘質經製 備性TLC純化（95 : 5 :微量之二氯甲淀/甲醇/NIj4〇h)。單離 出含產物之條帶，以95 : 5 :微量之二氯甲烷/甲醇/NH4OH 溶離。所得溶液減壓濃縮，產生游離鹼之產物，為白色固 體（3.2 mg，收率 2.5%)。4 NMR (CD3〇D，300 ΜΗζ) δ 7.84-7.72 (m，3Η)，7.66-7.63 (m，1Η)，7.42-7.26 (m，3Η)， 89248.doc -114- 200418454 7.22-7.13 (m? 2H), 6.98-6.91(m? 1H)5 5.91 (s5 1H), 3.32-3.23 (m，1H)，3.19-3.09 (m，2H)，2.51-2.26 (m，3H)，2.〇6-194 (叫 1H)，1.85-1.74 (m，2H)，1·52·1·38 (m，1H)，1.15 (d，J=7 Hz， 3H)。MS (DCI-NH3) [M+H] + 364。 實例11 (2 R) - 21 基:1 -農查度 異p咢唑 標題化合物係依實例3A-3C之方法製備，但改用3,5_二甲 基-4-異1唑基二羥硼酸替代實例3八之弘乙醯基苯基二羥硼 酸（38 mg，收率 U% )。屯 NMR (CD3OD，300 ΜΗζ) δ 7.95 (dd， J-2，12，2H)，7.85 (dbr，J=12 Hz，2H)，7.56-7.45 (m，2H)， 3.84-3.65 (m? 2H)? 3.63-3.47 (m5 1H), 3.43-3.15 (m, 4H)5 2.46 (s，3H)，2.42-2.26 (m，1H)，2.30 (s，3H)，2.21-2.01 (m， 2H)5 1.84- 1.68 (m? m)5 1.48 (d? J=7 Hz, 3H) 〇 MS (DCI.NH3) [M+H]+ 335。 實例12 甲基VI-吡咯啶某1 Λ某卜2-茗基）苯基氰 標題化合物係依實例1Η之方法製備，但其中改用（2S)-2-峨&quot;各呢基甲醇替代（2R)-2-甲基吡咯啶。iH NMR (CD3〇D， 300 MHz) δ 8·13 (s，1H)，7.87-7.96 (m，4H)，7.71-7.85 (m， 4H)5 7.41 (d. J-6Hz? 1H)5 3.5 1-3.64 (m? 2H)? 3.2-3.34 (m5 2H)，I93-3·1 (m，2H)，2.69-2.75 (m，2H)，2.4 (q，J二6 Hz， 1H)，L9-2·4 (m，叩，1.95-2.05 (m，2H)，1.81-1.91 (m，lH)。 MS (DCI-NH3) [M+H]+ 357 〇 89248.doc -115 - 200418454 t Μ 13 -—H.咯堂^丄乙基卜2 -萁某、芄其i τ I化a物係依貫例1H之方法製備，但其中改用 比口疋醇替代（2R)-2-甲基吡咯啶。4 NMR (CD3〇D，300 MHz) δ 8.13 (s? ιΗ)5 7.87-7.96 (m? 4H)? 7.71-7.85 (m, 4H), 7.41 (d’ J 6 Hz，1H)，4.34-4.43 (m，ih)，2.82-3.08 (m，6H)， 2.67 2.78 (m5 1H)9 2.61 (d5 J=5.7 Hz? 1H)3 2.1 1-2.24 (m, 1H)? 1·71 2·03 (m，1H)。MS (DCI-NH3) [M+H]+ 343。 令 實例Li 卜吡咯盡乙基-2-萁某i苯玉^ 標題化合物係依實例1H之方法製備，但其中改用孓異丁 基吡各啶替代（2R)-2-甲基吡啥啶。ljj NMR (cd3〇d，3仙 MHz) δ 8.13 (s，1Η)，7.87-7·96 (m，4Η)，7·71-7 85 (m，4H)， 7.41 (d，J=6 Hz，1H)，3·31-3·44 (m，2H)，2.9_311 (m，2H)， 2.4-2.53(m，2H)，2.31(q，J=5.7Hz)，1.9-2.12(m，2H)，l.4-1.65 (m，3H)，1.22-1.36 (m，1H)，·92 (d，J二5.6 Hz，3H)，.87 (d, J-5.6 Hz，3H)。MS (DCI-NH3) [m+H]+ 383。The title compound was prepared according to the method of Example 8, but the 3-pyridyl group was replaced by boric acid instead of 4-p-pyridyl group by boric acid (16 mg, yield 26%). NMR (CD3OD, 300 MHz) δ 9.35-9.32 (m, 1H), 9.11-9.06 (m, 1H), 8.89-8.85 (m, 1H), 8.41 (d, J = 2 Hz, 1H), 8 · 26-8 · 20 (m, 1H), 8.08 (t, J 2 9 Hz, 2H), 7.98-7.93 (m, 2H), 7.62 (dd, J = 2, 12 Hz, 1H), 3.86-3.69 (m, 2H), 3.65-3.49 (m, 1H), 3.45-3.22 (m, 4H), 2.43-2.31 "m, 1H), 2.23-2.01 (m, 2H), 1.86-1.71 (m, 1H) , 1.51 (d, J = 7 Hz, 3H). MS (DCI-NH3) [M + H] + 317. Example 10 (j · .-like base.) (6- {2-「(2R)- 2-Methyl-Bisamidol &quot; [ethyl} _2-:: yl) Methanol was added dropwise to a 1.7 mM dibutyl dipentyl sintered solution (0.41 mL, 0.69 1 mmol '2.2 angstroms) ) To -78 C in a stirred solution of the product of Example 2B (loo mg, 0.314 mmol) in anhydrous THF (3 mL). After stirring the reaction mixture at -78 for 20 minutes, 3-fluorobenzaldehyde (0.04) was added dropwise. mL, 377 mmol, 1.2 eq.) into the reaction mixture. After stirring at -78 ° C for 10 minutes, the reaction mixture was brought back to the main dish and then separated in ethyl acetate and saturated Na] C03 solution. Between. The organic layer was dehydrated (magnesium sulfate) and filtered. The filtrate The solution was concentrated under pressure, and the residue was purified by preparative TLC (95: 5: trace dichloromethane / methanol / NIj40h). The product-containing band was isolated, and 95: 5: trace dichloromethane / methanol / NH4OH. The resulting solution was concentrated under reduced pressure to give the product of the free base as a white solid (3.2 mg, yield 2.5%). 4 NMR (CD30D, 300 ΜΗζ) δ 7.84-7.72 (m, 3Η), 7.66 -7.63 (m, 1Η), 7.42-7.26 (m, 3Η), 89248.doc -114- 200418454 7.22-7.13 (m? 2H), 6.98-6.91 (m? 1H) 5 5.91 (s5 1H), 3.32- 3.23 (m, 1H), 3.19-3.09 (m, 2H), 2.51-2.26 (m, 3H), 2.06-194 (called 1H), 1.85-1.74 (m, 2H), 1.52 · 1 38 (m, 1H), 1.15 (d, J = 7 Hz, 3H). MS (DCI-NH3) [M + H] + 364. Example 11 (2 R)-21 group: 1-Nongchaduisopoxazole The title compound was prepared according to the method of Examples 3A-3C, but 3,5-dimethyl-4-iso1azolyldihydroxy was used instead. Boric acid was used in place of Example 3 Yashiro acetamidophenyl dihydroxyboronic acid (38 mg, yield U%). Tun NMR (CD3OD, 300 MHz) δ 7.95 (dd, J-2, 12, 2H), 7.85 (dbr, J = 12 Hz, 2H), 7.56-7.45 (m, 2H), 3.84-3.65 (m? 2H )? 3.63-3.47 (m5 1H), 3.43-3.15 (m, 4H) 5 2.46 (s, 3H), 2.42-2.26 (m, 1H), 2.30 (s, 3H), 2.21-2.01 (m, 2H) 5 1.84- 1.68 (m? M) 5 1.48 (d? J = 7 Hz, 3H) 〇MS (DCI.NH3) [M + H] + 335. Example 12 The title compound of methyl VI-pyrrolidine 1 1 Λ certain 2-fluorenyl) phenyl cyanide was prepared according to the method of Example 1, but in which (2S) -2-E &quot; 2R) -2-methylpyrrolidine. iH NMR (CD3OD, 300 MHz) δ 8.13 (s, 1H), 7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H) 5 7.41 (d. J-6Hz? 1H) 5 3.5 1-3.64 (m? 2H)? 3.2-3.34 (m5 2H), I93-3 · 1 (m, 2H), 2.69-2.75 (m, 2H), 2.4 (q, J 2 6 Hz, 1H), L9 -2.4 (m, 叩, 1.95-2.05 (m, 2H), 1.81-1.91 (m, 1H). MS (DCI-NH3) [M + H] + 357 〇89248.doc -115-200418454 t Μ 13 --- H. Slightly ^ ethyl ethyl 2- 2-, and its i τ I-α a system was prepared according to the method of Example 1H, but in which the (2R) -2-A Pyrrolidine. 4 NMR (CD30D, 300 MHz) δ 8.13 (s? ΙΗ) 5 7.87-7.96 (m? 4H)? 7.71-7.85 (m, 4H), 7.41 (d 'J 6 Hz, 1H) , 4.34-4.43 (m, ih), 2.82-3.08 (m, 6H), 2.67 2.78 (m5 1H) 9 2.61 (d5 J = 5.7 Hz? 1H) 3 2.1 1-2.24 (m, 1H)? 1.71 2 · 03 (m, 1H). MS (DCI-NH3) [M + H] + 343. Let Example Li Bupyrrole ethyl-2- 萁 i benzene jade ^ The title compound was prepared according to the method of Example 1H, However, instead of (2R) -2-methylpyridine, 孓 isobutylpyridine was used instead. Ljj NMR (cd30d, 3 sen MHz) δ 8.13 (s, 1Η), 7.87-7 · 96 (m , 4Η), 7.71 -7 85 (m, 4H), 7.41 (d, J = 6 Hz, 1H), 3.3-31-3 · 44 (m, 2H), 2.9_311 (m, 2H), 2.4-2.53 (m, 2H) , 2.31 (q, J = 5.7Hz), 1.9-2.12 (m, 2H), 1.4-1.65 (m, 3H), 1.22-1.36 (m, 1H), · 92 (d, J = 5.6 Hz, 3H), .87 (d, J-5.6 Hz, 3H). MS (DCI-NH3) [m + H] + 383.

實例U 基-1-吡咯乙基_2_茬某 標題化合物係依實例1H之方法製備，但其中改用孓異丙 基峨洛咬替代（2R)-2-甲基吡咯啶。iH NMR (CD3〇d，3〇〇 MHz) δ 8.13 (s，1H)，7.87-7.96 (m，4H)，7.71-7.85 (m，4H)， 7·41 (d，J=6 Hz，1H)，3.11-3.22 (m，1H)，mu] (m，2H)， 2.46-2.62 (m5 1H), 2.41-2.45 (m?2H)5 1.8-1.93 (m) 1H)? S9248.doc -116- 200418454 1.68-1.8 (m，4H)，1.54-1.63 (m 1H)，.92 (d，J=5.6 Hz，3H)，.79 (d，J=5.6 Hz，3H)。MS (DCI-NH3) [M+H]+ 369。 實例16 4J6-(2-「（3R)-3-(二甲基胺基）-1-吡咯啶某1乙某卜2-¾:某）茉 基氰 標題化合物係依實例1H之方法製備，但其中改用 (3R)-N，N-二甲基-3-吡咯啶胺替代（2R)-2-甲基吡咯啶。4 NMR (CD3〇D，300 ΜΗζ) δ 8.13 (s，1H)，7.87-7.96 (m, 4H)， 7.71-7.85^ (m，4H)，7·41 (d. J=6 Hz，1Η)，2.98-3.08 (m，4H)， 2.83-2.95 (m，3H)，2.72-2.76 (m，1H) 2.5-2.58 (m，1H)，2.31 (s，6H)，2.01-2.13 (m，1H)，1.75-1.85 (m，lH)。MS (DCI-NH3) [M+H]+ 370。 實例17Example U-yl-1-pyrroleethyl_2_ Some of the title compounds were prepared according to the method of Example 1H, but instead of (2R) -2-methylpyrrolidin, isopropyl erlotene was used instead. iH NMR (CD3Od, 300MHz) δ 8.13 (s, 1H), 7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d, J = 6 Hz, 1H ), 3.11-3.22 (m, 1H), mu] (m, 2H), 2.46-2.62 (m5 1H), 2.41-2.45 (m? 2H) 5 1.8-1.93 (m) 1H)? S9248.doc -116 -200418454 1.68-1.8 (m, 4H), 1.54-1.63 (m 1H), .92 (d, J = 5.6 Hz, 3H), .79 (d, J = 5.6 Hz, 3H). MS (DCI-NH3) [M + H] + 369. Example 16 The title compound of 4J6- (2-"(3R) -3- (dimethylamino) -1-pyrrolidine, 1 ethyl, 2 2-::, 2) was prepared according to the method of Example 1H. However, (3R) -N, N-dimethyl-3-pyrrolidinamine was used instead of (2R) -2-methylpyrrolidine. 4 NMR (CD30D, 300 ΜΗζ) δ 8.13 (s, 1H) , 7.87-7.96 (m, 4H), 7.71-7.85 ^ (m, 4H), 7.41 (d. J = 6 Hz, 1Η), 2.98-3.08 (m, 4H), 2.83-2.95 (m, 3H ), 2.72-2.76 (m, 1H) 2.5-2.58 (m, 1H), 2.31 (s, 6H), 2.01-2.13 (m, 1H), 1.75-1.85 (m, 1H). MS (DCI-NH3) [M + H] + 370. Example 17

乙 1-2-¾:某 1茉某 I 標題化合物係依實例1H之方法製備，但其中改用二乙基 月女曰代（2R)|甲基p比哈淀。iH NMR (cD3〇D，3〇〇 ΜΗζ) δ 8.13 (s3 1Η)5 7.87^7.96 (m? 4Η)? 7.71^7.85 (m? 4Η)5 7.41 (d. ，1Η)’ 3,53 (t，J==3·3 Ηζ，2Η)，3·31 (q，J=3.6 Ηζ，4Η)， 3.22 (t, J=3.3 JT7 otj\ ，H)，1.35 (t，J=3.6 Hz，6H)。MS (DCI-NH3) [M+H]+ 329 〇 4-{6-Γο 甲基胺基）乙基]-2-審基}苯基氰 — 才禾過化合物係你余 扶 ’、只列1H之方法製備，但其中改二甲基胺 曰代（2R)-2-甲基比 土 ^各呢。iHNMRWhODdooMHeu.u 89248.doc -117- 200418454 (s，1H)，7.87-7.96 (m，4H)，7.71-7.85 (m，4H)，7.41 (d· J = 6Ethyl 1-2-¾: The title compound was prepared according to the method of Example 1H, but it was replaced by diethyl hydrazone (2R) | methyl p Bihadian. iH NMR (cD3OD, 300MΗζ) δ 8.13 (s3 1Η) 5 7.87 ^ 7.96 (m? 4Η)? 7.71 ^ 7.85 (m? 4Η) 5 7.41 (d., 1Η) '3,53 (t , J == 3 · 3 Ηζ, 2Η), 3.31 (q, J = 3.6 Ηζ, 4Η), 3.22 (t, J = 3.3 JT7 otj \, H), 1.35 (t, J = 3.6 Hz, 6H ). MS (DCI-NH3) [M + H] + 329 〇 4- {6-Γο methylamino) ethyl] -2-hexyl} phenyl cyanide — the only chemical compound you Yufu ', only listed It is prepared by the method of 1H, but the dimethylamine is replaced by (2R) -2-methyl-pyridine. iHNMRWhODdooMHeu.u 89248.doc -117- 200418454 (s, 1H), 7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d · J = 6

Hz，1H)，3.49-3.54 (t，J二3.3 Hz，2H)，3.23-3.28 (t，J=3.3 Hz， 2H)，2.97 (s，6H)。MS (DCI-NH3) [M+H]+ 301。 實例19 (異丙基）胺基1乙某:某 標題化合物係依實例1H之方法製備，但其中改用異丙基 乙基胺替代（2R)-2-甲基吡咯啶。NMR (CD3〇D，300 MHz) δ 8.13 (s，1H)，7.87-7.96 (m，4H)，7.71-7.85 (m，4H)，7·41 (d， J=6 Hz，；H)，3.8-3.87 (m，1H)，3.1-3.57 (m，6H)，1·3η·45 (m，9H)。MS (DCI-NH3) [M+H]+ 343。 實例20 基,（甲基）胺AL乙基卜2-客某）革Μ 標題化合物係依實例1 η之方法製備，但其中改用第三丁 基甲基胺替代（2R)-2-甲基吡咯啶。咕NMR (CD3〇d，3〇〇 MHz) δ 8.13 (s，1H)，7.87-7.96 (m，4H)，7,71-7.85 (m，4H)， 7·41 (d，J=6 Hz，1H)，3.68-3.75 (m，1H)，3 3_3·43 (m，2H)， 2.31-3.28 (m? 1H)5 3.11-3.19 (m51 H)? 2.7 (s, 3H)5 1.45 (s5 9H) 。MS (DCI-NH3) [M+H]+ 343。 實例21 吡咯宜羞丄乙某}_2_:甚、1其# 標題化合物係依實例1H之方法製備，但其中改用（2s)_2_ 甲基吡咯啶替代（2R)_2_甲基吡咯啶。lH NMR (CD3〇D，3⑼ MHz) δ 8.13 (s, 1H), 7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d, J=6 Hz, 1H), 3.34-3.45 (m, 1H), 3.24-3.35 (m, 1H), 89248.doc -118- 200418454 2.97-3.18 (m5 2H)? 2.55-2.78 (m5 3H)5 2.02-2.15 (m5 iH) 1.82-1.94 (m，2H)，1.48-1.59 (m，1H)，i.ii (d，&gt;6 Hz，3H)。 MS (DCI-NH3) [M+H]+ 341。 實例22 4·二..(6-{2·!!^^-基-卜六氯吨^乙基}_2_:某n 標題化合物係依實例1H之方法製備，但其中改用（2R)_2_ 曱基六氫吡啶替代（2R)_2_曱基吡咯啶。1H NMR (CD30D， 300 MHz) δ 8.13 (s，1H)，7.87-7.96 (m，4H)，7.71-7.85 (m, 4H)，7.U(d，Hz，1H)，2.86-3.13 (m，5H)，2•休2 55 (m， 2H)，1.67-1.81 (m，4H)，1.33-1.46(m，2H)，1.08 (d，J=6 Hz， 3H)。MS (DCI-NH3) [M+H]+ 355。 實例23 氫-1H-被咯-1-基丄^基萁某}1葚氰 標題化合物係依實例1H之方法製備，但其中改用2，弘二 氫-1H-哈替代（2R)-2-甲基吡咯啶。iH NMR (CD3〇d，3〇〇 MHz) δ 8·13 (s，1H)，7.87-7.96 (m，4H)，7.71-7.85 (m，4H)， 7·41 (d，J=6 Hz，1H)，5.83,（s，2H)，3·57 (m，4H)，2.99 (m， 4H)。MS (DCI-NH3) [M+H]+ 325。 f例24 4-(6-{2-[甲基（丙基）胺基]乙基卜2-莕基）苯基氰 才*題化合物係依實例1Η之方法製備，但其中改用丙基甲 基胺替代（2R)-2-甲基口比嘻淀。1H NMR (CD3〇D，300 MHz〇 δ 8·13 (s，1Η)，7.87-7.96 (m，4Η)，7.71-7.85 (m，4Η), 7.41 (d， &gt;6 Hz，1H)，2.94-3.03 (m，2H)，2.74-2.81 (m，2H)，2.45-2.53 89248.doc -119- 200418454 (m，2H)，2.38 (s，3H)，1.51-1.65 (m，2H)，.91(1，J=6.3 Hz，3H) 。MS (DCI-NH3) [M+H]+ 329。 實例25 基）（甲基）胺基i乙某卜2-苯苯基氰 標題化合物係依實例1H之方法製備，但其中改用2_(甲基 胺基）乙醇替代（2R)-2-甲基吡咯啶。h NMR (CD3〇D，300Hz, 1H), 3.49-3.54 (t, J = 3.3 Hz, 2H), 3.23-3.28 (t, J = 3.3 Hz, 2H), 2.97 (s, 6H). MS (DCI-NH3) [M + H] + 301. Example 19 (Isopropyl) amino 1 ethyl: The title compound was prepared according to the method of Example 1H, but in this case, isopropyl ethylamine was used instead of (2R) -2-methylpyrrolidine. NMR (CD3OD, 300 MHz) δ 8.13 (s, 1H), 7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d, J = 6 Hz, H), 3.8-3.87 (m, 1H), 3.1-3.57 (m, 6H), 1 · 3η · 45 (m, 9H). MS (DCI-NH3) [M + H] + 343. Example 20 The title compound was prepared according to the method of Example 1 η, except that the (2R) -2-methylpyrrole was replaced with a third butyl methylamine. Pyridine. NMR (CD3Od, 300MHz) δ 8.13 (s, 1H), 7.87-7.96 (m, 4H), 7,71-7.85 (m, 4H), 7.41 (d, J = 6 Hz , 1H), 3.68-3.75 (m, 1H), 3 3_3 · 43 (m, 2H), 2.31-3.28 (m? 1H) 5 3.11-3.19 (m51 H)? 2.7 (s, 3H) 5 1.45 (s5 9H). MS (DCI-NH3) [M + H] + 343. Example 21 Pyrrole should be used in a certain state} _2_: even, 1qi # The title compound was prepared according to the method of Example 1H, but (2s) _2_methylpyridine was used instead of (2R) _2_methylpyrrolidine. lH NMR (CD3OD, 3⑼ MHz) δ 8.13 (s, 1H), 7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d, J = 6 Hz, 1H), 3.34- 3.45 (m, 1H), 3.24-3.35 (m, 1H), 89248.doc -118- 200418454 2.97-3.18 (m5 2H)? 2.55-2.78 (m5 3H) 5 2.02-2.15 (m5 iH) 1.82-1.94 ( m, 2H), 1.48-1.59 (m, 1H), i.ii (d, &gt; 6 Hz, 3H). MS (DCI-NH3) [M + H] + 341. Example 22 4 · II .. (6- {2 · !! ^^-yl-buhexachlorot ^ ethyl} _2_: An n title compound was prepared according to the method of Example 1H, but (2R) _2_ was used instead. Fluorenylhexahydropyridine instead of (2R) _2_fluorenylpyrrolidine. 1H NMR (CD30D, 300 MHz) δ 8.13 (s, 1H), 7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.U (d, Hz, 1H), 2.86-3.13 (m, 5H), 2 · 25 2 (m, 2H), 1.67-1.81 (m, 4H), 1.33-1.46 (m, 2H), 1.08 (d, J = 6 Hz, 3H). MS (DCI-NH3) [M + H] + 355. Example 23 Hydrogen-1H-pyrrole-1-yl 丄 ^ yl 萁 1} The title compound is based on cyanide Prepared according to the method of Example 1H, but in which 2,2'-dihydro-1H-Ha was used instead of (2R) -2-methylpyrrolidine. IH NMR (CD3Od, 300MHz) δ 8 · 13 (s, 1H ), 7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d, J = 6 Hz, 1H), 5.83, (s, 2H), 3.57 (m, 4H) , 2.99 (m, 4H). MS (DCI-NH3) [M + H] + 325. fExample 24 4- (6- {2- [methyl (propyl) amino] ethyl 2-fluorenyl ) The compound of phenyl cyanocyanine * title was prepared according to the method of Example 1Η, but propylmethylamine was used instead of (2R) -2-methyl orbital. 1H NMR (CD3OD, 3 00 MHz 0δ 8.13 (s, 1Η), 7.87-7.96 (m, 4Η), 7.71-7.85 (m, 4Η), 7.41 (d, &gt; 6 Hz, 1H), 2.94-3.03 (m, 2H ), 2.74-2.81 (m, 2H), 2.45-2.53 89248.doc -119- 200418454 (m, 2H), 2.38 (s, 3H), 1.51-1.65 (m, 2H), .91 (1, J = 6.3 Hz, 3H). MS (DCI-NH3) [M + H] + 329. Example 25 The (meth) amino (ethyl) -2-phenylphenylcyanide title compound was prepared according to the method of Example 1H. However, 2- (methylamino) ethanol was used instead of (2R) -2-methylpyrrolidine. H NMR (CD30D, 300

MHz) δ 8·13 (s，1H)，7·87-7·96 (m，4H)，7.71-7.85 (m，4H)， 7·41 (d，J=6 Ηζ，1Η)，3·67 (t，J=6 Ηζ，2Η)，2.96-3.04 (m，2Η)， 2.90-2.98,（m，2H)，2.66 (t，J=5.3 Hz，2H)，2.42 (s，3H)。MS (DCI-NH3) [M+H]+ 331。 實例26 lz_(6-{2-「（2R)-2 -甲基·1-吡咯啶某1乙某卜2-¾:某咗MHz) δ 8 · 13 (s, 1H), 7.87-7 · 96 (m, 4H), 7.71-7.85 (m, 4H), 7 · 41 (d, J = 6 Ηζ, 1Η), 3 · 67 (t, J = 6 Ηζ, 2Η), 2.96-3.04 (m, 2Η), 2.90-2.98, (m, 2H), 2.66 (t, J = 5.3 Hz, 2H), 2.42 (s, 3H). MS (DCI-NH3) [M + H] + 331. Example 26 lz_ (6- {2-"(2R) -2 -methyl · 1-pyrrolidine, 1B, 1B, 2-2- ::

實例26A 12-(6-溴-2-苯基）乙氧基1(第三丁某）二曱基矽烷 取含實例 1E產物（2.51 g，10 mmol)、咪口坐（0.715 g，10.5 mmol，1·〇5 當量）與 DMAP (8 mg，0.066 mmol，0.0060 當量） 之無水二氯甲烷（65 mL)攪拌溶液於與無水氮蒙氣下冷 卻。慢慢慢添加含第三丁基二甲基矽烷基氯之無水二氯甲 :^元（1 5 mL) /谷液至反應混合物中。當添加完畢時，使反應混 合物回升至室溫’授拌18小時。添加檸檬酸水溶液（1 〇%) 至反應此合物中。有機層經鹽水洗務後，脫水（硫酸鎮）與過 濾。濾液減壓濃縮，殘質經管柱層析法純化（1 00%己院）： 取含產物之溶離份合併與減壓濃縮，產生白色固體產物 (3.25 g，收率 89%)。4 NMR (CDC13, 3 00 ΜΗζ) δ 7.95 (d，J =2 89248.doc -120- 200418454Example 26A 12- (6-bromo-2-phenyl) ethoxy 1 (third butyl) difluorenyl silane. The product containing the product of Example 1E (2.51 g, 10 mmol), and acetone (0.715 g, 10.5 mmol) , 1.05 eq.) And DMAP (8 mg, 0.066 mmol, 0.0060 eq.) In a stirred solution of anhydrous dichloromethane (65 mL) was cooled under an atmosphere of dry nitrogen. Slowly add anhydrous dichloromethane (15 mL) / valley solution containing tert-butyldimethylsilyl chloride to the reaction mixture. When the addition is complete, the reaction mixture is allowed to warm to room temperature 'and allowed to stir for 18 hours. Aqueous citric acid (10%) was added to the reaction mixture. After the organic layer was washed with brine, it was dehydrated (sulfate ballast) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (100%). The fractions containing the product were combined and concentrated under reduced pressure to give a white solid product (3.25 g, yield 89%). 4 NMR (CDC13, 3 00 ΜΗζ) δ 7.95 (d, J = 2 89248.doc -120- 200418454

Hz，1H)，7.68-7.60 (m，3H)，7·50 (dd，J=2，12 Hz，1H)，7.37 (dd，J二2，12 Hz，1H)，3.88 (t，J=6Hz，2H)，2.96 (t，J二6 Hz， 2H)，1.46 (s，9H)，-〇·〇4 (s，6H)。MS (DCI-NH3) [M+H]+ 365, [M+NH4]+ 382。Hz, 1H), 7.68-7.60 (m, 3H), 7.50 (dd, J = 2, 12 Hz, 1H), 7.37 (dd, J-2, 12 Hz, 1H), 3.88 (t, J = 6Hz, 2H), 2.96 (t, J = 6 Hz, 2H), 1.46 (s, 9H), -0.04 (s, 6H). MS (DCI-NH3) [M + H] + 365, [M + NH4] + 382.

實例26B Ι^ΧΑΐ^_Αΐ{2-「6-(4,4.5.5-四甲基-1,3,2-二氣硼戊環 i基V2-苯某1乙氣基丨矽烷 取含灵例26八產物（92〇11]^，2.518 111111〇1)、？(1(0八〇)2(28 11^ ’ 0.126 ;nmol，〇·〇5當量）、2-(二環己基膦基）聯苯（176 mg ’ 0.504 mmol，0.2 當量）與 Et3N (1.4 mL，10.07 mmo卜 4 當 I)之二呤烷（15 mL)溶液於無水氮蒙氣與於室溫下攪拌。滴 加四甲基乙二醇甲硼烷（11 mL，7.553 mmol，3當量）至反 應混合物中。當添加完畢時，反應於8(^c下攪拌丨小時。冷 卻至室溫後，反應混合物減壓濃縮。殘質分溶於飽和Nh4c 1 水溶液與Et2〇之間。有機層脫水（硫酸鎂），過漉。濾液減壓 濃縮，殘質經管柱層析法純化（98 : 2己烷/乙酸乙酯）。取含 產物之溶離份合併與減壓濃縮，產生黃色固體產物（66〇mg ，收率 64%)。NMR (CDC13, 300 MHz) δ 8.32 (d，J=2 Hz，1H)， 7.83- 7.77 (m，3H)，7.64-7.62 (m，1H)，7·33 (dd，J =2，12Hz， 1H), 4.51 (t5 5.7 J-Hz, 2H)5 3.22 (t5 J-5.7 Hz? 2H)? 1.39, (s5 12H)，0.86 (s，9H)，0.04 (s，6H)。MS (DCI-NH3) [M+NH4]+ 430。 實例26C ' 三丁基（二甲基）矽烷基1氣丨乙基V2-:某1嘧畦 取含實例 26B產物（206 mg，0.5 mmol)、5-溪 p密淀（79.5 mg 89248.doc -121 - 200418454 ，0.5 mmol)、Pd(PPh3)4 (28·9 mg，0.025 mmo卜 0.05當量） 與Na2C〇3(106mg，1 mmol，2當量）之甲苯（10mL)與蒸館水 (1.5 mL)溶液於回流下與無水氮蒙氣下攪拌3小時。冷卻至 室溫後，混合物減壓濃縮，殘質分溶於乙酸乙酯與飽和 NasCO3水溶液之間。有機層脫水（硫酸鎂）與過濾。濾液減 壓濃縮，殘質經管柱層析法純化（8 : 2己烷/乙酸乙酯）。取 含產物之溶離份合併與減壓濃縮，產生灰白色固體產物（57 mg，31%)。'Η NMR (CDC13, 300 ΜΗζ) δ 9·23 (sbr，1H)，9.08 (sbr，2Η)，，8·02 (d5 卜2 Ηζ，1Η)，7·93 (dbr，J=7 Ηζ，1Η)，7·86 (dbr，J=7 Hz，1H)，7·72 (Sbr，1H)，7.66 (dd，&gt;2, 12 Hz，1H)， 7.44 (dd，J=2，12 Hz，1H)，3.92 (1，J=6 Hz，2H)，3.01 (1，J=6 Hz, 2H), 0.88 (s，9H)，-〇·〇2 (s，6H)。MS (DCI-NH3) [M+H] + 365 °Example 26B I ^ χΑΐ ^ _Αΐ {2- "6- (4,4.5.5-tetramethyl-1,3,2-difluoroboranyl i-group V2-benzene 1 ethyl acetyl group silane Example 26 Eight products (92〇11) ^, 2.518 111111〇1),? (1 (080) 2 (28 11 ^ '0.126; nmol, 0.05 equivalent), 2- (dicyclohexylphosphine) ) A solution of biphenyl (176 mg '0.504 mmol, 0.2 equivalent) and Et3N (1.4 mL, 10.07 mm) (4 mL) of dioxin (15 mL) in anhydrous nitrogen and stirred at room temperature. Add four Methyl glycol borane (11 mL, 7.553 mmol, 3 eq.) Was added to the reaction mixture. When the addition was complete, the reaction was stirred at 8 ° C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in a saturated aqueous solution of Nh4c 1 and Et20. The organic layer was dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (98: 2 hexane / ethyl acetate). ). The fractions containing the product were combined and concentrated under reduced pressure to give a yellow solid product (66 mg, yield 64%). NMR (CDC13, 300 MHz) δ 8.32 (d, J = 2 Hz, 1H), 7.83 -7.77 (m, 3H), 7.64-7.62 (m, 1H), 7.33 (dd, J = 2 12Hz, 1H), 4.51 (t5 5.7 J-Hz, 2H) 5 3.22 (t5 J-5.7 Hz? 2H)? 1.39, (s5 12H), 0.86 (s, 9H), 0.04 (s, 6H). MS ( DCI-NH3) [M + NH4] + 430. Example 26C 'Tributyl (dimethyl) silyl 1 gas 丨 Ethyl V2-: a pyrimidine containing the product of Example 26B (206 mg, 0.5 mmol), 5-xi p dense lake (79.5 mg 89248.doc -121-200418454, 0.5 mmol), Pd (PPh3) 4 (28.9 mg, 0.025 mmo, 0.05 equivalent) and Na2CO3 (106 mg, 1 mmol, 2 equivalents) ) The solution of toluene (10mL) and distilled water (1.5mL) was stirred under reflux with anhydrous nitrogen for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and saturated NasCO3. Between aqueous solutions. The organic layer was dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (8: 2 hexane / ethyl acetate). The fractions containing the product were combined and concentrated under reduced pressure. , Yielding an off-white solid product (57 mg, 31%). Η NMR (CDC13, 300 ΜΗζ) δ 9 · 23 (sbr, 1H), 9.08 (sbr, 2Η), 8.02 (d5 2 2 Ηζ, 1Η ), 7.93 (dbr, J = 7 Ηζ, 1Η), 7.86 (dbr, J = 7 Hz, 1H), 7.72 (Sbr, 1H), 7.66 (dd, &gt; 2, 12 Hz, 1H), 7.44 (dd, J = 2, 12 Hz, 1H), 3.92 (1, J = 6 Hz, 2H), 3.01 (1, J = 6 Hz, 2H), 0.88 (s, 9H), -0.02 (s, 6H). MS (DCI-NH3) [M + H] + 365 °

實例26D 密啶基篇某1乙醇 取 έ 貝例 26C產物（56 mg，〇· 154 mmol)與 TBAF · H2〇（48 mg，0·184 mmol，1·2當量）之丁HF (3 mL)溶液於室溫與無水 氮冡氣下攪拌30分鐘。混合物分溶於乙酸乙酯與飽和 Na2C〇3水溶液之間。有機層經鹽水洗滌，然後脫水（硫酸鎂） 與過濾。濾液減壓濃縮，產生標題化合物之灰白色固體（32 mg，收率83%)，未再純化即用於下一個步驟。 實例26E &quot; 1·橫酸嘧啶甚V2-苯甚1啼 標題化合物係依實例3]8之方法製備’但其中改用實例 89248.doc •122- 200418454 26D產物替代實例3A產物，產生灰白色固體。Example 26D Methimidine based on 1 ethanol extraction Example 26C product (56 mg, 0.154 mmol) and TBAF · H20 (48 mg, 0.184 mmol, 1.2 equivalents) butane HF (3 mL) The solution was stirred at room temperature under anhydrous nitrogen gas for 30 minutes. The mixture was partitioned between ethyl acetate and saturated aqueous Na2CO3 solution. The organic layer was washed with brine, then dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure to give the title compound as an off-white solid (32 mg, yield 83%), which was used in the next step without further purification. Example 26E &quot; 1. Pyridamidine V2-benzoxyl 1 The title compound was prepared according to the method of Example 3] 8 ', but the Example 89248.doc • 122- 200418454 26D product was used instead of the product of Example 3A to produce an off-white solid .

Aj^L26F 乙基卜2-苯基）嘧啶 柃々化口物係依貫例3C之方法製備，但其中改用實例me 產物曰代見例3B產物（17 mg，收率36%)。iH NMR (Cd3〇d， 300 MHz) δ 9·35 (sb。2H)，9·28 (sb。1Η)，8·32 (d，1=2 Hz， 1H)5 8.09-8.03 (m, 2H)5 7.94-7.88 (m? 2H)? 7.60-7.55 (m5 1H)，3.85-3.69 (m，2H)，3.62-3.50 (m，ih)，3.44-3.18 (m， 4H)，2.43-2.30 (m，1H)，2.27-2.01 (m，2H)，1.84-1.70 (m, 1H)，1.50 (d，J=6 Hz，3H)。MS (DCI-丽3) [m+H]+ 318。 實例27 基-l-吡i啶基1乙某卜？_苏基）嗎啉 取 έ 貝例 2B產物（318 mg，1·0 mm〇i)、嗎淋（0.87 mL，ι·〇Aj ^ L26F ethyl ethyl 2-phenyl) pyrimidine The peptone was prepared according to the method of Example 3C, but the product of Example me was replaced by the product of Example 3B (17 mg, yield 36%). iH NMR (Cd30d, 300 MHz) δ 9.35 (sb. 2H), 9.28 (sb. 1Η), 8.32 (d, 1 = 2 Hz, 1H) 5 8.09-8.03 (m, 2H ) 5 7.94-7.88 (m? 2H)? 7.60-7.55 (m5 1H), 3.85-3.69 (m, 2H), 3.62-3.50 (m, ih), 3.44-3.18 (m, 4H), 2.43-2.30 ( m, 1H), 2.27-2.01 (m, 2H), 1.84-1.70 (m, 1H), 1.50 (d, J = 6 Hz, 3H). MS (DCI-Li 3) [m + H] + 318. Example 27 Isyl-l-pyridinyl 1 ethyl? _Threo) morpholine Take the product of Example 2B (318 mg, 1.0 mm), Morin (0.87 mL, ι · 〇)

mmol)、Pd2(dba)3 (18·3 mg，0·〇2 mmol，0.02 當量）、（t-Bu)3P (3.6mg，〇·〇16 mmol，0.016當量）與第三丁醇鈉（144 2 mg， 1.5 mmol，1.5當量）之甲苯（2 mL)混合物於室溫與無水氮蒙 氣下攪拌66小時。反應混合物分溶於乙酸乙酯與飽和 NaaCO3水溶液之間。有機層經鹽水洗滌，脫水（硫酸鎂）與 過濾。濾液減壓濃縮，殘質經管柱層析法純化（97 : 3 :微 量之二氯甲烷/甲醇/NH4〇h)。取含產物之溶離份合併，減 壓濃縮，產生之產物溶於EhO中，經HC1 (氣體）處理。此混 合物減壓濃縮’產生產物之二鹽酸鹽，為灰白色吸濕性固 體（100 mg，收率 31%)。咕 NMR (CD3OD，300 ΜΗζ) δ 8.21 (d， J=6 Hz，2H)，8.12-8.00 (m，2H)，7·95 (sbr，3H)，7.80 (dd，J=2, 89248.doc -123 - 200418454 12 Hz，1H)，7.64 (dd，卜2，12 Ηζ，1Η)，4.18_4·13 (m，4H)， 3.94-3.67 (m，2H)，3.92-3.87 (m，4H)，3.63-3.47 (m，1H)， 3.47-3.21 (m，4H)，2.42-2.30 (m，1H)，2.23-2.00 (m，2H), 1.85-1.70 (m，1H)，1.50 (d，J=6 Hz, 3H)° MS (DCI-NH3) [M+H]+ 325。 實例28 ^^.(.6-{2-「（2!1)二^甲基_14比咯啶基~|乙基^2_苯基）_1,3_嘧唑mmol), Pd2 (dba) 3 (18 · 3 mg, 0.02 mmol, 0.02 equivalent), (t-Bu) 3P (3.6 mg, 0.0016 mmol, 0.016 equivalent), and sodium tert-butoxide ( A mixture of 144 2 mg, 1.5 mmol, 1.5 equivalents of toluene (2 mL) was stirred at room temperature under anhydrous nitrogen for 66 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NaaCO3 solution. The organic layer was washed with brine, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (97: 3: micro amount of dichloromethane / methanol / NH40h). The dissolved fractions containing the product were combined and concentrated under reduced pressure. The resulting product was dissolved in EhO and treated with HC1 (gas). This mixture was concentrated under reduced pressure to produce the dihydrochloride salt of the product as an off-white hygroscopic solid (100 mg, yield 31%). NMR (CD3OD, 300 MHz) δ 8.21 (d, J = 6 Hz, 2H), 8.12-8.00 (m, 2H), 7.95 (sbr, 3H), 7.80 (dd, J = 2, 89248.doc -123-200418454 12 Hz, 1H), 7.64 (dd, Bu 2, 12 Ηζ, 1Η), 4.18_4 · 13 (m, 4H), 3.94-3.67 (m, 2H), 3.92-3.87 (m, 4H) , 3.63-3.47 (m, 1H), 3.47-3.21 (m, 4H), 2.42-2.30 (m, 1H), 2.23-2.00 (m, 2H), 1.85-1.70 (m, 1H), 1.50 (d, J = 6 Hz, 3H) ° MS (DCI-NH3) [M + H] + 325. Example 28 ^^. (. 6- {2-"(2! 1) Di ^ methyl-14 pyrrolidinyl ~ | ethyl ^ 2_phenyl) _1,3_pyrazole

實例28A 足二Ι·々-(2-：[「第二甲基）矽烷某〕氫丨Λ基）_2_苯基 標題化合物係依實例26C之方法製備，但其中改用2_溴噻 唑替代5-溴嘧啶（40 mg，收率22%)。lH NMR (CDC13, 3⑽Example 28A Zirconium I-2-(2-: ["Second Methyl) Silane]] Hydrogen 丨 Λ group) 2-phenyl The title compound was prepared according to the method of Example 26C, but 2-bromothiazole was used instead. 5-Bromopyrimidine (40 mg, yield 22%). 1H NMR (CDC13, 3⑽

[M + H]+ 370 〇[M + H] + 370 〇

^it^2~r6-n.3-uf^ 2，：^ it ^ 2 ~ r6-n.3-uf ^ 2 ,:

基]酿 卜但其中改用實例28Β 89248.doc 200418454 產物替代實例3A產物，產生灰白色固體Based] but instead use the product of Example 28B 89248.doc 200418454 instead of the product of Example 3A, resulting in an off-white solid

i^L28Di ^ L28D

苯某 嚓唑 方法製備，但其中改用實例28C 甲某-1-毗呔 標題化合物係依實例3 c之 產物替代實例3B產物（鹽酸鹽，4 mg，收率14%)。巾nmr (CD3OD5 300 MHz) δ 8.55 (d5 J==2 Hz? 1H)? 8.12 (d5 J^3 Hz? 1H), 8.10-8.02 (m, 3H)? 7.95-7.92 (m? iH)? 7.89 (d, J=3 Hz, 1H)，7.61 (dd，&gt;2, 12 Hz，1H)，3.84-3.69 (m，2H)，3.64-3.49 (m，1Η)5ιβ·43·3.19 (m，4H)，2.43-2.30 (m，1H)，2.23-2.00 (m， 2H)，1.83-1.69 (m，1H)，1.50(d，J = 6 Hz，3H)。MS (DCI-NH3) [M+H]+ 323。 實例29 4jLi^m(2s)-2-(氟甲—基）小吡咯啶某1乙某m某）装某氰 標題化合物係依實例1H之方法製備，但其中改用（2s)-2-( 氟甲基）吡咯啶替代（2R)-2_甲基吡咯啶。4 NMR (CD3〇D， 300 MHz) δ 8.13 (s，1H)，7·87-7·96 (m，4H)，7·71-7·85 (m， 4Η)，7·41 (d，J=6 Ηζ，1Η)，4.44 (d，J=1.3 Ηζ，1Η)，4.28 (d， J 二 1·3 Hz，1H)，3.18-3.35 (m，2H)，2.98-3.06 (m，2H)， 2.84-2.99 (m，1H)，2.69-2.78 (M，1H)，2.41-2.53 (m，1H)， 1.92-2.03 (m，1H)，1.75-1.88 ( m，2H)，1.58-1.7 (m，1H)。MS (DCI-NH3) [M+H]+ 359。 實例30 &quot; (3-氟笨基）（6-(2-「(210-2-甲某-14比咯啶某1乙基卜2-羞基）甲酮 取含實例10產物（3.2 mg，0.009 mmol)與二氧化摄（5.4 mg 89248.doc -125 * 200418454 ’〇·062 mmol，7當量）之無水二氯甲烷（1 mL)混合物於室溫 下攪拌3.5小時。反應混合物經矽藻土過濾，濾液減壓濃縮 。殘質經製備性丁LC純化（95 : 5 :微量之二氯甲烷/甲醇 /NH4〇H)。單離出含產物之條帶，以95 : 5 :微量之二氯甲 垸/甲醇/NH4〇H溶離。所得溶液減壓濃縮，產生游離鹼產物 (0.91 mg，收率 28.5%)。4 NMR (CD3OD，3 00 ΜΗζ) δ 8.27 (d， Hz，1H)，8.02-7.86 (m，4H)，7.65-7.51 (m，4H)，7.46-7.39 (m，1H)，3·56-3·37 (m，2Η)，3·26-3·07 (m，2H)，3.02-2.74 (m， 2H)，2.2 4-2.10 (m，1H)，2.02-1.88 (m，2H)，1.69-1.52 (m， 2H), 1.30 (d，J=6 Hz，3H)。MS (DCI-NH3) [M+H]+ 362。 實例3 1Benzoxazole was prepared by the method, but in which Example 28C methyl-1-1-pyridine was used instead. The title compound was replaced with the product of Example 3c according to the product of Example 3c (hydrochloride, 4 mg, yield 14%). Nmr (CD3OD5 300 MHz) δ 8.55 (d5 J == 2 Hz? 1H)? 8.12 (d5 J ^ 3 Hz? 1H), 8.10-8.02 (m, 3H)? 7.95-7.92 (m? IH)? 7.89 (d, J = 3 Hz, 1H), 7.61 (dd, &gt; 2, 12 Hz, 1H), 3.84-3.69 (m, 2H), 3.64-3.49 (m, 1Η) 5 μβ · 43 · 3.19 (m, 4H), 2.43-2.30 (m, 1H), 2.23-2.00 (m, 2H), 1.83-1.69 (m, 1H), 1.50 (d, J = 6 Hz, 3H). MS (DCI-NH3) [M + H] + 323. Example 29 4jLi ^ m (2s) -2- (fluoromethyl-yl) pyrrolidine, 1B, 1M, 2M, and 1C) The title compound was prepared according to the method of Example 1H, but (2s) -2- (Fluoromethyl) pyrrolidine replaces (2R) -2-methylpyrrolidine. 4 NMR (CD3OD, 300 MHz) δ 8.13 (s, 1H), 7.87-7 · 96 (m, 4H), 7.71-7 · 85 (m, 4Η), 7.41 (d, J = 6 Ηζ, 1Η), 4.44 (d, J = 1.3 Ηζ, 1Η), 4.28 (d, J 2 1.3 Hz, 1H), 3.18-3.35 (m, 2H), 2.98-3.06 (m, 2H ), 2.84-2.99 (m, 1H), 2.69-2.78 (M, 1H), 2.41-2.53 (m, 1H), 1.92-2.03 (m, 1H), 1.75-1.88 (m, 2H), 1.58-1.7 (m, 1H). MS (DCI-NH3) [M + H] + 359. Example 30 &quot; (3-Fluorobenzyl) (6- (2-"(210-2-methyl--14-pyridine-1 1-ethyl 2-2-methyl) methanone) contains the product of Example 10 (3.2 mg , 0.009 mmol) and a mixture of dichloromethane (5.4 mg 89248.doc -125 * 200418454 '0 · 062 mmol, 7 eq.) In anhydrous dichloromethane (1 mL) was stirred at room temperature for 3.5 hours. The reaction mixture was passed through diatoms. The filtrate was concentrated under reduced pressure, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative DLC (95: 5: trace amount of dichloromethane / methanol / NH4〇H). The product-containing band was isolated, and 95: 5: trace amount Dichloromethane / methanol / NH4OH was dissolved. The resulting solution was concentrated under reduced pressure to give a free base product (0.91 mg, yield 28.5%). 4 NMR (CD3OD, 3 00 ΜΗζ) δ 8.27 (d, Hz, 1H) , 8.02-7.86 (m, 4H), 7.65-7.51 (m, 4H), 7.46-7.39 (m, 1H), 3.56-3 · 37 (m, 2Η), 3.26-3 · 07 (m , 2H), 3.02-2.74 (m, 2H), 2.2 4-2.10 (m, 1H), 2.02-1.88 (m, 2H), 1.69-1.52 (m, 2H), 1.30 (d, J = 6 Hz, 3H). MS (DCI-NH3) [M + H] + 362. Example 3 1

甲某-lw比咯啶-1-基μ乙基卜2_茗-2-基）-2H-嗒畊-3-酮 實例31A (6-溴-萁-2-基V甲醇Methyl-lw than pyrrolidin-1-yl μethylbuthen-2-yl-2-yl) -2H-dagen-3-one Example 31A (6-bromo-fluoren-2-yl V methanol

在攪拌之1.0 Μ氫化經銘溶液（108 mL，108 mmol)中，以 20分鐘時間滴加6-溴-2-莕甲酸甲酯（18.9g，71.3 mmol)之 THF (180 mL)溶液，同時保持反應溫度在-5°C以下。當添加 完畢時，反應混合物於-10°C下攪拌1小時，然後依序滴加 悉館水（4 mL)、2N Na2C〇3水溶液（4 mL)與蒸館水（12 mL) 中止反應。於室溫下攪拌15分鐘後，反應混合物過濾。濾 塊經乙酸乙酯（3 X 100 mL)洗滌，合併之濾液脫水（硫酸‘） 與過濾。此濾液減壓濃縮，產生之白色固體於40°C下真空乾 燥一夜，產生產物（16.84 g，收率 99%)。M.p. 149.9-151.6 °C 89248.doc -126- 200418454 NMR (CDC13, 300 MHz) δ 7·99 (d，J二2 Hz，1H)，7.79-7.67 (m，3H)，7.55 (dd，J二2, 12 Hz，1H)，7.52 (dd，J=2，12 Hz，1H)， 4.85 (s，2H)。MS (DCI-NH3)[M]+ 236。In a stirred 1.0 M hydrogenated Jingming solution (108 mL, 108 mmol), a solution of methyl 6-bromo-2-fluorenic acid methyl ester (18.9 g, 71.3 mmol) in THF (180 mL) was added dropwise over 20 minutes, while Keep the reaction temperature below -5 ° C. When the addition was complete, the reaction mixture was stirred at -10 ° C for 1 hour, and then the reaction was stopped by dropwise addition of Ciguan water (4 mL), 2N Na2CO3 aqueous solution (4 mL), and distilled water (12 mL). After stirring at room temperature for 15 minutes, the reaction mixture was filtered. The filter block was washed with ethyl acetate (3 X 100 mL), and the combined filtrates were dehydrated (sulfuric acid ') and filtered. The filtrate was concentrated under reduced pressure, and the resulting white solid was dried under vacuum at 40 ° C overnight to give the product (16.84 g, 99% yield). Mp 149.9-151.6 ° C 89248.doc -126- 200418454 NMR (CDC13, 300 MHz) δ 7.99 (d, J 2 2 Hz, 1H), 7.79-7.67 (m, 3H), 7.55 (dd, J 2 2, 12 Hz, 1H), 7.52 (dd, J = 2, 12 Hz, 1H), 4.85 (s, 2H). MS (DCI-NH3) [M] + 236.

實例31B 2-溴-6-氣甲基-茬 取含實例31A產物（30.5 g，129 mmol)之二号燒（320 mL) 攪:掉洛液於無水氮蒙氣下冷卻至-10 °C。一次添加全量無水 ZnC 12固體（5 14 mg，3.77 mmol，0.03當量），然後滴加亞硫 酉&amp;氯（19·$ mL，264 mmol，2.0當量）。使反應混合物回升至 室溫，然後再攪拌2小時。此反應混合物減壓濃縮，殘質分 溶於二氯甲烷與飽和NaHCCb (500 mL)水溶液之間。有機層 經鹽水（2 X 1〇〇 mL)洗滌，脫水（硫酸鎂）與過濾。濾液減壓 濃縮，產生白色固體。於40°C下真空乾燥一夜，產生產物Example 31B 2-Bromo-6-gas methyl-Stubble No. 2 (320 mL) containing the product of Example 31A (30.5 g, 129 mmol) Stirring: The solution was cooled to -10 ° C under anhydrous nitrogen. . An entire amount of anhydrous ZnC 12 solid (5 14 mg, 3.77 mmol, 0.03 equivalent) was added in one portion, and then thionyl chloride &amp; chlorine (19.9 mL, 264 mmol, 2.0 equivalent) was added dropwise. The reaction mixture was warmed to room temperature and then stirred for another 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and a saturated aqueous solution of NaHCCb (500 mL). The organic layer was washed with brine (2 X 100 mL), dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a white solid. Vacuum drying at 40 ° C overnight to produce the product

(32.6 g，收率 99%)°Μ·ρ· 133.l-134.rC。4 NMR (CDC13, 300 MHz) δ 8.00 (d，J=2 Hz，1H)，7.81-7.67 (m，3H)，7.56 (dd， &gt;2, 12 Hz，1H)，7.54 (dd，J=2, 12 Hz，1H)，4.73 (s，2H)。MS (DCI-NH3) [M]+ 254。(32.6 g, yield 99%) ° M · ρ · 133.1-134.rC. 4 NMR (CDC13, 300 MHz) δ 8.00 (d, J = 2 Hz, 1H), 7.81-7.67 (m, 3H), 7.56 (dd, &gt; 2, 12 Hz, 1H), 7.54 (dd, J = 2, 12 Hz, 1H), 4.73 (s, 2H). MS (DCI-NH3) [M] + 254.

實例31CExample 31C

(6-、/臭-各-2-基）-乙月I 取含實例 31B產物（32.2 g，126 mmol)與 NaCN (7.44 g，152 mmol，1·2當量）之乙腈（314 mL)與蒸餾水（Μ mL)混合物於 無水氮蒙氣下回流攪拌21小時。反應混合物冷卻至室溫' 然後減壓濃縮。殘質與蒸館水（3 14 mL)攪掉45分鐘。所得白 色固體經過滤單離，以蒸館水（1500 mL)洗條。於4〇°C下真空 89248.doc -127- 200418454 乾燥一夜，產生產物（32.2 g，收率 97%)。Μ.p. 119.6-120.6°C 。NMR(CDC13, 300 MHz) δ 8·01 (d，J二2 Hz，1H)，7.82-7.68 (m，3H)，7.60 (dd，J=2, 12 Hz，1H)，7.41 (dd，J=2, 12 Hz，1H)， 3.90 (s, 2H)。MS (DCI-NH3) [M+NH4]+ 263，[M+NH4.NH3] + 280 °(6-, / smell-each-2-yl) -ethoxyl I. Acetonitrile (314 mL) containing the product of Example 31B (32.2 g, 126 mmol) and NaCN (7.44 g, 152 mmol, 1.2 equivalents) and The mixture of distilled water (M mL) was stirred at reflux under anhydrous nitrogen for 21 hours. The reaction mixture was cooled to room temperature 'and then concentrated under reduced pressure. The residue was stirred with steamed water (3 14 mL) for 45 minutes. The resulting white solid was isolated by filtration and washed with distilled water (1500 mL). Dry overnight at 40 ° C under vacuum 89248.doc -127- 200418454 to yield the product (32.2 g, yield 97%). M.p. 119.6-120.6 ° C. NMR (CDC13, 300 MHz) δ 8 · 01 (d, J 2 Hz, 1H), 7.82-7.68 (m, 3H), 7.60 (dd, J = 2, 12 Hz, 1H), 7.41 (dd, J = 2, 12 Hz, 1H), 3.90 (s, 2H). MS (DCI-NH3) [M + NH4] + 263, [M + NH4.NH3] + 280 °

實例31D (6 -&gt;臭-奈-2-基）-乙酸 取含實例3 1C產物（29.62 g，120 mmol)之冰醋酸（300 mL) 與蒸餾水，（150 mL)攪拌混合物於無水氮蒙氣下冷卻至_i5°C 。以20分時間滴加濃硫酸（120 mL，4.32 mol，36·0當量）， 同時維持反應溫度在l〇°C以下。反應混合物於回流下攪拌2 小時。冷卻至35°C後，加冰（500 g)至混合物中，續攪拌45 分鐘。所得白色固體經過濾單離，以蒸餾水（丨50〇 mL)洗滌 。於40°C下真空乾燥一夜，產生產物（29.57 g，收率93%)。 'H NMR (CDC13? 300 MHz) δ 7.99 (d, 1=2 Hz5 1H)3 7.76-7.64 (m，3H)，7·54 (dd，J=2, 12 Hz，1H)，7.44 (dd，J=2, 12 Hz，lH)， 3.81 (s，2H)。MS (DCI-NH3) [M+NH4]+ 282。Example 31D (6-> O-naphthalene-2-yl) -acetic acid Take the glacial acetic acid (300 mL) and distilled water (150 mL) containing the product of Example 3 1C (29.62 g, 120 mmol), and stir the mixture in anhydrous nitrogen. Cool to _i5 ° C under air. Concentrated sulfuric acid (120 mL, 4.32 mol, 36.0 equivalents) was added dropwise over 20 minutes while maintaining the reaction temperature below 10 ° C. The reaction mixture was stirred at reflux for 2 hours. After cooling to 35 ° C, add ice (500 g) to the mixture and continue stirring for 45 minutes. The resulting white solid was isolated by filtration and washed with distilled water (50 mL). Drying under vacuum at 40 ° C. overnight yielded the product (29.57 g, yield 93%). 'H NMR (CDC13? 300 MHz) δ 7.99 (d, 1 = 2 Hz5 1H) 3 7.76-7.64 (m, 3H), 7.54 (dd, J = 2, 12 Hz, 1H), 7.44 (dd, J = 2, 12 Hz, lH), 3.81 (s, 2H). MS (DCI-NH3) [M + NH4] + 282.

實例31E 2-(6-溴-萁-2-某V乙醢 於無水氮蒙氣下，以15分鐘時間，在-15°C之含實例31D 產物（28.6 g，1〇8 mmol)之無水THF (143 mL)攪拌溶液中滴 力口1.0 1\/16113-丁《^溶液（409 1111^，409 111111〇1，3.8當量），同時&gt;(呆 持反應溫度在〇°C以下。當添加完畢時，反應混合物於_丨5°c 下攪拌15分鐘，然後使之回升至室溫，再攪拌2小時。反應 89248.doc -128- 200418454 混合物隨後冷卻至-1 〇°c，以蒸館水（1 04 mL)中止反應。於 室溫下攪拌1 5分鐘後，反應混合物減壓濃縮。殘質分溶於 二氣甲fe (3 50 mL)與蒸館水（200 mL)之間，水層經二氯甲抗 (2 X 100 mL)萃取。合併之有機萃液經蒸館水（3 X 100 mL)洗 滌，脫水（硫酸鎂）與過濾。濾液減壓濃縮，產生白色固體。 於40°C下真空乾燥一夜，產生產物（26.1 g，收率96%)。M.p. 102.3-103.rc。4 NMR (CDC13, 300 ΜΗζ) δ 7.98 (d，J=2 Hz， 1H)，7.74-7.63 (m，3H)，7.53 (dd，J二2, 12 Hz，1H)，7.49 (dd， J-2, 12 1H), 4.00-3.92 (m5 2H), 3.02 (t? J=6 Hz, 2H)? 1.43-1.35 (t br，J=6 Hz，1H)。MS (DCI-NH3) [M+NH4]+ 268。Example 31E 2- (6-Bromo-fluorene-2-V-acetamidine in anhydrous nitrogen, for 15 minutes, at -15 ° C, containing anhydrous product of Example 31D (28.6 g, 108 mmol) In a stirred solution of THF (143 mL), a dropwise force of 1.0 1 / 16113-Ding solution (409 1111 ^, 409 111111〇1, 3.8 equivalents), and at the same time (> hold the reaction temperature below 0 ° C. When When the addition was complete, the reaction mixture was stirred at _5 ° C for 15 minutes, then allowed to warm to room temperature and stirred for another 2 hours. Reaction 89248.doc -128- 200418454 The mixture was then cooled to -10 ° C to evaporate. Tuan water (104 mL) stopped the reaction. After stirring at room temperature for 15 minutes, the reaction mixture was concentrated under reduced pressure. The residue was dissolved between diqijia fe (3 50 mL) and steamed hall water (200 mL). The aqueous layer was extracted with dichloromethane (2 X 100 mL). The combined organic extracts were washed with distilled water (3 X 100 mL), dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure to give a white solid. Drying under vacuum at 40 ° C overnight yielded the product (26.1 g, yield 96%). Mp 102.3-103.rc. 4 NMR (CDC13, 300 ΜΗζ) δ 7.98 (d, J = 2 Hz, 1H), 7.74 -7.63 (m, 3H), 7. 53 (dd, J-2, 12 Hz, 1H), 7.49 (dd, J-2, 12 1H), 4.00-3.92 (m5 2H), 3.02 (t? J = 6 Hz, 2H)? 1.43-1.35 ( t br, J = 6 Hz, 1H). MS (DCI-NH3) [M + NH4] + 268.

實例31F _2-「6-(2-羥某-乙某萁-2-基1-2H-嗒畊-3-酮 取含實例 31E產物（500 mg，1.87 mmol)、2H-嗒畊-3-酮（180 mg，1.87 mmol)、銅粉（120 mg，1.87 mmol)與 K2C〇3 (775 mg ，5.61 mmol，3當量）之吡啶（75 mL)混合物於回流與無水氮 蒙氣下攪拌20小時。反應混合物冷卻至室溫，然後減壓濃 縮。與甲苯重覆蒸發排除殘留之吡啶。殘質分溶於乙酸乙 酯（350 mL)與飽和Na2C03水溶液之間。有機層經NH4OH水 溶液洗滌2次，脫水（硫酸鎂），過濾，濾液減壓濃縮。殘質 經管柱層析法純化（75 ·· 25乙酸乙酯/己烷），產生標題化合 物（270 mg，收率 54%)。4 NMR (CDC13, 300 ΜΗζ) δ 8.11 (d， J=2Hz，lH)，7.97-7.93 (m，lH)，7.88(t，J=9Hz，2H)，7.75-7.68 (m，2H)，7.41 (dd，J=2, 12 Hz，1H)，7.31-7.24 (m，1H)， 7.10 (dd，J=2, 12 Hz，1H)，3.97 (t，J=6 Hz，2H)，3.06 (t，J=6 89248.doc -129- 200418454Example 31F _2- "6- (2-Hydroxy-1,2-ethyl-2,2-Hydroxy-2-yl 1-2H-dagen-3-one) Example 31E (500 mg, 1.87 mmol), 2H-dagen-3 A mixture of ketone (180 mg, 1.87 mmol), copper powder (120 mg, 1.87 mmol) and K2CO3 (775 mg, 5.61 mmol, 3 eq) in pyridine (75 mL) was stirred under reflux and anhydrous nitrogen for 20 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Repeated evaporation with toluene to remove residual pyridine. The residue was dissolved between ethyl acetate (350 mL) and saturated aqueous Na2C03 solution. The organic layer was washed twice with aqueous NH4OH solution. , Dehydrated (magnesium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (75 · 25 ethyl acetate / hexane) to give the title compound (270 mg, yield 54%). 4 NMR (CDC13, 300 ΜΗζ) δ 8.11 (d, J = 2Hz, 1H), 7.97-7.93 (m, 1H), 7.88 (t, J = 9Hz, 2H), 7.75-7.68 (m, 2H), 7.41 (dd , J = 2, 12 Hz, 1H), 7.31-7.24 (m, 1H), 7.10 (dd, J = 2, 12 Hz, 1H), 3.97 (t, J = 6 Hz, 2H), 3.06 (t, J = 6 89248.doc -129- 200418454

Hz，2H)。MS (DCI-NH3) [M+H] + 267, [M+NH4]+ 284。Hz, 2H). MS (DCI-NH3) [M + H] + 267, [M + NH4] + 284.

實例31G 氣代 _6H-嗒啩-1-基）-苯-2_ 某 | 利用針同滴加甲石黃酿氯（〇· 1〇 mL，1 ·33 mmol，1 ·3當量）Example 31G Gas generation _6H-da- 1-yl) -benzene-2_ Some | Same addition of methotrex chloride (0 · 10 mL, 1.33 mmol, 1.3 equivalent)

至 0C 之含實例 31 F產物（0.27 g，1·01 mmol)與 Et3N (0.28 mL ’ 2·02 mmol ’ 2.0當量）之攪拌溶液中。1小時後離開冰浴， 反應混合物於室溫下攪拌2小時。反應混合物減壓濃縮。殘 質分溶於EtOAc與飽和NaaCO3水溶液之間。水層經EtOAc萃 取。合併τ之有機萃液脫水（硫酸鎂）與過濾。濾液減壓濃縮後 ，經硬膠填料使用EtOAc過濾後，再次排除溶劑，產生標題 中間物之灰白色固體（300 mg，收率87%)。巾NMR (CDC13, 300 MHz) δ 8.12 (d，J=2 Hz，1H)，7.97-7.94 (m，1H)，7·89 (t， J=9 Hz，2H)，7.76-7.71 (m，2H)，7.41 (dd，J=2，12 Hz，1H)， 7.31-7.25 (m，1H)，7.10 (dd，J=2, 12 Hz，1H)，4.53 (t，J=6 Hz， 2H)，3.24 (t，J=6 Hz, 2H)，2.83 (s，3H)。MS (DCI-NH3) [M+H]+ 345, [M+NH4]+ 362。To 0C in a stirred solution containing the product 31 F (0.27 g, 1.01 mmol) and Et3N (0.28 mL ′ 2.02 mmol ′ 2.0 equivalents). After 1 hour, the ice bath was left and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and a saturated aqueous NaaCO3 solution. The aqueous layer was extracted with EtOAc. The combined organic extracts of τ are dehydrated (magnesium sulfate) and filtered. After the filtrate was concentrated under reduced pressure, after filtering through a hard plug with EtOAc, the solvent was removed again to give the title intermediate as an off-white solid (300 mg, yield 87%). NMR (CDC13, 300 MHz) δ 8.12 (d, J = 2 Hz, 1H), 7.97-7.94 (m, 1H), 7.89 (t, J = 9 Hz, 2H), 7.76-7.71 (m, 2H), 7.41 (dd, J = 2, 12 Hz, 1H), 7.31-7.25 (m, 1H), 7.10 (dd, J = 2, 12 Hz, 1H), 4.53 (t, J = 6 Hz, 2H ), 3.24 (t, J = 6 Hz, 2H), 2.83 (s, 3H). MS (DCI-NH3) [M + H] + 345, [M + NH4] + 362.

實例31H 甲基-1-吡咯咗-1-某1-乙基卜2-苯-2-基）-2H- 嗒畊-3-酮 取含實例31G產物（0.30 g，0.87 mmol)與（2R)-2-甲基吡咯 淀（0.37 g，4.3 6 mmol，5.0當量）之無水乙腈（3.5 mL)混合物 於密封試管中，於室溫下攪拌66小時。反應混合物減壓濃 縮。殘質分溶於乙酸乙酯與飽和Na2C03水溶液之間。水層 經乙蚊乙g旨萃取，合併之有機萃液脫水（硫酸鎂）與過滤。濾、 89248.doc -130- 200418454 液減壓濃縮，殘質經管柱層析法純化（97 : 3 :微量之二氣 甲烷/甲醇/NH4〇H)。取含產物之溶離份合併，減壓濃縮， 產生游離鹼產物（220 mg，收率75.7%)。游離鹼溶於Et2〇中 ，通入HC1氣體，直到pH 2。所得沉澱自Me〇H/Et2〇中結晶 ，產生鹽酸鹽。Μ·ρ· 198.9-201.5°C。4 NMR (CD3OD，300 MHz) δ 8.12-8.07 (m，2H)，8.00-7.88 (m，3H)，7.68 (dd，J=2, 12 Hz，1H), 7.57-7.49 (m，2H)，7·13 (dd5 J=2，12 Hz，1H)， 3.84- 3.64 (m，2H)，3.64-3.46 (m，lH)，3.46-3.13 (m，4H)， 2.43-2.2^ (m, 1H), 2.22-1.99 (m? 2H)5 1.85- 1.67 (m3 1H)? 1·48 (d，J二6 Hz，3H)。MS (DCI-NH3) [M+H]+ 334。 實例32 氧基-5-(K2-「（2RV2:甲基_1-p比略淀基1乙某卜2-基某、 p比淀 標題化合物係依實例8之方法製備，但其中改用6-甲氧基 -3-4啶基二羥硼酸替代4-说啶基二輕硼酸（37 mg，收率 24%)。巾 NMR (CD3OD，300 ΜΗζ) δ 8.50 (d，J=2 Hz，1H)， 8.10-8.05 (m，2H)，7.98-7.92 (m，2H)，7.85-7.83 (m，1H)， 7.75 (dd，J=2, l〇 Hz，1H)，7.50 (dd，J=2, 12 Hz，1H)，6.93 (d， J=9 Hz，1H)，4·43 (s，2H)，3.97 (s，3H)，3.81-3.47 (m，3H)， 3.42-3.17 (m, 4H)? 2.41-2.28 (m? 1H), 2.26-2.04 (m? 2H)? 1.85- 1.71 (m，1H)，1·47 (d，J=6 Hz，3H)。MS (DCI-NH3) [M+H]+ 347 〇 — 實例33 軺甲基）-1-吡咯啶基1乙某丨_2-裏：某）茉某氰 -131 - 89248.doc 200418454 標題化合物係依實例1H之方法製備，但其中改用（2R)_2_ 说σ呢基甲醇替代（2R)_2-甲基吡咯咬。！h NMR (CD3〇D， 300 MHz) δ 8.13 (s, 1H), 7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d. J-6 Hz, 1H), 3.51-3.64 (m, 2H), 3.2-3.34 (m, 2H)，2.93-3」（m, 2H), 2·69_2·75 (m, 2h)，2 4 (q，j=6 Hz， 1H), 1.9-2.4 (m, 1H), 1.95-2.05 (m, 2H), 1.81-1.91(m, 1H) 〇 MS (DCI-NH3) [M+H]+ 357。 實例34_ 比略淀基丄匕^基1-2-¾:某丨茉某教 標題化合物係依實例1]9[之方法製備，但其中改用消旋性 -2-甲基吡咯哫替代（2R)-2-甲基吡咯啶。1h (cD3〇d， 300 MHz) δ 8.13 (s5 1Η)5 7.87-7.96 (m? 4Η)5 7.71-7.85 (m? 4Η), 7.41 (d, J=6 Hz, 1H)? 3.68-3.83 (m? 2H)? 3.51-3.61 (m? 1H)，3.17-3.42 (m，4H)，2.3-2.43 (m，1H)，2.02-2.12 (m，2H)， 1.68-1.82 (m，1H)，1·44 (d，J=6 Hz，3H)。MS (DCI-NH3) [M+H]+ 341 〇 實例35 咯啶基）乙基H苯基丨茉某氨 標題化合物係依實例1H之方法製備，但其中改用吡咯啶 替代（2R)-2-甲基吡咯啶。iH NMR (CD3〇D，300 ΜΗζ) δ 8.13 (s，1Η)，7.87-7.96 (m，4Η)，7.71-7.85 (m，4Η)，7·41 (d. J=6 Hz，1Η)，3·56·3·62 (m，1H)，3.1-3.18 (m，ih)，2.84-2.91 (m， 1H)5 2.75-2.8 (m? ih)? 2.66-2.73 (m, 4H)5 1.84-1.9 (m5 4H) 。MS (DCI-NH3) [M+H]+ 327。 89248.doc -132- 200418454 實例36Example 31H Methyl-1-pyrrolidin-1-one 1-ethylbutan-2-phenyl-2-yl) -2H-dagen-3-one The product containing Example 31G (0.30 g, 0.87 mmol) and (2R ) -2-Methylpyrrole (0.37 g, 4.3 6 mmol, 5.0 eq.) In anhydrous acetonitrile (3.5 mL) was mixed in a sealed test tube and stirred at room temperature for 66 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and saturated aqueous Na2C03 solution. The water layer was extracted with ethyl mosquito, and the combined organic extracts were dehydrated (magnesium sulfate) and filtered. It was filtered, 89248.doc -130- 200418454 was concentrated under reduced pressure, and the residue was purified by column chromatography (97: 3: trace amount of methane / methanol / NH4OH). The product-containing fractions were combined and concentrated under reduced pressure to produce a free base product (220 mg, yield 75.7%). The free base was dissolved in Et2O and HC1 gas was passed through until pH 2 was reached. The resulting precipitate was crystallized from MeOH / Et20 to give the hydrochloride. M · ρ · 198.9-201.5 ° C. 4 NMR (CD3OD, 300 MHz) δ 8.12-8.07 (m, 2H), 8.00-7.88 (m, 3H), 7.68 (dd, J = 2, 12 Hz, 1H), 7.57-7.49 (m, 2H), 7 · 13 (dd5 J = 2, 12 Hz, 1H), 3.84- 3.64 (m, 2H), 3.64-3.46 (m, lH), 3.46-3.13 (m, 4H), 2.43-2.2 ^ (m, 1H ), 2.22-1.99 (m? 2H) 5 1.85- 1.67 (m3 1H)? 1.48 (d, J 2 6 Hz, 3H). MS (DCI-NH3) [M + H] + 334. Example 32 Oxy-5--5- (K2-"(2RV2: methyl_1-p than slightly ydoyl, 1 ethyl, 2-yl, etc.) The title compound was prepared according to the method of Example 8, but it was used instead. 6-methoxy-3-4pyridyldihydroxyboric acid replaces 4-s-pyridyldiphenylboronic acid (37 mg, yield 24%). NMR (CD3OD, 300 ΜΗζ) δ 8.50 (d, J = 2 Hz , 1H), 8.10-8.05 (m, 2H), 7.98-7.92 (m, 2H), 7.85-7.83 (m, 1H), 7.75 (dd, J = 2, 10Hz, 1H), 7.50 (dd, J = 2, 12 Hz, 1H), 6.93 (d, J = 9 Hz, 1H), 4.43 (s, 2H), 3.97 (s, 3H), 3.81-3.47 (m, 3H), 3.42-3.17 (m, 4H)? 2.41-2.28 (m? 1H), 2.26-2.04 (m? 2H)? 1.85- 1.71 (m, 1H), 1.47 (d, J = 6 Hz, 3H). MS (DCI -NH3) [M + H] + 347 〇— Example 33 轺 methyl) -1-pyrrolidinyl 1 ethyl 丨 _2- li: a) jasmine cyanide-131-89248.doc 200418454 The title compound is based on the examples 1H method, but in which (2R) _2_ is used instead of (2R) _2-methylpyrrole.! H NMR (CD30D, 300 MHz) δ 8.13 (s, 1H), 7.87- 7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d. J-6 Hz, 1H), 3.51-3.64 (m, 2H), 3.2-3.34 (m, 2H) 2.93-3 "(m, 2H), 2.69_2 · 75 (m, 2h), 2 4 (q, j = 6 Hz, 1H), 1.9-2.4 (m, 1H), 1.95-2.05 (m, 2H ), 1.81-1.91 (m, 1H), MS (DCI-NH3) [M + H] + 357. Example 34_ Pyridinium base 1-2-¾: A certain title compound was prepared according to the method of Example 1] 9 [, but the racemic 2-methylpyrrole was used instead ( 2R) -2-methylpyrrolidine. 1h (cD3〇d, 300 MHz) δ 8.13 (s5 1Η) 5 7.87-7.96 (m? 4Η) 5 7.71-7.85 (m? 4Η), 7.41 (d, J = 6 Hz, 1H)? 3.68-3.83 ( m? 2H)? 3.51-3.61 (m? 1H), 3.17-3.42 (m, 4H), 2.3-2.43 (m, 1H), 2.02-2.12 (m, 2H), 1.68-1.82 (m, 1H), 1.44 (d, J = 6 Hz, 3H). MS (DCI-NH3) [M + H] + 341 〇 Example 35 pyrrolidyl) ethyl Hphenyl 丨 a certain ammonia title compound was prepared according to the method of Example 1H, but in which the pyrrolidine was used instead of (2R)- 2-methylpyrrolidine. iH NMR (CD30D, 300 ΜΗζ) δ 8.13 (s, 1Η), 7.87-7.96 (m, 4Η), 7.71-7.85 (m, 4Η), 7.41 (d. J = 6 Hz, 1Η), 3 · 56 · 3 · 62 (m, 1H), 3.1-3.18 (m, ih), 2.84-2.91 (m, 1H) 5 2.75-2.8 (m? Ih)? 2.66-2.73 (m, 4H) 5 1.84 -1.9 (m5 4H). MS (DCI-NH3) [M + H] + 327. 89248.doc -132- 200418454 Example 36

標題化合物係依實例27之方法製備，但其中改用硫代嗎 啉替代嗎啉。丨H NMR (CD3〇D, 3〇〇 MHz) s 7·62_7 69 ㈤， 2Η), 7.53 (s, 1H), 7.21-7.3 (m, 2H), 7.13 (s, 1H), 3.53 (m, 4H), 3.23-4.0 (m, 1H), 3.06-3.16 (m, 1H), 2.82-3.01 (m, 2H), 2.73(m, 4H), 2.25-2.48 (m, 3H), 1.94-2.04 (m, 1H), 1.72-1.84 (m, 2H), 1.38-1.41 (m, 1H), l.n (d, J=6 Ηζ? 3H) 〇 MS (DCI-NH5) [M+H]+ 341 〇 實例37The title compound was prepared in the same manner as in Example 27, except that thiomorpholine was used instead of morpholine.丨 H NMR (CD3OD, 300MHz) s 7.62_7 69 ㈤, 2Η), 7.53 (s, 1H), 7.21-7.3 (m, 2H), 7.13 (s, 1H), 3.53 (m, 4H), 3.23-4.0 (m, 1H), 3.06-3.16 (m, 1H), 2.82-3.01 (m, 2H), 2.73 (m, 4H), 2.25-2.48 (m, 3H), 1.94-2.04 ( m, 1H), 1.72-1.84 (m, 2H), 1.38-1.41 (m, 1H), ln (d, J = 6 Ηζ? 3H) 〇MS (DCI-NH5) [M + H] + 341 〇 Examples 37

溴-2-蕃基）氧乙某！？比味戒 實例37A U臭-6-(2二溴乙氣某）基 取含 1.0 g (4.5 mmol)6·溴 _2_ 莕酚、1,2-二溴乙烷（135 mmol，12 mL)、氫氧化鉀（5 mL· 40%溶液）與四丁基銨化溴 (1.3 5 mmol，0.43 g)之圓底燒瓶於10〇t；下加熱3小時。反應 混合物經150mLCH2Cl2稀釋，以水與鹽水洗務，經硫酸鈉 脫水與真空濃縮，產生所需化合物，1〇〇%，為淺褐色固體 ；lH NMR (300 MHz,CDC13) δ 3.70 (t, 2H)5 4.40 (t5 2H)5 7.05-7.90 (m，6H)。MS (DCI) m/z 330 (M+)。Bromo-2-benzyl) oxyethyl ? Comparison of taste or example 37A U odor-6- (2 dibromoethane) is based on 1.0 g (4.5 mmol) 6 · bromo_2_ phenol, 1,2-dibromoethane (135 mmol, 12 mL) A round bottom flask of potassium hydroxide (5 mL · 40% solution) and tetrabutylammonium bromide (1.3 5 mmol, 0.43 g) was heated at 100 t for 3 hours. The reaction mixture was diluted with 150 mL of CH2Cl2, washed with water and brine, dehydrated with sodium sulfate and concentrated in vacuo to give the desired compound, 100% as a light brown solid; 1H NMR (300 MHz, CDC13) δ 3.70 (t, 2H ) 5 4.40 (t5 2H) 5 7.05-7.90 (m, 6H). MS (DCI) m / z 330 (M +).

實例37B 1 - {2-「（6-溴-2-:某）氣1乙基丨？比p各哈 在含0.5 g (1,5 mmol)實例37A產物之燒瓶中添加1〇 mL吡 哈啶。於80°C下攪拌3小時後，反應混合物真空濃縮。殘質 89248.doc -133 - 200418454 經100 rnL CH2C12稀釋，依序經水、破酸氫鈉與鹽水洗條， 脫水及減壓蒸發。經矽膠層析（Me〇H : CH2C12，95 : 5)， 產生所需物質，收率 98% 。iHNMr (300 MHz，CDC13) δ 1.80 (m，4Η)，2·6 (m，4Η)，2.97 (t，2Η)，4·20 (t，2Η)，2·49 (m，2Η) 7.10-7.90 (m，6H); MS(ESI) m/z 321 (M+H)+。 實例38 咯啶某）乙氣基_2_茬基1笟甚鲁 取含貫例37B產物（35 mg，0.11 mmol)、3-氰基苯基二經 硼酸（22 _，〇·ΐ5 mmol)、pdcl2(pph3)2 (4 2 mg，6 μιη〇1)與 異丙醇（0.5 mL)之混合物經2 μ碳酸鈉水溶液（80 μΙ^)處理， 於85°C下加熱一夜。混合物冷卻至室溫，分溶於2 M ν&amp;〇η 水溶液與二氯甲烷之間。分離水相，以二氣甲烷萃取。合 併之有機相經矽藻土過滤，濃縮，經矽石層析，使用 0%/5 0°/〇/50%至10%/40%/50%甲醇/乙酸乙酯/二氣甲烷梯度 溶離後，以8%甲醇/二氯甲烷溶離，產生標題化合物。1h NMR (300 MHz，CD3〇D) δ 1·86 (m，4H)，2·73 (m，4H)，3·〇1 (t，2Η)，4·28 (t，2Η)，7·22 (dd，1Η)，7.31 (d，1Η)，7·65 (t，1Η)， 7.70 (dt5 1H)? 7.75 (dd? 1H)? 7.85-7.92 (m? 2H)5 8.06 (dt5 1H)! 8.07-8.13 (m，2H); MS (ESI) m/z 343 (M+H)+。 i二{6-「2-(1_说咯咬羞:某 取實例37B產物與^((^、四甲基七允”二氧硼戊環 -2-基比啶依實例38之方法處理，但其中進行第二次管柱 層析法，產生10 mg標題化合物。iH NMR (3〇〇 MHz，ci^〇D) 89248.doc -134- 200418454 δ 1.86 (m，4H)，2.74 (m，4H)，3.02 (t，2H)，4·29 (t，2H)，7.23 (dd，1H)，7.31 (d，1H)，7.56 (ddd，1H)，7·76 (dd，1H)， 7.86-7.93 (m，2H)，8.10 (d，1H)，8.20 (ddd，1H)，8.52 (dd， 1H)，8.91 (dd，1H); MS (ESI) m/z 319 (M+H)+。 實例40 3-(6-{2-「（21〇-2-甲基-1-吡咯啶某1乙氣某}-2-苯基）茉甚iExample 37B 1-{2-"(6-Bromo-2-: some) gas 1 ethyl 丨? P each halo In a flask containing 0.5 g (1,5 mmol) of the product of Example 37A was added 10 mL of Piha Pyridine. After stirring at 80 ° C for 3 hours, the reaction mixture was concentrated in vacuo. The residue 89248.doc -133-200418454 was diluted with 100 rnL CH2C12, and the strips were sequentially washed with water, sodium bicarbonate and brine, dehydrated and decompressed. Evaporation. Silica gel chromatography (Me0H: CH2C12, 95: 5) yielded the desired material with a yield of 98%. IHNMr (300 MHz, CDC13) δ 1.80 (m, 4Η), 2 · 6 (m, 4Η) ), 2.97 (t, 2Η), 4.20 (t, 2Η), 2.49 (m, 2Η) 7.10-7.90 (m, 6H); MS (ESI) m / z 321 (M + H) +. Example 38: Pyridine: Ethyl-2-yl radical, 1-yl radical, which contains the product of Example 37B (35 mg, 0.11 mmol), and 3-cyanophenyl diboronic acid (22-, 0.5 mmol) A mixture of pdcl2 (pph3) 2 (4 2 mg, 6 μιη〇1) and isopropanol (0.5 mL) was treated with 2 μ sodium carbonate aqueous solution (80 μΙ ^) and heated at 85 ° C overnight. The mixture was cooled to At room temperature, dissolve in 2 M ν &amp; 〇η aqueous solution and dichloromethane. The aqueous phase was separated and extracted with methane gas. Combined The organic phase was filtered through diatomaceous earth, concentrated, and subjected to silica chromatography using a gradient of 0% / 5 0 ° / 〇 / 50% to 10% / 40% / 50% methanol / ethyl acetate / digas methane. Isolate with 8% methanol / dichloromethane to give the title compound. 1h NMR (300 MHz, CD3OD) δ 1.86 (m, 4H), 2.73 (m, 4H), 3.01 (t, 2Η), 4.28 (t, 2Η), 7.22 (dd, 1Η), 7.31 (d, 1Η), 7.65 (t, 1Η), 7.70 (dt5 1H)? 7.75 (dd? 1H)? 7.85-7.92 (m? 2H) 5 8.06 (dt5 1H)! 8.07-8.13 (m, 2H); MS (ESI) m / z 343 (M + H) +. I 二 {6- 「2- (1_ Speaking of biting shame: A certain product of Example 37B and ^ ((^, tetramethylheptamin) dioxolan-2-ylpyridine were treated according to the method of Example 38, but a second column chromatography was performed. Method to produce 10 mg of the title compound. IH NMR (300 MHz, ci ^ 〇D) 89248.doc -134- 200418454 δ 1.86 (m, 4H), 2.74 (m, 4H), 3.02 (t, 2H), 4.29 (t, 2H), 7.23 (dd, 1H), 7.31 (d, 1H), 7.56 (ddd, 1H), 7.76 (dd, 1H), 7.86-7.93 (m, 2H), 8.10 ( d, 1H), 8.20 (ddd, 1H), 8.52 (dd, 1H), 8.91 (dd, 1H); MS (ESI) m / z 319 (M + H) +. Example 40 3- (6- {2-"(21〇-2-methyl-1-pyrrolidine, 1 ethyl gas, 1} -2-phenyl) mosquito

貫例40A 二1 -丨2-[0-溴- 2-¾:某）氧1乙基丨-2-甲基ρ比哈·咬 取（（2ig_2-甲基吡咯啶（L)-酒石酸鹽（541 mg，2.3 mmol) 分溶於2 M Na〇H水溶液（2·5 mL)與甲苯（0.6 mL)之間。分 離水相，以鹽水（0.3 mL)稀釋，以甲苯（2 X 0·3 mL)萃取。 合併之有機相脫水（硫酸鈉）與以甲苯（〇·3 mL)潤洗進入下 一個步驟。 取實例 37 A產物（495 mg，1.5 mmol)、碳酸鉀（207 mg，1.5 mmol)與上述甲苯溶液懸浮在dmf (3 mL)中，於50°C下加熱 一夜。使反應混合物回到室溫，分溶於〇2 M NaOH水溶液 (20 mL)與二氯甲烷（ίο mL)之間。分離水相，以二氯甲烷萃 取，合.併之有機相經〇·2 MNa〇H水溶液洗滌，脫水（硫酸鈉） ，及經矽石填料，使用〇至1〇%甲醇/二氯甲烷梯度迅速過漉 。濾液分洛於水與2 : 1二氯甲烷/己烷之間。分離水相，以 20%己烷/一氯甲烷萃取，合併之有機相濃縮，經矽石層析 ，以！&gt; I己烷/二氯甲烷溶離後，以〇至1〇%甲醇/二氯甲烷 梯度溶離。合併適當之溶離份，於高度真空下濃縮，產生 45 1 mg標題化合物與起始之氯化物之6 :丨混合物，未再純化 89248.doc 200418454 即用於下一個步驟；MS (ESI APCI) m/z 334 / 336 (M + H)+。Example 40A Bi 1-丨 2- [0-Bromo-2- 2-¾: Certain) Oxy 1ethyl 丨 -2-methylρ Biha · Bite ((2ig_2-methylpyrrolidine (L) -tartrate (541 mg, 2.3 mmol) was partitioned between 2 M NaOH aqueous solution (2.5 mL) and toluene (0.6 mL). The aqueous phase was separated, diluted with brine (0.3 mL), and toluene (2 X 0 ·· 3 mL) extraction. The combined organic phases were dehydrated (sodium sulfate) and rinsed with toluene (0.3 mL) and moved to the next step. The product of Example 37 A (495 mg, 1.5 mmol), potassium carbonate (207 mg, 1.5 mmol) and the above toluene solution were suspended in dmf (3 mL), and heated at 50 ° C. overnight. The reaction mixture was returned to room temperature, and dissolved in 0 2 M aqueous NaOH (20 mL) and dichloromethane (ίο mL). ). The aqueous phase was separated, extracted with dichloromethane, and the combined organic phases were washed with a 0.2 M NaOH aqueous solution, dehydrated (sodium sulfate), and passed through a silica filler using 0 to 10% methanol / The dichloromethane gradient quickly passed. The filtrate was partitioned between water and 2: 1 dichloromethane / hexane. The aqueous phase was separated and extracted with 20% hexane / monochloromethane. The combined organic phases were concentrated and passed through silica. Tomography! &Gt; I After the alkane / dichloromethane dissociates, dissolve in a gradient of 0 to 10% methanol / dichloromethane. The appropriate fractions are combined and concentrated under high vacuum to yield 45 1 mg of the title compound and the initial chloride 6: The mixture was used without further purification 89248.doc 200418454 for the next step; MS (ESI APCI) m / z 334/336 (M + H) +.

實例40B 3-(6-{U(2R)-2-_Y 基-l-吡咯啶某乙氮基卜2_墓基）笨基氰 取含實例40A產物（147 mg，約0.38 mmol)、3-氰基苯基二 羥硼酸（96 mg，0.65 mmol)、PdCl2(PPh3)2 (28 mg，0.04 mmol) 與異丙醇（2.5 mL)之混合物經2 M碳酸鈉水溶液（700 jiL)處 理，於55°C下加熱一夜後，於85°C 2天。混合物冷卻至室 溫，分溶於2MNaOH水溶液（2mL)與二氯甲烷（i〇mL)之間 。分離水，相’以二氯甲燒萃取。合併之有機相經石夕藻土過 濾，濃縮，經矽石層析，以〇%/5〇%/50%至1〇%/4〇%/5〇%甲 醇/乙酸乙酯/二氯甲烷梯度溶離一次，第二次層析法以 0%/0%/100%至 0%/50%/50%至 5%/45%/50% 甲醇 / 乙酸乙酉旨 /二氣甲烷溶離，產生28 mg橙色膠質；1H NMR (300 CD3OD) δ 1·10 (d，3H)，1.48 (m，1H)，1.75-1.88 (m，2H)，2·01 (m，1H)，2·40 (m，1H)，2.53 (m，1H)，2·65 (m，1H)，3·23-3 38 (m，2H)，4.22-4.34 (m，2H)，7.22 (dd，1H)，7·30 (d，1H)，7.65 (t，1H)，7.70 (dt，1H)，7.75 (dd, 1H)，7.85-7.92 (m，2H)，8 〇6 (dt，1Η)，8·07-8·12 (m，2H); MS (ESI) m/z 357 (M+H)+。 實例41 甲基比洛淀基1乙氣某I9·莫某 取實例40A產物與3-(4,4,5,5-四甲基-[1，3,2]二氧硼戊環 -2-基）-吡啶依實例40B之方法處理，但其中進行單次層析法 ，以0%/50%/50%至10%/40%/50〇/〇甲醇/乙酸乙酿/二氯甲户 之梯度溶離後，以8%甲醇/二氯甲烷溶離，產生標題化合物 89248.doc -136- 200418454 。NMR (300 MHz，CD3OD) δ 1·10 (d，3H)，1·47 (m，1H)， 1.75-1.88 (m，2H)，2.02 (m，1H)，2.41 (m，1H)，2.54 (m，1H)， 2.66 (m，1H)，3.22-3.39 (m，2H)，4·24_4·33 (m，2H)，7·22 (dd， 1H)，7·31 (d，1H)，7.55 (ddd，1H)，7.76 (dd，1H)，7.86-7.94 (m，2H)，8.10 (d，1H)，8.21 (ddd，1H)，8.52 (dd，1H)，8.91 (dd，1H); MS (ESI) m/z 333 (M+H)+。 實例42Example 40B 3- (6- {U (2R) -2-_Y-yl-l-pyrrolidine, an ethazyl group, 2-benzyl) benzyl cyanide, containing the product of Example 40A (147 mg, about 0.38 mmol), 3 -A mixture of cyanophenyldihydroxyboric acid (96 mg, 0.65 mmol), PdCl2 (PPh3) 2 (28 mg, 0.04 mmol) and isopropanol (2.5 mL), treated with 2 M aqueous sodium carbonate solution (700 jiL), After heating at 55 ° C overnight, 85 ° C for 2 days. The mixture was cooled to room temperature and partitioned between 2M aqueous NaOH (2 mL) and dichloromethane (10 mL). The water was separated and the phase was extracted with dichloromethane. The combined organic phases were filtered through celite, concentrated, and subjected to silica chromatography at 0% / 50% / 50% to 10% / 40% / 50% methanol / ethyl acetate / dichloromethane. Gradient dissociation once, and the second chromatography method dissolves from 0% / 0% / 100% to 0% / 50% / 50% to 5% / 45% / 50% methanol / acetic acid acetate / digas methane, yielding 28 mg orange gum; 1H NMR (300 CD3OD) δ 1 · 10 (d, 3H), 1.48 (m, 1H), 1.75-1.88 (m, 2H), 2.01 (m, 1H), 2.40 (m , 1H), 2.53 (m, 1H), 2.65 (m, 1H), 3.23-3 38 (m, 2H), 4.22-4.34 (m, 2H), 7.22 (dd, 1H), 7 · 30 (d, 1H), 7.65 (t, 1H), 7.70 (dt, 1H), 7.75 (dd, 1H), 7.85-7.92 (m, 2H), 8 〇6 (dt, 1Η), 8.07- 8 · 12 (m, 2H); MS (ESI) m / z 357 (M + H) +. Example 41 Methylpyridyl 1 Ethane I9 · Momo Take the product of Example 40A and 3- (4,4,5,5-tetramethyl- [1,3,2] dioxolane-2 -Yl) -pyridine was treated according to the method of Example 40B, but a single chromatography method was performed at 0% / 50% / 50% to 10% / 40% / 50 // methanol / ethyl acetate / dichloromethyl After the gradient dissolution, it was dissolved with 8% methanol / dichloromethane to give the title compound 89248.doc -136- 200418454. NMR (300 MHz, CD3OD) δ 1.10 (d, 3H), 1.47 (m, 1H), 1.75-1.88 (m, 2H), 2.02 (m, 1H), 2.41 (m, 1H), 2.54 (m, 1H), 2.66 (m, 1H), 3.22-3.39 (m, 2H), 4.24_4 · 33 (m, 2H), 7.22 (dd, 1H), 7.31 (d, 1H) , 7.55 (ddd, 1H), 7.76 (dd, 1H), 7.86-7.94 (m, 2H), 8.10 (d, 1H), 8.21 (ddd, 1H), 8.52 (dd, 1H), 8.91 (dd, 1H) ); MS (ESI) m / z 333 (M + H) +. Example 42

4-(2_ {2-「（2R)-2 -甲基- Ι-p比略淀基1乙基卜6-p奋?林某）苯甚氛 ， 實例42A 溴-2-唓啉基）乙酸乙酯 於- 78C下’在含一異丙胺（19.2 g’ 0.19莫耳）之乙酸（2〇〇 mL)溶液中添加2.5 Μ正丁基41之己燒溶液（74 mL，0· 1 85莫 耳）。此澄清溶液混合30分鐘後，於-78°C下慢慢添加6-溴-2-甲基奎啉（13.32 g，0.060莫耳）之醚（200 mL)溶液。該褐色 溶液攪拌0.5小時，以針筒慢慢添加氯甲酸乙酯（7.g， 0.069 mole)之醚（50 mL)溶液至混合物中，以使内溫不超過 -70 C。黃色反應混合物經添加50 mL水中止反應後，使之 回升至室溫，以乙酸乙酯（300 mL)稀釋。溶液經5%碳酸氫 鈉水溶液（7〇〇 mL X 3)、25%鹽水（700 mL)洗滌，經硫酸鎂 脫水與過濾。有機相濃縮至約50 mL體積，漿狀物經庚烷（50 mL)稀釋。於〇°C下攪拌漿狀物2小時，過漉收集固體，以冰 冷之庚烷：乙酸乙酯（1〇 mL，2 : 1)潤洗，於50°C下真空乾 燥’產生黃色固體（12·〇 g)。母液濃縮，產生第二批產物（3.6 g)。總收率：88% ; mp: 100-101°C (未校正）；MS (ESI): 294, 89248.doc -137- 200418454 296 (M+H) + ; W-NMR (CDC13) δ 8·02 (1 H，d，J=8 5 Hz)，7.94 (1H，d，J=2.2 Hz)，7·91 (1H，d，Ju Hz)，7·74 (1H，dd， J=8.9，2·2 Ηζ)，7·44 (1H，d，J=8.5 Hz)，4 2〇 (2H，q，J=7.1 Hz)， 4.01 (2H? s)? 1.27 (3H? t, 1=7A Hz)； 13C-NMR (CDC13) δ 169.7, 154.9，146.0, 135.1，132.6, 130.5, 128 9 127 8 122 3 119.9, 61.2, 44.9, 14.5。4- (2_ {2-"(2R) -2 -methyl-l-p-pyridyl 1-ethyl 6-p-phenone) Benzene, Example 42A Bromo-2-fluorinyl) Ethyl acetate at -78C was added to a solution of monoisopropylamine (19.2 g '0.19 mole) in acetic acid (200 mL) at a temperature of 2.5 M n-butyl 41 in hexane (74 mL, 0.185 Mol). After mixing this clear solution for 30 minutes, slowly add 6-bromo-2-methylquinoline (13.32 g, 0.060 mole) in ether (200 mL) at -78 ° C. The brown solution After stirring for 0.5 hours, a solution of ethyl chloroformate (7.g, 0.069 mole) in ether (50 mL) was slowly added to the mixture through a syringe so that the internal temperature did not exceed -70 C. The yellow reaction mixture was added by 50 mL After stopping the reaction in water, it was warmed up to room temperature and diluted with ethyl acetate (300 mL). The solution was washed with 5% aqueous sodium hydrogen carbonate solution (700 mL X 3), 25% brine (700 mL), and sulfuric acid The magnesium was dehydrated and filtered. The organic phase was concentrated to a volume of about 50 mL, and the slurry was diluted with heptane (50 mL). The slurry was stirred at 0 ° C for 2 hours, and the solid was collected by centrifugation. Ethyl acetate (10 mL, 2: 1) Drying under vacuum at 50 ° C yielded a yellow solid (12.0 g). The mother liquor was concentrated to give a second crop (3.6 g). Total yield: 88%; mp: 100-101 ° C (uncorrected); MS (ESI): 294, 89248.doc -137- 200418454 296 (M + H) +; W-NMR (CDC13) δ 8 · 02 (1 H, d, J = 8 5 Hz), 7.94 (1H, d, J = 2.2 Hz), 7.91 (1H, d, Ju Hz), 7.74 (1H, dd, J = 8.9, 2.2 Ηζ), 7.44 (1H, d, J = 8.5 Hz), 4 2〇 (2H, q, J = 7.1 Hz), 4.01 (2H? S)? 1.27 (3H? T, 1 = 7A Hz); 13C-NMR (CDC13) δ 169.7, 154.9, 146.0, 135.1, 132.6, 130.5, 128 9 127 8 122 3 119.9, 61.2, 44.9, 14.5.

實例42B 2-(6-溴-2 j林基 於鼠蒙?氣下’在1 L圓底燒瓶中添加實例42a產物（120 g ’ 0.0408 莫耳）、氫删化經（1.78 g ’ 0.00816 莫耳）與 THF (450 mL)。於&lt;25°C下慢慢添加乙醇（18.8 g，0.408莫耳），黃色混 合物於室溫下授掉4小時。小心添加甲醇（4〇 mL),混合物 濃縮至約50 mL體積。混合物經乙酸乙酯（25〇 mL)稀釋，以 5%NaHC〇3水溶液與水（3〇〇mL)洗滌。有機層濃縮，與乙酸 乙酉旨（2 5 0 mL X 2)共)弗至體積約5 0 mL。所得沉殿經庚燒（5 〇 mL)稀釋，於室溫下攪拌一夜後，於5下攪拌2小時。固 體過滤，以庚烷（20 mL)潤洗，於50°C下乾燥，產生7.70 g 產物（收率 75%); mp: 103-104°C (未校正）；MS (ESI)·· 251，253 (M+H) + ; iH-NMR (CDC13) δ 7.96 (1 H，d，J=8.4 Hz)，7.90 (1 H，d，J=2.2 Hz)，7.84 (1 H，d，J=8.9 Hz)，7.72 (1 H，dd，J=8.9, 2.2 Hz)，7.27 (1 H，d，J=8.4 Hz)，4.13 (2H，d，J=5.6 Hz)，3.19 (2H，d，J=5.6 Hz) ; 13C-NMR (CDC13) δ 161.3, 145.4, 135.1， 132.6, 130.1，129·2, 127.5, 122.4, 119.5, 61.2, 39.7。Example 42B 2- (6-Bromo-2 j-Lin based on rat Mongolian gas' was added to the 1 L round bottom flask with the product of Example 42a (120 g '0.0408 mol), Hydrodeletion Script (1.78 g' 0.00816 mol ) And THF (450 mL). Ethanol (18.8 g, 0.408 mol) was slowly added at &lt; 25 ° C, and the yellow mixture was allowed to cool at room temperature for 4 hours. Careful addition of methanol (40 mL), the mixture was concentrated To about 50 mL volume. The mixture was diluted with ethyl acetate (250 mL), washed with 5% NaHC03 aqueous solution and water (300 mL). The organic layer was concentrated and concentrated with ethyl acetate (250 mL X 2 ) A total of about 50 mL volume. The obtained Shen Dian was diluted with heptane (50 mL), and after stirring at room temperature overnight, it was stirred at 5 for 2 hours. The solid was filtered, rinsed with heptane (20 mL), and dried at 50 ° C, yielding 7.70 g of product (75% yield); mp: 103-104 ° C (uncorrected); MS (ESI) · 251 , 253 (M + H) +; iH-NMR (CDC13) δ 7.96 (1 H, d, J = 8.4 Hz), 7.90 (1 H, d, J = 2.2 Hz), 7.84 (1 H, d, J = 8.9 Hz), 7.72 (1 H, dd, J = 8.9, 2.2 Hz), 7.27 (1 H, d, J = 8.4 Hz), 4.13 (2H, d, J = 5.6 Hz), 3.19 (2H, d , J = 5.6 Hz); 13C-NMR (CDC13) δ 161.3, 145.4, 135.1, 132.6, 130.1, 129.2, 127.5, 122.4, 119.5, 61.2, 39.7.

實例42C -138- 89248.doc 200418454 全二甲基酸2 - (6 -漠-2 - p奎淋基）乙 在5〇0 mL圓底燒瓶中添加實例產物（7.65 g，0.030莫 耳）、4-N，N_二甲胺基吡啶（0.36 g，0.003莫耳）、二氯甲烷（100 mL)與二乙胺（9.3 g，〇·〇92 mmol)。分批添加對甲苯續醯氯 (11 · 5 g，0.060莫耳），溶液於室溫下攪拌6小時。溶液汽提 至乾’粗產物溶於乙酸乙酯（15〇 mL)與5% NaHC〇3水溶液 (150 mL)中。上層有機相經水（15〇 mL)洗滌，濃縮，與乙酸 乙酯（250 mL X 2)共沸至體積約50 mL。漿狀物經庚燒（50 mL)稀釋，，於室溫下攪拌一夜後，於下8小時。過濾收集 沉澱，以庚烷（20 mL)潤洗，於50°C下真空乾燥一夜，產生 10.80g灰白色固體產物；mp 107-109°C ; MS (ESI): 406, 408 (M+H) + ; &quot;H-NMR (CDC13) δ 7.92 (1 H，m)，7·91 (1 H，m)，7.7 (2H，m)，7·58 (2H，m )，7.25 (1 H，d，J=8.4 Hz)，7.09 (2H，m)， 4.56 (2H，t，J=6.3 Hz)，3·27 (2H，t，J=6.3 Hz)，2.33 (3H，s); i3C-NMR (CDC13) δ 157.2，145.9，144.1，135.0，132.5，132.3, 130.3，129.2, 129.2，127.7，127.4，122·5，119.6，69·2，38.0, 21.8 °Example 42C -138- 89248.doc 200418454 Full dimethyl acid 2- (6-mo-2 -p-quinolyl) e In a 5000 mL round bottom flask was added the product of the example (7.65 g, 0.030 mole), 4-N, N-dimethylaminopyridine (0.36 g, 0.003 mole), dichloromethane (100 mL) and diethylamine (9.3 g, 0.092 mmol). P-toluene chloride (11.5 g, 0.060 mol) was added in portions, and the solution was stirred at room temperature for 6 hours. The solution was stripped to dryness and the crude product was dissolved in ethyl acetate (150 mL) and 5% aqueous NaHC03 solution (150 mL). The upper organic phase was washed with water (150 mL), concentrated, and azeotroped with ethyl acetate (250 mL X 2) to a volume of about 50 mL. The slurry was diluted with heptane (50 mL) and stirred overnight at room temperature for 8 hours. The precipitate was collected by filtration, rinsed with heptane (20 mL), and dried under vacuum at 50 ° C overnight, yielding 10.80 g of off-white solid product; mp 107-109 ° C; MS (ESI): 406, 408 (M + H) +; &quot; H-NMR (CDC13) δ 7.92 (1 H, m), 7.91 (1 H, m), 7.7 (2H, m), 7.58 (2H, m), 7.25 (1 H, d, J = 8.4 Hz), 7.09 (2H, m), 4.56 (2H, t, J = 6.3 Hz), 3.27 (2H, t, J = 6.3 Hz), 2.33 (3H, s); i3C- NMR (CDC13) δ 157.2, 145.9, 144.1, 135.0, 132.5, 132.3, 130.3, 129.2, 129.2, 127.7, 127.4, 122.5, 119.6, 69.2, 38.0, 21.8 °

實例42D 6-溴__:2 - {2-f(2R)-2_甲基- I”比洛咬某1乙基卜奎g林 取（2R)-2-甲基吡咯啶L-酒石酸鹽（7.00 g，0.0298 mole， 磨粉）、碳酸鉀（9.04 g，0.065 5 mole，磨粉）與乙腈（190 mL) 合併，於60°C下攪拌加熱48小時。使混合物冷卻至30°C ; 經實例42C產物（8.00 g，0.0197莫耳）處理。反應混合物於 約60°C下加熱36小時後，蒸餾至約1/4體積，添加乙酸異 89248.doc -139- 200418454 丙醋（200 mL)。混合物經5% NaHC〇3水溶液（200 mL χ 2)與 25%鹽水（200 mL)洗滌。上層有機相經無水硫酸鈉脫水，過 濾’濾液濃縮至乾。粗產物經短管柱矽膠，以庚烷：乙酸 乙酯：TEA (60 : 40 : 1)溶離純化，產生5·8 g (收率92%)油 狀產物，靜置時即固化；mp 49-5CTC (未校正）：MS (ESI): 319, 311 (M+H)VH-NMR (CDC13) δ 7·95 (1 H，d，J=8.5 Ηζ)，7·91 (1H，d，J=2.2 Hz)，7·89 (1 H，d，J=8.9 Hz)，7.72 (1 H，dd， J=8.9, 2.2 Hz)，7·35 (1H，d，J=8.5 Hz)，3·23 (2H，m)，3.18 (2H，m)，J.55 (1H，m)，2·38 (1H，m)，2.25 (1H，q，J=8.9 Hz)， 1·93 (1H，m)，1.80 (1H，m)，1·71 (1H，m)，1·42 (1H，m)，l.ll (3H，d，J=6.0 Hz); 13C-NMR (CDC13) δ 161.3, 146.1，134.7, 132.3，130.3，129.2，127.6，122.2，119·2，59.9，54.0，53.6, 38·6, 33.0, 22.0, 19·4。 實例42Ε 甲基比咯啶某1乙基啉基）苯某氧 取實例42D產物（160 mg，0.5 mmol)、4-氰基苯基二羥硼 酸（0.75 mmol)與二氯雙（三苯基膦）鈀（π)(35 1 mg，〇 〇5 mmol)於異丙醇（5·〇 mL)與 〇·2 Μ K3P〇4 水溶液（5.〇 mL，} 〇 mmol)中合併，於6〇°C下加熱24小時。反應混合物冷卻至 室溫’以乙酸乙酯（20 mL)稀釋。分離有機相，以5% NaHC〇3 (25 mL· X 3)、25%鹽水（25 mL)洗滌，經硫酸鈉脫水，過漉 慮液;辰縮至乾。殘質經管柱層析法純化（庚院：丙酮' CH2C12 ·· TEA (60 : 40 : 5 : 1)，產生標題化合物。標題化合 物經一當量L-酒石酸，於IPA:乙醇中處理，產生酒石酸鹽 89248.doc -140- 200418454 。mp 164°C; MS (ESI) 342 (M + H)4·; 4 NMR (DMS〇-d6) δ 8.40 (1H，d)，8·38 (1H，d)，8·12 (1H，d)，8.06 (1H，d), 8·04 (2H，d)，7.98 (2H，d)，7·58 (1H，d)，4.05 (2H，s)，3.63 (1H， m)，3.50 (1H，m)，3.33 (2H，t)，3.15 (2H，m)，2.88 (1H，m)， 2.09 (1H, m), 1.86 (2H，m)，1.55 (1H，m)，1.29 (3H，d)。 實例43 鼠夺.基）-2-{2-「（2R)_2-甲基-1-啦各啶某1 某}?奋4 標題化合物係依實例42Ε之方法製備，但其中改用4-氟苯Example 42D 6-Bromo __: 2-{2-f (2R) -2_methyl-I "Billot bite a certain ethyl ethyl quinine glin to take (2R) -2-methylpyrrolidine L-tartaric acid Salt (7.00 g, 0.0298 mole, ground powder), potassium carbonate (9.04 g, 0.065 5 mole, ground powder) and acetonitrile (190 mL) were combined and stirred and heated at 60 ° C for 48 hours. The mixture was cooled to 30 ° C Treated with the product of Example 42C (8.00 g, 0.0197 mol). After heating the reaction mixture at about 60 ° C for 36 hours, it was distilled to about 1/4 volume, and acetic acid iso 89248.doc -139- 200418454 propionate (200 mL). The mixture was washed with 5% NaHC03 aqueous solution (200 mL x 2) and 25% brine (200 mL). The upper organic phase was dehydrated over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness. The crude product was passed through a short column of silica gel. , Purified by dissolution and purification with heptane: ethyl acetate: TEA (60: 40: 1) to produce 5.8 g (92% yield) of oily product, which solidifies when standing; mp 49-5CTC (uncorrected): MS (ESI): 319, 311 (M + H) VH-NMR (CDC13) δ 7.95 (1 H, d, J = 8.5 Ηζ), 7.91 (1H, d, J = 2.2 Hz), 7 · 89 (1 H, d, J = 8.9 Hz), 7.72 (1 H, dd, J = 8.9, 2.2 Hz), 7.35 (1H, d, J = 8.5 Hz ), 3.23 (2H, m), 3.18 (2H, m), J.55 (1H, m), 2.38 (1H, m), 2.25 (1H, q, J = 8.9 Hz), 1 · 93 (1H, m), 1.80 (1H, m), 1.71 (1H, m), 1.42 (1H, m), 1.11 (3H, d, J = 6.0 Hz); 13C-NMR ( CDC13) δ 161.3, 146.1, 134.7, 132.3, 130.3, 129.2, 127.6, 122.2, 119.2, 59.9, 54.0, 53.6, 38.6, 33.0, 22.0, 19.4. Example 42E Methylpyrrolidine 1 Ethyl phosphono) benzene oxygen was obtained from the product of Example 42D (160 mg, 0.5 mmol), 4-cyanophenyldihydroxyboronic acid (0.75 mmol) and dichlorobis (triphenylphosphine) palladium (π) (35 1 mg, 0.05 mmol) in isopropanol (5.0 mL) and 0.2 M K3P04 aqueous solution (5.0 mL,} mmol) were combined and heated at 60 ° C for 24 hours. The reaction The mixture was cooled to room temperature 'and diluted with ethyl acetate (20 mL). The organic phase was separated, washed with 5% NaHC03 (25 mL · X 3), 25% brine (25 mL), dehydrated with sodium sulfate, and filtered through an aqueous solution; shrink to dryness. The residue was purified by column chromatography (Gengyuan: Acetone 'CH2C12 ·· TEA (60: 40: 5: 1) to give the title compound. The title compound was treated with one equivalent of L-tartaric acid in IPA: ethanol to produce tartaric acid. Salt 89248.doc -140- 200418454.mp 164 ° C; MS (ESI) 342 (M + H) 4 ·; 4 NMR (DMS〇-d6) δ 8.40 (1H, d), 8.38 (1H, d ), 8.12 (1H, d), 8.06 (1H, d), 8.04 (2H, d), 7.98 (2H, d), 7.58 (1H, d), 4.05 (2H, s), 3.63 (1H, m), 3.50 (1H, m), 3.33 (2H, t), 3.15 (2H, m), 2.88 (1H, m), 2.09 (1H, m), 1.86 (2H, m), 1.55 (1H, m), 1.29 (3H, d). Example 43 Murine. 2) 2- {2-"(2R) _2-methyl-1-lagodine 1 1}? 4 Title Compound System Prepared according to the method of Example 42E, but using 4-fluorobenzene instead

基一备佩酸替代4-夜基苯基二禮酸。標題化合物經hc 1 ，於IPA:乙酸乙酯中處理，產生二鹽酸鹽。mpM5t：;MS (ESI) 335 (M+H) ； ιΗ NMR (DMSO-d6) δ 8.88 (1H5 d)5 8.5 (1H，br)，8·42 (1H，d)，8·37 (1H，d)，7·97 (1H，d)，7·91 (2H， dd)，7.40 (2H，t)，3·93 (1H，br)，3·72 (3H，b〇, 3.5 (2H，br)， 3·26 (1H，br)，2·2 (1H，m)，2.0 (2H，br)，1·7 (1H，br)，1.42 (3H，br)。 實例44 基-丨-峨一哈啶基1乙基啉基）笨某教 標題化合物係依實例42Ε之方法製備，但其中改用弘氰基 苯基二羥硼酸替代4-氰基苯基二羥硼酸。標題化合物經一當 量L-酒石酸，於ΙΡΑ:乙醇中處理，產生酒石酸鹽。mp 172它 ;MS (ESI) 342 (M+H) + ; lE NMR (DMSO-d6) δ 9.2 (1H? d)? 8.61 (1H，d)，8.42 (2H，重疊），8·21 (1H，d)，8 19 (1H，d)， 8.17 (1H，dt)，7.82 (1H，dt)，7.75 (lH，t)，4.88 (2H，s)，4.06 (lH，m)，3.90 (3H，m)，3·65 (2H，m)，2.40 (1H，m)，2.20 (2H， 89248.doc -141 - 200418454 m)，1.84 (1H，m)，1.59 (3H，d)。 實例45 乙某卜6-4 啉基）笨基 1 乙酮 標題化合物係依實例42E之方法製備，但其中改用弘乙醯 苯基一羥硼酸替代4-氰基苯基二羥硼酸。標題化合物經HC j ，於IPA:乙酸乙酯中處理，產生二鹽酸鹽。mp 174」75r ；MS (ESI) 359 (M+H)+ ； NMR (CD3OD) δ 9.14 (1H5 d)? 8·56, 8·5Ρ (1H，d)，8·4 (2H，m)，8.33, 7·79 (lH，t)，8·14 (1H， dd)，8.05(1H，dt)，7.74, 7·52 (1H，dt)，7·62, 7·50(1Η，t), 4·02 (1H，m)，3·83 (2H，m)，3·60 (2H，m)，3·41 (1H，m)，2·62 (1H， m)，2·37 (1H，m)，2·15 (3H，m)，1.80 (1H，m)，1.53 (3H，s)， 1.1 (3H，d)。 實例46 苯基VU2-『（2R)-2·甲某-U,比咯啶某基卜套啉 標題化合物係依實例42Ε之方法製備，但其中改用4-甲氧 苯基二羥硼酸替代4-.氰基苯·基二羥硼酸。標題化合物經HC1 ’於ΙΡΑ :乙酸乙酯中處理，產生二鹽酸鹽。mp 165。〇(分 解）；MS (ESI) 347 (M+H)+ ; 4 NMR (CD3OD) δ 9.12 (1H，d)， 8.46 (2H，m)，8.36 (1H，d)，8·11 (1H，d)，7·80 (2H，d)，7.10 (2H，d)，4.02 (1H，m)，3.90 (3H，s)，3.82 (2H，m)，3·62 (2H， m)，3.41 (1H，m)，2.39 (2H，m)，2.18 (2H，m)，1·82 (1 H，m)， 1·56 (3H，d)。 實例47 89248.doc -142- 200418454 比咯啶基1乙某}_6_「4_(三氟甲基）笨基1 口奎口林 標題化合物係依實例42E之方法製備，但其中改用4-(三 氟甲基）苯基二獲硼酸替代4-氰基苯基二經硼酸。標題化合 物經HC1，於IPA :乙酸乙酯中處理，產生二鹽酸鹽。mp 143-145 C (分解）；MS (ESI) 385 (M+H)+; 4 NMR (DMSO-d6) δ 8·65 (1H，d)，8·50 (1H，s)，8·23 (2H，m)，8.09 (2H，d)，7.91 (2H，d)，7·74 (1H，d)，4·0_3·4 (6H，br，m)，3.22 (1H，br)，2.22 (1H，br)，3.0 (2H，m)，1.70 (1H，m)，1.44 (3H，br)。 實例48 K2-「（2R)_2~：X^:i-够—查直基1乙^^_「4_(甲碏醯某^茉某] 口奎琳 標題化合物係依實例42Ε之方法製備，但其中改用4_(甲 磺醯基）苯基二羥硼酸替代4_氰基苯基二羥硼酸。標題化合 物經HC1，於ΙΡΑ:乙酸乙酯中處理，產生二鹽酸鹽。Ms (esi) 395 (Μ+Η)+ ； *H NMR (CD3OD) δ 9.05 (lH, d), 8.56 (1H, d), 8.45 (1H, dd), 8.38 (1H, d) , 8.10 (4H, m), 8.02 (1H, d),4.03 (1H, br, m), 3.85 (1H, br, m), 3.75 (2H, br, m), 3.62 (2H, br, m), 3.41 (1H, m),3.18(3H, s), 2.39 (1H, m), 2.18(2H, m), 1.82 (1H，m)，1·57 (3H，br，d)。 實例49 m·-二氟笨咬某]乙基^杏淋-標題化合物係依實例42E之方法製備，但其中改用3,5_二氟 苯基二㈣酸替代4_氰基苯基：_酸。標題化合物經⑽ 89248.doc -143 - 200418454 ，於IPA:乙酸乙酯中處理，產生二鹽酸鹽。mp 164_165t：; MS (ESI) 353 (M+H)+ ; 4 NMR (DMS〇-d6) δ 8·72 (1H，d)， 8·59 (1H，s)，8.31 (2H，m)，7·76 (1H，d)，7·63 (2H，dd)，7.55 (1H，tt)，3·90 (1H，br)，3.63 (2H，br，m)，3.50 (2H，br，m)， 3·23 (1H，br)，2.9-2.6 (1H，br，m)，2.2 (1H，m)，1.98 (2H，br， m)，1.64 (1H，br，m)，1.45 (3H，br)。 實例50 LI:氟苯基3(2-{2-「(2R)」^甲基小p比咯啶基1乙某丨L林基） ^ 甲酮 於-78°C下，取含實例42D產物（320 mg，ΐ·〇 mm〇i)之THF (10 mL)經 2·5 Μ正丁基鍾（〇·5 mL，1.25 mmol)處理。此溶液 混合15分鐘’於-78°C下，以含3-氟-N-甲氧基-N-甲基苯醯 胺（2.0 mmol)之THF (5.0 mL)溶液處理。使混合物回升至室 溫一夜’以1 mL乙醇中止反應，濃縮，以乙酸乙酯稀釋。 混合物經 5% NaHC03 (25 mL X 3)、25% 鹽水（25 mL)洗滌， 經硫酸鈉脫水，過濾，濾液濃縮至乾。殘質經管柱層析法 純化（庚烷：丙酮：CH2C12 : TEA (60 : 40 : 5 : 1)，產生標 題化合物。標題化合物經HC1，於IPA :乙酸乙酯中處理， 產生二鹽酸鹽。mp 162-164。(：（分解）；MS (ESI) 363 (M+H) + ;4 NMR (DMSO-d6) δ 8·79 (1H，d)，8.53 (1H，d)，8.30 (1H， d)，8.21 (1H，dd)，7·82 (1H，d)，7·6 (4H，m)，3·9 (1H，br，m)， 3·63 (2H，bi*，m)，3.50 (2H，br，m)，3.21 (1H，bi*，m)，2.2 (1H， m)，1.98 (2H，bi*，m)，1·7 (1H，br，m)，1.46 (1H，m)，1.30 (3H， d) ° 89248.doc -144- 200418454 實例5 1 2-{2-「（2_民）-2-甲某-1-吡咯啶基1乙基丨-6-(3-说啶基&gt;奎啉 取肆（三苯基膦巴（0)(28.8 mg，0.025 mmol)、2-(二環己 基膦基）聯苯（35.0 mg，0.10 mmol)、3-p比淀基二幾硼酸（0.375 mmol)與碳酸鈉（40·0 mg，0.3 75 mmol)於 1，2-二甲氧乙烷（4 mL)與水（1.5 mL)中合併。混合物經實例42D產物（80 mg， 0.25 mmol)處理，於80°C下加熱24小時。使反應混合物冷 卻至室溫，以乙酸乙酯（20 mL)稀釋。分離有機層，以5% NaHC〇3 ζ25 mL X 3)、25%鹽水（25 mL)洗滌，經硫酸鈉脫水 ’過漉’漉液濃縮至乾。殘質經管柱層析法純化（庚燒：丙 酮：CH2C12 : TEA (60 : 40 : 5 : 1)，產生標題化合物。標 題化合物經HC1，於IPA ··乙酸乙酯中處理，產生三鹽酸鹽 。mp 205-207°C ; MS (ESI) 318 (M+H)+ ; 4 NMR (DMSO-d6) δ 9.48 (1H，br，s)，9.05 (1H，d)，8.96 (1H，d)，9.00 (1H, d)， 8·86 (1H，bi*，s)，8.60 (1H，d)，8.59 (1H，d)，8·32 (1H，dd)， 8.23 (1H，d)，4·08 (1H，br，m)，3·9〇 (2H，br，叫，3.65 (2H，br， m)，3·46 (1H，q)，2'40 (ih，m)，2.19 (2H，m)，1.84 (1H， m)，1.58 (3H，d)。 t例52 lr..(3-{2-「(2R)-2-甲基二L-咬基i乙基異，套啉某）笨基氰A substituted amino acid is used instead of 4-phenylphenyl diacetic acid. The title compound was treated with hc 1 in IPA: ethyl acetate to give the dihydrochloride salt. mpM5t :; MS (ESI) 335 (M + H); ιΗ NMR (DMSO-d6) δ 8.88 (1H5 d) 5 8.5 (1H, br), 8.42 (1H, d), 8.37 (1H, d), 7.97 (1H, d), 7.91 (2H, dd), 7.40 (2H, t), 3.93 (1H, br), 3.72 (3H, b0, 3.5 (2H, br), 3.26 (1H, br), 2.2 (1H, m), 2.0 (2H, br), 1.7 (1H, br), 1.42 (3H, br). Example 44 Base-丨- Ethharidinyl 1-Etholinyl) The title compound was prepared according to the method of Example 42E, but the cyanophenyldihydroxyboronic acid was used instead of 4-cyanophenyldihydroxyboronic acid. The title compound was treated with one equivalent of L-tartaric acid in IPA: ethanol to give a tartrate salt. mp 172 it; MS (ESI) 342 (M + H) +; 1E NMR (DMSO-d6) δ 9.2 (1H? d)? 8.61 (1H, d), 8.42 (2H, overlap), 8.21 (1H , D), 8 19 (1H, d), 8.17 (1H, dt), 7.82 (1H, dt), 7.75 (lH, t), 4.88 (2H, s), 4.06 (lH, m), 3.90 (3H M), 3.65 (2H, m), 2.40 (1H, m), 2.20 (2H, 89248.doc -141-200418454 m), 1.84 (1H, m), 1.59 (3H, d). Example 45 Ethyl 6-6 phosphono) benzyl 1 ethyl ketone The title compound was prepared according to the method of Example 42E, but in which the diethyl phenylmonohydroxyboronic acid was used instead of 4-cyanophenyldihydroxyboronic acid. The title compound was treated with HCj in IPA: ethyl acetate to give the dihydrochloride. mp 174 ″ 75r; MS (ESI) 359 (M + H) +; NMR (CD3OD) δ 9.14 (1H5 d)? 8.56, 8 · 5P (1H, d), 8.4 (2H, m), 8.33, 7.79 (lH, t), 8.14 (1H, dd), 8.05 (1H, dt), 7.74, 7.52 (1H, dt), 7.62, 7.50 (1Η, t) , 4.02 (1H, m), 3.83 (2H, m), 3.60 (2H, m), 3.41 (1H, m), 2.62 (1H, m), 2.37 ( 1H, m), 2.15 (3H, m), 1.80 (1H, m), 1.53 (3H, s), 1.1 (3H, d). Example 46 The title compound of phenyl VU2-[(2R) -2 · a-m-U, bipyridine and a propyl blocline was prepared according to the method of Example 42E, but 4-methoxyphenyldihydroxyboronic acid was used instead. 4-.Cyanobenzene · dihydroxyboronic acid. The title compound was treated with HC1 'in IPA: ethyl acetate to give the dihydrochloride salt. mp 165. 〇 (decomposition); MS (ESI) 347 (M + H) +; 4 NMR (CD3OD) δ 9.12 (1H, d), 8.46 (2H, m), 8.36 (1H, d), 8.11 (1H, d), 7.80 (2H, d), 7.10 (2H, d), 4.02 (1H, m), 3.90 (3H, s), 3.82 (2H, m), 3.62 (2H, m), 3.41 (1H, m), 2.39 (2H, m), 2.18 (2H, m), 1.82 (1 H, m), 1.56 (3H, d). Example 47 89248.doc -142- 200418454 pyrrolidinyl 1 ethyl} _6_ "4_ (trifluoromethyl) benzyl 1 koukoulin The title compound was prepared according to the method of Example 42E, but 4- (4) was used instead. Trifluoromethyl) phenyl diboronic acid replaces 4-cyanophenyl diboronic acid. The title compound is treated with HC1 in IPA: ethyl acetate to give the dihydrochloride salt. Mp 143-145 C (decomposition); MS (ESI) 385 (M + H) +; 4 NMR (DMSO-d6) δ 8.65 (1H, d), 8.50 (1H, s), 8.23 (2H, m), 8.09 (2H , D), 7.91 (2H, d), 7.74 (1H, d), 4.0 · 3.4 · 6 (6H, br, m), 3.22 (1H, br), 2.22 (1H, br), 3.0 (2H , M), 1.70 (1H, m), 1.44 (3H, br). Example 48 K2-"(2R) _2 ~: X ^: i-sufficient—Cha Zhiji 1 B ^^ _" 4_ (甲 碏 醯[Mr. Momo] The title compound was prepared according to the method of Example 42E, but 4_ (methylsulfonyl) phenyldihydroxyboronic acid was used instead of 4-cyanophenyldihydroxyboronic acid. The title compound was treated with HC1, Treatment in IPA: ethyl acetate to generate the dihydrochloride salt. Ms (esi) 395 (Μ + Η) +; * H NMR (CD3OD) δ 9.05 (lH, d), 8.56 (1H, d), 8.45 ( 1H, dd), 8.38 (1H, d), 8.1 0 (4H, m), 8.02 (1H, d), 4.03 (1H, br, m), 3.85 (1H, br, m), 3.75 (2H, br, m), 3.62 (2H, br, m), 3.41 (1H, m), 3.18 (3H, s), 2.39 (1H, m), 2.18 (2H, m), 1.82 (1H, m), 1.57 (3H, br, d). Example 49 m · -Difluorobenzyl] ethyl ^ Apricot-The title compound was prepared according to the method of Example 42E, but 3,5-difluorophenyldiphosphonic acid was used instead of 4-cyanophenyl: acid. The compound was treated with ⑽ 89248.doc -143-200418454 in IPA: ethyl acetate to produce a dihydrochloride salt. Mp 164_165t :; MS (ESI) 353 (M + H) +; 4 NMR (DMS〇-d6) δ 8.72 (1H, d), 8.59 (1H, s), 8.31 (2H, m), 7.76 (1H, d), 7.63 (2H, dd), 7.55 (1H, tt) , 3.90 (1H, br, m), 3.63 (2H, br, m), 3.50 (2H, br, m), 3.23 (1H, br), 2.9-2.6 (1H, br, m), 2.2 ( 1H, m), 1.98 (2H, br, m), 1.64 (1H, br, m), 1.45 (3H, br). Example 50 LI: Fluorophenyl 3 (2- {2-"(2R)" ^ methyl small p than pyridinyl 1 ethyl 丨 L linyl) ^ Methyl ketone at -78 ° C, containing Example 42D The product (320 mg, 1000 mm) in THF (10 mL) was treated with 2.5 M n-butyl bell (0.5 mL, 1.25 mmol). This solution was mixed for 15 minutes' at -78 ° C and treated with a solution of 3-fluoro-N-methoxy-N-methylphenylhydrazine (2.0 mmol) in THF (5.0 mL). The mixture was allowed to warm to room temperature overnight 'to terminate the reaction with 1 mL of ethanol, concentrated, and diluted with ethyl acetate. The mixture was washed with 5% NaHC03 (25 mL X 3), 25% brine (25 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (heptane: acetone: CH2C12: TEA (60: 40: 5: 1) to give the title compound. The title compound was treated with HC1 in IPA: ethyl acetate to give the dihydrochloride salt. .Mp 162-164. (: (Decomposition); MS (ESI) 363 (M + H) +; 4 NMR (DMSO-d6) δ 8 · 79 (1H, d), 8.53 (1H, d), 8.30 ( 1H, d), 8.21 (1H, dd), 7.82 (1H, d), 7.6 (4H, m), 3.9 (1H, br, m), 3.63 (2H, bi *, m), 3.50 (2H, br, m), 3.21 (1H, bi *, m), 2.2 (1H, m), 1.98 (2H, bi *, m), 1.7 (1H, br, m), 1.46 (1H, m), 1.30 (3H, d) ° 89248.doc -144- 200418454 Example 5 1 2- {2-"(2_min) -2-methyl-1-1-pyrrolidinyl 1ethyl 丨-6- (3-Samidinyl) & quinoline: Triphenylphosphine (0) (28.8 mg, 0.025 mmol), 2- (dicyclohexylphosphino) biphenyl (35.0 mg, 0.10 mmol) , 3-p-pyridyl dichioric acid (0.375 mmol) and sodium carbonate (40.0 mg, 0.3 75 mmol) were combined in 1,2-dimethoxyethane (4 mL) and water (1.5 mL). The mixture was treated with the product of Example 42D (80 mg, 0.25 mmol) and heated at 80 ° C. for 24 hours. The reaction was allowed to proceed The mixture was cooled to room temperature and diluted with ethyl acetate (20 mL). The organic layer was separated, washed with 5% NaHC03 (25 mL x 3), 25% brine (25 mL), and dehydrated over sodium sulfate. The solution was concentrated to dryness. The residue was purified by column chromatography (heptane: acetone: CH2C12: TEA (60: 40: 5: 1) to give the title compound. The title compound was treated with HC1 in IPA ·· ethyl acetate , Producing trihydrochloride. Mp 205-207 ° C; MS (ESI) 318 (M + H) +; 4 NMR (DMSO-d6) δ 9.48 (1H, br, s), 9.05 (1H, d), 8.96 (1H, d), 9.00 (1H, d), 8.86 (1H, bi *, s), 8.60 (1H, d), 8.59 (1H, d), 8.32 (1H, dd), 8.23 (1H, d), 4.08 (1H, br, m), 3.90 (2H, br, called, 3.65 (2H, br, m), 3.46 (1H, q), 2'40 ( ih, m), 2.19 (2H, m), 1.84 (1H, m), 1.58 (3H, d). Example 52 lr .. (3- {2-"(2R) -2-methyldi-L-methyl-i-isopropyl, iodoline) benzyl cyanide

XM52A (6-&gt;臭-1-乳益-2-某）乙酸乙酯 滴加正丁基裡（14 mL ’ 2 Μ戊燒溶液）至冷卻至_7〇°C之含 二異丙胺（2.86 g，28 mmol)之四氫呋喃（6〇 mL)溶液中。於 89248.doc -145 - 200418454 -70°C下攪拌30分鐘後，混合物經6-溴小茚滿酮（4 8 g，22 7 mmol)(依 J.Org. Chem·，49:4226-423 (1984)所述之方法製備） 於5分鐘内分兩份處理。1〇分鐘後，使混合物回升至_5(rc，以 溴乙酸乙g旨（4.8 g，28 mmol)處理。使混合物回升至， 於-10 土 -1 5 C下搜拌1小時。小心依序加水（go mL)與乙酸異 丙酯（60 mL)中止反應。分離有機層，依序以HC1水溶液（5〇 mL，使用濃HC1調整水之pH至2製成）及碳酸鉀水溶液（5〇 mL，5%)洗滌。有機層真空濃縮，產生標題化合物，未再 純化即用$於下一個步驟。 實例52B 溴小蕤某-2,3-二氤-1H-益-2-其、Λ齡 取含實例52Α產物之THF經第三丁基胺基甲硼烷（丨.丨8 g ’ 13.5 mmol)處理，於40-45°C下加熱2.5小時。混合物經氫 氧化鈉溶液（1.8 g含於水中，40 mL)處理，續加熱3〇分鐘。 使混合物冷卻至室溫，分離水層。有機層經乙酸異丙醋（4〇 mL)與水（40mL)稀釋，與水層合併。溶液冷卻至〇°c，然後 添加濃鹽酸調整pH至2。混合物過濾，濾塊於室溫下乾燥。 固體於二氯甲燒（6 mL)中形成漿物，再過濾，再乾燥，產 生標題化合物。XM52A (6- &gt; stinky-1-milk-2-some) ethyl acetate was added dropwise to n-butyl (14 mL '2 M pentamidine solution) until the diisopropylamine-containing ( 2.86 g, 28 mmol) in tetrahydrofuran (60 mL). After stirring at 89248.doc -145-200418454 -70 ° C for 30 minutes, the mixture was subjected to 6-bromominindone (4 8 g, 22 7 mmol) (according to J. Org. Chem., 49: 4226-423 (Prepared by the method described in (1984)). Treated in two portions within 5 minutes. After 10 minutes, the mixture was brought back to _5 (rc, treated with ethyl bromoacetate g (4.8 g, 28 mmol). The mixture was brought back to, and the mixture was stirred for 1 hour at -10 ° C to 1 5 ° C. Carefully follow Sequentially add water (go mL) and isopropyl acetate (60 mL) to stop the reaction. Separate the organic layer and sequentially use HC1 aqueous solution (50mL, adjust the pH of the water to 2 with concentrated HC1) and potassium carbonate aqueous solution (5 (0mL, 5%). The organic layer was concentrated in vacuo to give the title compound, which was used in the next step without further purification. Example 52B Brombeamidine-2,3-dihydrazone-1H-yi-2-Qi, The THF containing the product of Example 52A was treated with tert-butylaminoborane (丨. 8 g '13.5 mmol) and heated at 40-45 ° C for 2.5 hours. The mixture was subjected to sodium hydroxide solution (1.8 g in water, 40 mL), and continued heating for 30 minutes. The mixture was cooled to room temperature, and the aqueous layer was separated. The organic layer was diluted with isopropyl acetate (40 mL) and water (40 mL) and combined with the aqueous layer. The solution was cooled to 0 ° C, and then concentrated hydrochloric acid was added to adjust the pH to 2. The mixture was filtered, and the filter cake was dried at room temperature. The solid was slurried in dichloromethane (6 mL). , And then filtered and dried to give the title compound.

實例52C (5-溴-1H-莽-2-基）乙酸甲酯 取含實例52B產物（1.35 g，5 mmol)之甲醇（12 mL)經濃硫 紅（2 m L)處理’於溫和回流下加熱。2小時後，再加硫酸（1 mL)，續加熱2小時。混合物真空濃縮，殘質加水（丨5 mL)稀 89248.doc -146- 200418454 釋。混合物冷卻至10 C ’過滤，滤塊經水（5 ni L)洗務’乾 燦，產生標題化合物。4 NMR (CDC13) 53.42(s，2H);3.55 (s，2 H); 3·74 (s，3 H); 6.65 (m，1H); 7.22 -7.31 (m，2 Η)，7·44 (m，1H)。Example 52C (5-Bromo-1H-mangan-2-yl) methyl acetate. Methanol (12 mL) containing the product of Example 52B (1.35 g, 5 mmol) was treated with concentrated sulfur red (2 mL) under mild reflux Under heating. After 2 hours, add sulfuric acid (1 mL) and continue heating for 2 hours. The mixture was concentrated in vacuo and the residue was diluted with water (5 mL) 89248.doc -146- 200418454. The mixture was cooled to 10 C 'and filtered, and the filter cake was dried after washing with water (5 ni L) to give the title compound. 4 NMR (CDC13) 53.42 (s, 2H); 3.55 (s, 2 H); 3.74 (s, 3 H); 6.65 (m, 1H); 7.22 -7.31 (m, 2 Η), 7.44 (m, 1H).

實例52D L(5-溴-1H-益-2-基）乙醇 滴加含實例52C產物（1.1 g，4.1 mmol)之乙醚（5 mL)至含 氫化鋰鋁（0.125 g，3.3mmol)之乙醚（1〇 mL)懸浮液中，同時 保持内溫^在101：以下。攪拌30分鐘後，反應混合物經乙醚 (10 mL)稀釋，冷卻至〇°C，滴加飽和硫酸鈉水溶液處理。 傾析醚溶液，經硫酸鈉脫水，過漉，濾液濃縮，產生標題 化合物，未再純化即用於下一個步驟。NMR (CDC13) δ 2.77 (m，2H); 3.32 (s，2Η);3·88 (t，J=6.5 Hz，2H); 6·56 (m， 1H)，7·23 (m，2H); 7.40 (m，1H)。Example 52D L (5-bromo-1H-yi-2-yl) ethanol was added dropwise to a solution containing the product of Example 52C (1.1 g, 4.1 mmol) in ether (5 mL) to lithium aluminum hydride (0.125 g, 3.3 mmol) in ether (10 mL) suspension, while keeping the internal temperature at 101: or less. After stirring for 30 minutes, the reaction mixture was diluted with ether (10 mL), cooled to 0 ° C, and treated with saturated aqueous sodium sulfate solution dropwise. The ether solution was decanted, dehydrated over sodium sulfate, filtered, and the filtrate was concentrated to give the title compound, which was used in the next step without further purification. NMR (CDC13) δ 2.77 (m, 2H); 3.32 (s, 2Η); 3.88 (t, J = 6.5 Hz, 2H); 6.56 (m, 1H), 7.23 (m, 2H) 7.40 (m, 1H).

實例52E 2二(7 -溴-3 -吳4 p林某）乙醇 取含實例52D產物（0,85 g，_3.5 mmol)之甲醇（15 mL)於-70°C 下經臭氧處理至出現藍色為止（約1 〇分鐘）。混合物經二甲硫 (0.7 mL，過量）與碳酸氫鈉（〇·2 g)處理，使之回升至室溫。 攪拌3小時後，混合物經氫氧化鈉水溶液（7 4㈤乙，28%)處 理。再攪拌4小時後，反應混合物真空濃縮，以二氯甲烷（20 mL)稀釋。分離有機層，及蒸發，產生標題化合物，未再純 化即用於下一個步驟。iH NMR (CDC13) δ 3.13 (t，J=5.6 Hz， 2H); 4.07 (t，J=5.6 Hz，2H); 7.47 (s，1H); 7.61 (d，J=8.7 Hz， 89248.doc -147- 200418454 1H); 7·71 (dd，J=；L9，8.7 Hz，1H); 9·04 (s，1H);分析 CnHioBrNO :計算值 C，52·41; H，4.00; N，5.56。實測值： C，52·51; H，3.94; N，5·42。Example 52E 2 Bis (7-bromo-3-Wu 4 p Lin) ethanol Take methanol (15 mL) containing the product of Example 52D (0,85 g, _3.5 mmol) at -70 ° C and treat with ozone to Until blue appears (about 10 minutes). The mixture was treated with dimethylsulfide (0.7 mL, excess) and sodium bicarbonate (0.2 g) and allowed to warm to room temperature. After stirring for 3 hours, the mixture was treated with an aqueous solution of sodium hydroxide (74% ethyl, 28%). After stirring for another 4 hours, the reaction mixture was concentrated in vacuo and diluted with dichloromethane (20 mL). The organic layer was separated and evaporated to give the title compound, which was used in the next step without further purification. iH NMR (CDC13) δ 3.13 (t, J = 5.6 Hz, 2H); 4.07 (t, J = 5.6 Hz, 2H); 7.47 (s, 1H); 7.61 (d, J = 8.7 Hz, 89248.doc- 147- 200418454 1H); 7.71 (dd, J =; L9, 8.7 Hz, 1H); 9.04 (s, 1H); Analysis CnHioBrNO: calculated value C, 52 · 41; H, 4.00; N, 5.56 . Found: C, 52 · 51; H, 3.94; N, 5.42.

實例52F 4-甲......萎項酸2，（7 -溴-3-異ρ套4某）乙酯 取含貫例52Ε產物（0.51 g，2.0 mmol)、甲苯磺醯氯（0.68 g ，3·6 mmol)、三乙胺（〇·55 g，5·4 mmol)與 DMAP (25 mg， 0.2 mmol)於二氣甲烷（20 mL)中合併，於室溫下攪拌6小時 。混合物#水（0.5 mL)處理，攪拌2小時後，再以水（15 mL) 處理。分離有機層’以氯化鈉水溶液（i 〇 mL，丨〇%)處理， 真空蒸發，殘質與庚烷（15 mL)共沸，產生標題化合物，未 再純化即用於下一個步驟。Example 52F 4-methyl ..., 2,6- (7-bromo-3-isoρ) 4 ethyl ester of fulvic acid, containing the product of Example 52E (0.51 g, 2.0 mmol), tosylsulfonium chloride ( 0.68 g, 3.6 mmol), triethylamine (0.55 g, 5.5 mmol) and DMAP (25 mg, 0.2 mmol) in methane (20 mL) and stirred at room temperature for 6 hours . The mixture was treated with water (0.5 mL). After stirring for 2 hours, it was treated with water (15 mL). The separated organic layer was treated with an aqueous sodium chloride solution (100 mL, 100%), evaporated in vacuo, and the residue was azeotroped with heptane (15 mL) to give the title compound, which was used in the next step without further purification.

實例52G 2^..溴-3- {2-f(2R)-2-甲基-1-vr比味啶基1乙基}異4 4 取實例52F產物溶於含（2R)-2-甲基p比哈淀（0.26 g，3.0 mmol)之乙腈（20 mL)溶液中。溶液經石炭酸鉀（〇·5 g，3·6 mmol)處理，於密封燒瓶中.，在50-55Τ：下加熱20小時。使 混合物冷卻至室溫’過濾，濾液真空濃縮。殘質經MTBE (20 mL)與水（20 mL)稀釋，使用濃HC1調整pH至3-3.5。分離水 層，以MTBE (10mL)萃取，使用碳酸鉀調整pH至8-8.5，以 乙fe異丙酯（20 mL)萃取。分離有機層，真空濃縮。殘質溶 於庚烷（20 mL)中，過濾，濾液真空濃縮，產生標題化合物 。丨H NMR (CDC13) δ 1.10 (d，J=6.1 Hz，3H); 1.35-1.49 (m， 1H); 1.62-1.85 (m，2H); 1.85-1.98 (m，1H) ; 2.23 (q，J=8.8. 89248.doc -148 - 200418454Example 52G 2 ^ .. Bromo-3- {2-f (2R) -2-methyl-1-vr than amidinidyl 1ethyl} iso 4 4 The product of Example 52F was dissolved in (2R) -2- Methyl p-bihadine (0.26 g, 3.0 mmol) in acetonitrile (20 mL). The solution was treated with potassium carboxylate (0.5 g, 3.6 mmol) and placed in a sealed flask, and heated at 50-55 T: for 20 hours. The mixture was cooled to room temperature 'and filtered, and the filtrate was concentrated in vacuo. The residue was diluted with MTBE (20 mL) and water (20 mL), and the pH was adjusted to 3-3.5 using concentrated HC1. The aqueous layer was separated, extracted with MTBE (10 mL), adjusted to pH 8-8.5 with potassium carbonate, and extracted with ethyl isopropyl ester (20 mL). The organic layer was separated and concentrated in vacuo. The residue was dissolved in heptane (20 mL), filtered, and the filtrate was concentrated in vacuo to give the title compound.丨 H NMR (CDC13) δ 1.10 (d, J = 6.1 Hz, 3H); 1.35-1.49 (m, 1H); 1.62-1.85 (m, 2H); 1.85-1.98 (m, 1H); 2.23 (q, J = 8.8. 89248.doc -148-200418454

Hz，1H); 2.28-2.42 (m，1H); 2.46-2.57 (m，1H)，3.04-3.19 (m， 2H)，3.19-3.30 (m，2H); 7.47 (s，1H); 7.60 (d，Hz，1H)， 7.64-7.70 (m，1H)，8.05 (m，lH); 9·09 (s，1H); HRMS [C16H19BrN2 + H勹計算值：319.0810。實測值：319·0795。 1::(3二il_:K2R)-2-甲羞二各啶某1乙基}_7_異，苯基教 取含實例52G產物（0.2 g，〇·6 mm〇i)、4-氰基苯基二羥硼 酸（0.22 g，1.5 mmol)、雙（三苯基膦）鈀二氯化物（55 mg， 0.08mmcH)與磷酸鉀（7 mL，〇·2 M水溶液）於異丙醇（7 mL)中 合併，於密封燒瓶中，在60_65它下加熱7小時。混合物經 矽藻土過濾，濾液真空濃縮，然後分溶於MTBE (1〇 與 水（10 mL)之間。分離有機層，以碳酸氫鈉水溶液（5 %，1() mL)洗條後’以2 M HC1溶液（15 mL)萃取。使用碳酸4甲調 整性水層之pH ’以乙酸異丙g旨（15 mL)萃取。有機層真空 蒸發’在殘質中追加庚烷（10 mL)，產生標題化合物。NMR (CDC13) δ 1.12 (d? J=6.0 Hz, 3H); 1.37-1.50 (m? 1H); 1.64-1.85 (m, 2H), 1.85-1.98 (m? 1H); 2.26 (q3 J=8.8 Hz 1H). 2.32-2.43 (m, 1H) ； 2.50-2.60 (m5 1H)5 3.09-3.34 (m? 4H); 7 56 (m，1H); 7.73-7· 81 (m，4H)，7.84-7.87 (m，2H)，8.12 (m，1H)· 9.26 (s，1H) ; HRMS [C23H23N3 + H+]計算值：342 197〇。實 測值：342.1974。 實例53 - 甲』基異心汰其）笨某氛 標題化合物係依實例52H之方法製備，但其中改用3_氯基 89248.doc -149- 200418454 苯基二羥硼酸替代4-氰基苯基二羥硼酸。iHNMRCCDCh) δ 1.15 (d, J-6.1Hz, 3H); 1.39-1.54 (m5 1H); 1.66-1.87 (m52H); 1.88- 2.01 (m5 1H); 2.29 (q? J=8.8. Hz? 1H); 2.34-2.47 (m? 1H); 2.52-2.65 (m?lH)? 3.09-3.40 (m? 4H); 7.58 (m5 1H); 7.61 (d? J=7.8 Hz, 1H); 7.64-7.70 (m, lH)57.82-7.89 (m? 2H); 7.89- 7.95 (m，1H); 7·97 (m，1H)，8.10 (m，1H); 9·27 (s，1H)。 實例54Hz, 1H); 2.28-2.42 (m, 1H); 2.46-2.57 (m, 1H), 3.04-3.19 (m, 2H), 3.19-3.30 (m, 2H); 7.47 (s, 1H); 7.60 ( d, Hz, 1H), 7.64-7.70 (m, 1H), 8.05 (m, 1H); 9.09 (s, 1H); HRMS [C16H19BrN2 + H 勹 calculated value: 319.0810. Found: 319 · 0795. 1: :( 3-Di-il_: K2R) -2-Methyldipyridinium 1-ethyl} _7-iso, phenyl group contains the product of Example 52G (0.2 g, 0.6 mm), 4-cyano Phenyldihydroxyboric acid (0.22 g, 1.5 mmol), bis (triphenylphosphine) palladium dichloride (55 mg, 0.08mmcH) and potassium phosphate (7 mL, 0.2 M aqueous solution) in isopropanol (7 mL), combined in a sealed flask and heated at 60-65 for 7 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated in vacuo, and then separated into MTBE (10 and water (10 mL). The organic layer was separated and the strip was washed with an aqueous solution of sodium bicarbonate (5%, 1 () mL). Extract with 2 M HC1 solution (15 mL). Adjust the pH of the aqueous layer with 4A carbonic acid 'extract with isopropyl acetate (15 mL). Evaporate the organic layer under vacuum' Add heptane (10 mL) to the residue To produce the title compound. NMR (CDC13) δ 1.12 (d? J = 6.0 Hz, 3H); 1.37-1.50 (m? 1H); 1.64-1.85 (m, 2H), 1.85-1.98 (m? 1H); 2.26 (q3 J = 8.8 Hz 1H). 2.32-2.43 (m, 1H); 2.50-2.60 (m5 1H) 5 3.09-3.34 (m? 4H); 7 56 (m, 1H); 7.73-7 · 81 (m , 4H), 7.84-7.87 (m, 2H), 8.12 (m, 1H) · 9.26 (s, 1H); HRMS [C23H23N3 + H +] Calculated value: 342 197〇. Found: 342.1974. Example 53-A " The title compound was prepared according to the method of Example 52H, but 3-chloro 89248.doc -149- 200418454 was used instead of 4-cyanophenyldihydroxyboric acid. iHNMRCCDCh) δ 1.15 (d, J-6.1Hz, 3H); 1.39-1.54 (m5 1H); 1.66-1.87 (m52H); 1.88- 2.01 (m5 1H); 2.29 (q? J = 8.8. Hz? 1H) ; 2.34-2.47 (m? 1H); 2.52-2.65 (m? LH)? 3.09-3.40 (m? 4H); 7.58 (m5 1H); 7.61 (d? J = 7.8 Hz, 1H); 7.64-7.70 ( m, lH) 57.82-7.89 (m? 2H); 7.89- 7.95 (m, 1H); 7.97 (m, 1H), 8.10 (m, 1H); 9.27 (s, 1H). Example 54

6-{2-「（210-2-甲基-1-吡咯啶某1乙某丨-2-(3-吡啶基&gt;套啉 , 實例54A (2R)-2 -甲基- -石肖某苯基）乙基I?比p各淀 取（2R)-2-甲基吡咯啶L-酒石酸鹽（4.0 g，17.0 mmol)、1-(2-溴乙基）-4-硝基苯（9.8 g，43 mmol)與碳酸鉀（12 g，85 mmol) 於含於密封試管中之DMF(20mL)中合併，於50°C下激烈攪 拌16小時。使混合物冷卻至室溫，以乙醚（100 mL)稀釋， 以水洗滌（2次，100 mL，然後50 mL)，以1 M HC1萃取（2次 ，50 mL與25 mL)。合併酸性之水層萃液，以乙醚（50 mL) 洗滌，冷卻至〇°C，以50% NaOH溶液調至pH 14，以二氯 甲烷萃取（3次，50 mL)。合併二氣甲烷萃液，脫水（硫酸鎂） ，過濾，濾液濃縮，產生標題化合物。4 NMR (300 MHz， CDC13) δ 1.08 (d，J=6 Hz，3 H)，1.43 (m，1H)，1.75 (m，2 H)， 1.93 (m，1H)，2.19 (q，J=9 Hz，1H)，2.34 (m，2 H)，2.91 (m，2 H)，3.03 (m，1H)，3.22 (td，J=8, 3 Hz，1H)，7.38 (d，J=9 Hz，2 H)，8.15 (d，J=9 Hz，2 H); MS (DCI/NH3) m/z 235 (M+H)+。6- {2-"(210-2-methyl-1-pyrrolidinone, 1 ethyl, 1-2-(3-pyridyl) &gt; (2R) -2-methylpyrrolidine L-tartrate (4.0 g, 17.0 mmol), 1- (2-bromoethyl) -4-nitrobenzene (9.8 g, 43 mmol) and potassium carbonate (12 g, 85 mmol) were combined in DMF (20 mL) in a sealed tube, and stirred vigorously at 50 ° C for 16 hours. The mixture was cooled to room temperature, and ether was used. (100 mL) diluted, washed with water (twice, 100 mL, then 50 mL), and extracted with 1 M HC1 (twice, 50 mL and 25 mL). Combine the acidic aqueous layer extracts with ether (50 mL ) Wash, cool to 0 ° C, adjust to pH 14 with 50% NaOH solution, and extract with dichloromethane (3 times, 50 mL). Combine the two gaseous methane extracts, dehydrate (magnesium sulfate), filter, and concentrate the filtrate. The title compound was produced. 4 NMR (300 MHz, CDC13) δ 1.08 (d, J = 6 Hz, 3 H), 1.43 (m, 1H), 1.75 (m, 2 H), 1.93 (m, 1H), 2.19 ( q, J = 9 Hz, 1H), 2.34 (m, 2 H), 2.91 (m, 2 H), 3.03 (m, 1H), 3.22 (td, J = 8, 3 Hz, 1H), 7.38 (d , J = 9 Hz, 2 H), 8. 15 (d, J = 9 Hz, 2 H); MS (DCI / NH3) m / z 235 (M + H) +.

實例54B 89248.doc -150- 200418454 甲基乙基 &gt; 茉胺 取貝例54八產物（3.85 8，16.4 111111〇1)使用10%1)(1/(：(0.39§) ，於甲醇（20 mL)中，於1 atm Η:下氫化16小時。以N2置換 %後，混合物經甲醇（150 mL)稀釋，攪拌15分鐘，過濾， 濾液濃縮，產生標題化合物。A nmr poo mhi cdci3;&gt; δ 1.11 (d，J=6 Ηζ，3 Η)，1.43 (m，1Η)，1·74 (m，2 Η)，1·90 (m， 1Η)，2.25 (m，3 Η)，2.70 (m，2 Η)，2·97 (m，1Η)，3.24 (td，J=9 3 Hz，1H)，3.55 (s，2 H)，6.63 (d，J=8 Hz，2 H)，7.01 (d，J=8Example 54B 89248.doc -150- 200418454 Methyl ethyl &gt; Mossamine Take the eight products of Example 54 (3.85 8, 16.4 111111〇1) using 10% 1) (1 / (: (0.39§) in methanol ( 20 mL), hydrogenated at 1 atm Η for 16 hours. After replacing% with N2, the mixture was diluted with methanol (150 mL), stirred for 15 minutes, filtered, and the filtrate was concentrated to give the title compound. A nmr poo mhi cdci3; δ 1.11 (d, J = 6 Ηζ, 3 Η), 1.43 (m, 1 Η), 1.74 (m, 2 Η), 1.90 (m, 1 Η), 2.25 (m, 3 Η), 2.70 (m, 2 Η), 2.97 (m, 1 Η), 3.24 (td, J = 9 3 Hz, 1H), 3.55 (s, 2 H), 6.63 (d, J = 8 Hz, 2 H), 7.01 (d, J = 8

Hz，2 H);，MS(DCI/NH3) m/z 205 (M+H)、Hz, 2 H) ;, MS (DCI / NH3) m / z 205 (M + H),

實例54C U-二甲基-N-(4- {2-「（2R)-2-甲基_ 1 一p比p各咬某·|乙基I笨某' 丙縫胺 於氣蒙氣下’取貫例54B產物（2.77 g，14 mmol)溶於無 水二氣甲燒（70 mL)中，以三乙胺（2.3 mL，16 mmol)處理， 冷卻至0°C，以三甲基乙醯氯（1·9 mL，15 mmol)處理，於周 溫下攪拌60小時，以1 M NaOH (40 mL)處理。分層，水層 經二氯甲烷萃取（2次，40 mL)。合併之二氣甲烷層脫水（硫 酸鎂），過滤，滤液濃縮，產生4.0g標題化合物。h NMR (300 MHz, CDC13) δ 1·1〇 (d，J=6 Hz，3 H)，1.31 (s，9 Η)，1·44 (m， 1H)，1.76 (m，2 H)，1.92 (m，1H)，2.18 (q，J=9 Hz，1H)，2.27 (m，2H)，2.78 (m，2H)，2.99 (m，1H)，3·23 (td，J=9, 3 Hz，1H)， 7.17 (d，J=8 Hz，2H)，7.44 (d，J二8 Hz，2 H); MS (DCI/NH3) m/z 289 (M+H)+ 0Example 54C U-dimethyl-N- (4- {2-"(2R) -2-methyl_ 1-p-to-p each bite || Ethyl I stupid 'propanesamine under suffocation 'The product of Example 54B (2.77 g, 14 mmol) was dissolved in anhydrous digas (70 mL), treated with triethylamine (2.3 mL, 16 mmol), cooled to 0 ° C, and trimethylethyl Treated with chlorine (1.9 mL, 15 mmol), stirred at ambient temperature for 60 hours, and treated with 1 M NaOH (40 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 times, 40 mL). Combined The methane layer was dehydrated (magnesium sulfate), filtered, and the filtrate was concentrated to give 4.0 g of the title compound. H NMR (300 MHz, CDC13) δ 1.10 (d, J = 6 Hz, 3 H), 1.31 (s , 9 Η), 1.44 (m, 1H), 1.76 (m, 2 H), 1.92 (m, 1H), 2.18 (q, J = 9 Hz, 1H), 2.27 (m, 2H), 2.78 ( m, 2H), 2.99 (m, 1H), 3.23 (td, J = 9, 3 Hz, 1H), 7.17 (d, J = 8 Hz, 2H), 7.44 (d, J 8 Hz, 2 H); MS (DCI / NH3) m / z 289 (M + H) + 0

實例54D 89248.doc -151 - 200418454 Κ:·(2 -甲- {2-「（2R)-2 -甲基-1 - 口比p各攻某1乙基丨策某） _2,2 -二甲基丙酿胺 於氮冡氣下，取實例54C產物（4.0 g，13.9 mmol)，於無水 乙醚（140 mL)中，經n，N，N’N，-四甲基乙二胺（6.5 mL，43 mmol)處理’冷卻至_5°C，以10分鐘時間，以正丁基麵（16.7 mL 2.5 Μ己烷溶液）處理，於周溫下攪拌4小時，冷卻至乃它 ，以一次全量無水Ν，Ν-二甲基甲醯胺（6.5 mL，83 mmol)處 理，於周溫下攪拌16小時，以乙醚（1〇〇 mL)稀釋，以水（75 mL)洗滌/以鹽水洗滌，脫水（硫酸鎮），過濾，濾液濃縮。 殘質經碎膠層析法純化，以梯度2%、3.5%、5%與7.5% (9 :1 MeOH :濃NH4OH)之二氯甲烷溶液溶離，產生標題化合 物。1H NMR (300 MHz，CDC13) δ 1·1〇 (d，J=6 Hz，3 H)，1.35 (s，9 Η)，1·44 (m，1H)，1.75 (m，2H)，1·93 (m，1H)，2·19 (q， J=9 Hz，1H)，2.31 (m，2H)，2.85 (m，2H)，3.01 (m，1H)，3.23 (td，J=8, 3 Hz，1H)，7.47 (dd，J=8, 2 Hz，1H)，7.51 (d，J=2 Hz， 1H)，8·71 (d，J=8 Hz，1H)，9·92 (s，1H)，11.31 (s，1H); MS (DCI/NH3) m/z 317 (M+H)+。Example 54D 89248.doc -151-200418454 Κ: · (2-methyl- {2-"(2R) -2 -methyl-1-mouth ratio p each 1 ethyl 丨 policy certain) _2,2 -2 Methylpropanamine under nitrogen gas, the product of Example 54C (4.0 g, 13.9 mmol) was taken in anhydrous ether (140 mL), and n, N, N'N, -tetramethylethylenediamine (6.5 mL, 43 mmol) treatment 'Cool to _5 ° C, treat with n-butyl noodles (16.7 mL of 2.5 M hexane solution) for 10 minutes, stir at ambient temperature for 4 hours, cool to it, once Treated with an entire amount of anhydrous N, N-dimethylformamide (6.5 mL, 83 mmol), stirred at ambient temperature for 16 hours, diluted with ether (100 mL), washed with water (75 mL) / washed with brine , Dehydrated (sulfate), filtered, and the filtrate was concentrated. The residue was purified by gel chromatography and dissolved in a dichloromethane solution with a gradient of 2%, 3.5%, 5% and 7.5% (9: 1 MeOH: concentrated NH4OH). To give the title compound. 1H NMR (300 MHz, CDC13) δ 1.10 (d, J = 6 Hz, 3 H), 1.35 (s, 9 Η), 1.44 (m, 1H), 1.75 (m , 2H), 1.93 (m, 1H), 2.19 (q, J = 9 Hz, 1H), 2.31 (m, 2H), 2.85 (m, 2H), 3.01 (m, 1 H), 3.23 (td, J = 8, 3 Hz, 1H), 7.47 (dd, J = 8, 2 Hz, 1H), 7.51 (d, J = 2 Hz, 1H), 8.71 (d, J = 8 Hz, 1H), 9.92 (s, 1H), 11.31 (s, 1H); MS (DCI / NH3) m / z 317 (M + H) +.

實例54E 2-胺某-5-丨2-I(2R)-2-甲基- I—比咯啶基1乙某丨笨甲醛 取含實例 54D 產物（2·46 g，7.8 mmol)之 3M HC1 (40 mL) 於80°C下加熱4小時，使之冷卻至室溫，小心倒至1M Na〇H (250 mL)與二氯甲烷（75 mL)之混合物中。分層，水層經二 氯甲烷萃取（2次，乃mL)。合併之二氯甲烷層脫水（硫酸鎂） ，過濾，濾液濃縮。殘質經矽膠層析法純化，以梯度2%、 89248.doc -152- 200418454 3·5¾與5%(9:lMeOH:濃NH4OH)之二氯甲烷溶液溶離， 產生標題化合物。1H NMR (300 MHz，CDC13) δ 1.12 (d，Example 54E 2-Amine-5--5-2-I (2R) -2-methyl-I-pyrrolidinyl 1 ethyl Benzene formaldehyde Take 3M containing the product of Example 54D (2.46 g, 7.8 mmol) HC1 (40 mL) was heated at 80 ° C for 4 hours, allowed to cool to room temperature, and carefully poured into a mixture of 1M NaOH (250 mL) and dichloromethane (75 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 times, mL). The combined dichloromethane layers were dried (magnesium sulfate), filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography and dissolved in a gradient of 2%, 89248.doc -152- 200418454 3.525 and 5% (9: 1 MeOH: concentrated NH4OH) in dichloromethane to give the title compound. 1H NMR (300 MHz, CDC13) δ 1.12 (d,

Hz，3 H)，1·50 (m，1H)，1.76 (m，2H)，1.93 (m，1H)，2·25 (m，3 H)，2.76 (m，2H)，2.99 (m，1H)，3.25 (td，J二9, 3 Hz，1H)，5.99 (s，2H)，6.60 (d，J=8 Hz，1H)，7.19 (dd，J=8, 2 Hz，1H)，7.31 (d， J=2 Hz，1H)，9.85 (s，1H); MS (DCI/NH3) m/z 233 (M+H)+。Hz, 3 H), 1.50 (m, 1H), 1.76 (m, 2H), 1.93 (m, 1H), 2.25 (m, 3 H), 2.76 (m, 2H), 2.99 (m, 1H), 3.25 (td, J = 9, 3 Hz, 1H), 5.99 (s, 2H), 6.60 (d, J = 8 Hz, 1H), 7.19 (dd, J = 8, 2 Hz, 1H), 7.31 (d, J = 2 Hz, 1H), 9.85 (s, 1H); MS (DCI / NH3) m / z 233 (M + H) +.

實例54F U2-「C2R)-2-T基-_I-吡咯啶基1乙基丨-2-(3-吡啶某V奋4 取貫例^54E產物（32·5 mg，0· 14 mmol)與3 -乙龜基ρ比淀（17 mg，〇· 14 mmol)於乙醇（2 mL)中合併，以一滴飽和氫氧化鉀 之乙醇溶液處理，於8 0 °C下加熱16小時。使混合物冷卻至 室溫，濃縮。殘質經矽膠層析法純化，以梯度1 〇 ·· 1 : 1至6 • 1 · 1至4 · 1 : 1乙酸乙醋：甲酸：水溶離。收集含產物 之溶離份，濃縮，殘質再經矽膠層析法純化，以梯度2。/〇、 3,5%與5%(9:1乂6〇!1:濃&gt;^4011)之二氣甲烷溶液溶離， 產生標題化合物。1H NMR (300 MHz，CD3OD) δ 1.17 (d，J-6 Ηζ，3Η)，1.47 (m，1Η)，1.82 (m，2Η)，2·02 (m，1Η)，2·35 (q， J=9 Hz，1H)，2.47 (m，2H)，3.04 (m，2H)，3.19 (m，2H)，7.62 (dd，J=8, 5 Hz，1H)，7·72 (dd，J=9, 2 Hz，1H)，7.82 (d，J=2 Hz， 1H)，8.04 (d，J=9 Hz，lH)，8.08 (d，J=9 Hz，1H)，8.40 (d，J=9 Hz，1H)，8.60 (dt，J=8, 2 Hz，1H)，8.64 (dd，J=5，1Hz，1H)， 9.32 (d，J=lHz，1H); MS (DCI/NH3) m/z 318 (M+H)+。 實例55 石-{2-「（2R)-2 -甲基-1-p比略淀基1乙基丨-2-(4-0比峻某V套淋 89248.doc -153 - 200418454 標題化合物係依實例54F之方法製備，但其中改用4_乙醯 基吡哫酸替代夂乙醯基吡啶。咕NMR (300 MHz，CDc13：&gt; δ 1·14 (d，6 ΗΖ，3 Η)，1.48 (m，1Η)，1.78 (m，2Η)，1.96 (m， 1H)，2·25 (q，㈣ Hz，1H)，2·42 (m，2H)，3.09 (m，3 Η)，3·30 (td，J—9, 3 Hz，1H)，7·66 (m，2H)，7.89 (d，J=9 Hz，1H)，8.05 (dd，卜4, 2 Hz，2H)，8.12 (d，&gt;9 Hz，1H)，8.23 (dd，㈣，1Hz，1H)， 8.78 (dd，J=4, 2 Hz，2H); MS (DCI/NH3) m/z 318 (M+H)+。 實例56 P各淀基1乙某比咬基套淋 標題化合物係依實例54F之方法製備，但其中改用2-乙醯 基说淀酸替代3-乙醯吡啶。1H NMR (300 MHz，CDC13) δ 1·14 (d，J=6 Ηζ，3 Η)，1.46 (m，1Η)，1.77 (m，2Η)，1·94 (m， 1H)，2.25 (q，J=9 Hz，1H)，2.40 (m，2H)，3·03 (m，2H)，3·14 (m，1H)，3·30 (td，J=9, 3 Hz，1H)，7.35 (ddd，J=8, 5，1Hz， 1H)，7.62 (dd，J=9, 2 Hz，1H)，7.67 (d，J=lHz，1H)，7.86 (td， J=8, 2 Hz，1H)，8.10 (d，J=9 Hz，1H)，8.22 (d，J=9 Hz，1H)， 8.53 (d，J=9 Hz，1H)，8.63 (d，Hz，1H)，8.73 (m，1H); MS (DCI/NH3) m/z 318 (M+H)+。 實例57 U2-f(2R)-2-甲基-lw比咯啶某1乙基丨-2-Π.3-4唑-2-基）喳啉 取實例 54E 產物（46 mg，0.20 mmol)與 1-(1，3-嘧唑-2·基） 乙酉同（52 mg，0.41 mmol)於乙醇（0.4 mL)中合併，以一滴飽 和氫氧化鉀之乙醇溶液處理，於80°C下加熱16小時。使混 合物冷卻至室溫，濃縮。殘質經矽膠層析法純化，以梯度 89248.doc -154- 200418454 2%與3.5% (9 : 1 MeOH :濃NH4OH)之二氯甲烷溶液溶離， 產生標題化合物。NMR(300 MHz，CDC13) δ 1.13 (d，J=6Example 54F U2- "C2R) -2-T-I-I-pyrrolidinyl 1ethyl 丨 -2- (3-pyridine) and 4 Example 4 54E product (32 · 5 mg, 0.14 mmol) Combined with 3-ethylpyridyl phosphate (17 mg, 0.14 mmol) in ethanol (2 mL), treated with a drop of saturated potassium hydroxide in ethanol solution, and heated at 80 ° C for 16 hours. The mixture was allowed to Cooled to room temperature and concentrated. The residue was purified by silica gel chromatography with a gradient of 10 ·· 1: 1 to 6 • 1 · 1 to 4 · 1: 1 ethyl acetate: formic acid: water. The product containing The fractions were concentrated, and the residue was purified by silica gel chromatography with a gradient of 2/0, 3,5%, and 5% (9: 1 乂 60〇! 1: concentration> ^ 4011) in a gas solution of methane. Dissociation to give the title compound. 1H NMR (300 MHz, CD3OD) δ 1.17 (d, J-6 Ηζ, 3Η), 1.47 (m, 1Η), 1.82 (m, 2Η), 2.02 (m, 1Η), 2.35 (q, J = 9 Hz, 1H), 2.47 (m, 2H), 3.04 (m, 2H), 3.19 (m, 2H), 7.62 (dd, J = 8, 5 Hz, 1H), 7 72 (dd, J = 9, 2 Hz, 1H), 7.82 (d, J = 2 Hz, 1H), 8.04 (d, J = 9 Hz, 1H), 8.08 (d, J = 9 Hz, 1H) , 8.40 (d, J = 9 Hz, 1H), 8.60 (dt, J = 8, 2 Hz, 1H), 8.64 (dd, J = 5, 1Hz, 1H), 9.32 (d, J = lHz, 1H); MS (DCI / NH3) m / z 318 (M + H) +. Example 55 Shi-{2-"( 2R) -2 -methyl-1-p-pyridyl 1ethyl 丨 -2- (4-0-pyridine V sheath 89348.doc -153-200418454 The title compound was prepared according to the method of Example 54F, but Among them, 4-ethylpyridinic acid was used instead of ethylpyridinylpyridine. NMR (300 MHz, CDc13: &gt; δ 1.14 (d, 6 ΗZ, 3 Η), 1.48 (m, 1Η), 1.78 (m, 2Η), 1.96 (m, 1H), 2.25 (q, ㈣ Hz, 1H), 2.42 (m, 2H), 3.09 (m, 3 Η), 3.30 (td, J— 9, 3 Hz, 1H), 7.66 (m, 2H), 7.89 (d, J = 9 Hz, 1H), 8.05 (dd, Bu 4, 2 Hz, 2H), 8.12 (d, &gt; 9 Hz , 1H), 8.23 (dd, ㈣, 1Hz, 1H), 8.78 (dd, J = 4, 2 Hz, 2H); MS (DCI / NH3) m / z 318 (M + H) +. Example 56: P, 1-yl, 2-ethyl, 2-, 2-, 2-tetrahydropyrene. The title compound was prepared according to the method of Example 54F, but 2-acetylsulfonyl acid was used instead of 3-acetamidine. 1H NMR (300 MHz, CDC13) δ 1.14 (d, J = 6 Ηζ, 3 Η), 1.46 (m, 1Η), 1.77 (m, 2Η), 1.94 (m, 1H), 2.25 (q , J = 9 Hz, 1H), 2.40 (m, 2H), 3.03 (m, 2H), 3.14 (m, 1H), 3.30 (td, J = 9, 3 Hz, 1H), 7.35 (ddd, J = 8, 5, 1Hz, 1H), 7.62 (dd, J = 9, 2 Hz, 1H), 7.67 (d, J = lHz, 1H), 7.86 (td, J = 8, 2 Hz , 1H), 8.10 (d, J = 9 Hz, 1H), 8.22 (d, J = 9 Hz, 1H), 8.53 (d, J = 9 Hz, 1H), 8.63 (d, Hz, 1H), 8.73 (m, 1H); MS (DCI / NH3) m / z 318 (M + H) +. Example 57 U2-f (2R) -2-methyl-lw than pyridinium 1ethyl 丨 -2-Π.3-4azol-2-yl) fluorinate Take the product of Example 54E (46 mg, 0.20 mmol) Combine with 1- (1,3-pyrimazole-2 · yl) acetamidine (52 mg, 0.41 mmol) in ethanol (0.4 mL), treat with one drop of saturated potassium hydroxide in ethanol solution, and heat at 80 ° C 16 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography using a gradient of 89248.doc-154-200418454 2% and 3.5% (9: 1 MeOH: conc. NH4OH) in dichloromethane to give the title compound. NMR (300 MHz, CDC13) δ 1.13 (d, J = 6

Hz，3 H)，1.46 (m，iH)，1.77 (m，2H)，1.93 (m，1H)，2.24 (q， J=9 Hz，1Η)，2·39 (m，2H)，3.01 (m，2H)，3.11 (m，1H)，3·29 (td，J二9, 3 Hz，iH)，7 48 (d，J=3Hz，1H)，7·63 (m，2H)，7.97 (d，J二3 Hz，1H)，8.06 (d，J二9 Hz，1H)，8.19 (d，J=9 Hz，1H)， 8.31 (d，J=9 Hz，ih); (DCI/NH3) m/z 324 (M+H)+。 實例58 Ζ·ΐί2,4-^ 甲羞二塞唑 _5·某 v6_(2_「i2]R^2_ 甲某 吡咯啶 基1乙基丨4啉Hz, 3 H), 1.46 (m, iH), 1.77 (m, 2H), 1.93 (m, 1H), 2.24 (q, J = 9 Hz, 1Η), 2.39 (m, 2H), 3.01 ( m, 2H), 3.11 (m, 1H), 3.29 (td, J = 9, 3 Hz, iH), 7 48 (d, J = 3Hz, 1H), 7.63 (m, 2H), 7.97 (d, J = 3 Hz, 1H), 8.06 (d, J = 9 Hz, 1H), 8.19 (d, J = 9 Hz, 1H), 8.31 (d, J = 9 Hz, ih); (DCI / NH3) m / z 324 (M + H) +. Example 58 ΐ2,4- ^ Methyldisozole _5 · a certain v6_ (2_ 「i2] R ^ 2_ a certain a pyrrolidinyl 1 ethyl 4

標題化合物係依實例57之方法製備，但其中改用1-(2,4-二甲基-l，3-u塞唑基）乙酮替代ι-(1，3_噻唑基）乙酮。lH NMR (300 MHz, CDC13) δ 1.13 (d，J=6 Hz，3 H)，1.48 (m，lH)， 1.76 (m，2H)，1·94 (m，m)，2 24 (q，J=9 Hz, 1H)，2 39 (m， 2H)，2.72 (S，3H)，2·75 (s，3 H)，3.01 (m，2H)，3·12 (m，1H)， 3.29 (td，J=9, 2 Hz，1H)，7.62 (m，3H)，7.99 (d，J=9 Hz，1H)， 8.11 (d，J=9 Hz，1H); (DCI/NH3) m/z 352 (M+H)+。 實例59 吡咯啶基1乙基丨-2-(2-吡畊基V套啉 標題化合物係依實例57之方法製備，但其中改用ι_(2-井基）乙酉同替代W1，3·嘍唑-2-基）乙酮。咕NMR (300 MHz， CDC13) δ 1.14 (d5 J-6 Hz? 3 H)5 1.46 (m5 1H), 1.78 (m, 2H), 1.94 (m，1H)，2.25 (q，&gt;9 Hz，1H)，2.40 (m，2H)，3.05 (m， 2H)，3.16 (m，1H)，3.30 (td，J=9, 3 Hz，1H)，7.65 (dd，J=8, 2 89248.doc 200418454The title compound was prepared according to the procedure of Example 57 except that 1- (2,4-dimethyl-1,3-uthiazolyl) ethanone was used instead of ι- (1,3-thiazolyl) ethanone. lH NMR (300 MHz, CDC13) δ 1.13 (d, J = 6 Hz, 3 H), 1.48 (m, lH), 1.76 (m, 2H), 1.94 (m, m), 2 24 (q, J = 9 Hz, 1H), 2 39 (m, 2H), 2.72 (S, 3H), 2.75 (s, 3 H), 3.01 (m, 2H), 3.12 (m, 1H), 3.29 (td, J = 9, 2 Hz, 1H), 7.62 (m, 3H), 7.99 (d, J = 9 Hz, 1H), 8.11 (d, J = 9 Hz, 1H); (DCI / NH3) m / z 352 (M + H) +. Example 59 The title compound of pyrrolidinyl 1-ethyl-2- (2-pyridinyl V mantleline was prepared according to the method of Example 57, but ι_ (2-wellyl) acetamidine was used instead of W1,3 · 3 Azole-2-yl) ethanone. NMR (300 MHz, CDC13) δ 1.14 (d5 J-6 Hz? 3 H) 5 1.46 (m5 1H), 1.78 (m, 2H), 1.94 (m, 1H), 2.25 (q, &gt; 9 Hz, 1H), 2.40 (m, 2H), 3.05 (m, 2H), 3.16 (m, 1H), 3.30 (td, J = 9, 3 Hz, 1H), 7.65 (dd, J = 8, 2 89248.doc 200418454

Hz, 1H)5 7.68 (br s 1H) R 1^ /j ^ · - H). 8.13 (d, J-8Hz5 1H)? 8.24 (d5 J=8Hz, 1H) 5 7.68 (br s 1H) R 1 ^ / j ^--H). 8.13 (d, J-8Hz5 1H)? 8.24 (d5 J = 8

Hz，1H)，8·46 (d J二9 Hz im 〇 n 1， ，1H)，8·63 (d，J=2 Hz，1H)，8.66 (dd， 1H); (DCI/NH3) m/z 319 2 Hz? ih)5 9.86 (d5 J^ih2? (M+H)+。 ’ ^JH60 乙基卜2-4.基）-2-吡 〜匕口物係依貫例57之方法製備，但其中改用2,6-二乙 醒基气替代iWL坐I基）乙酮。iH nMr (则mHz， CDC13) δ 1.14 (d，J=6 Hz，3 H)，1.48 (m，1H)，1.78 (m，2H)， 1·95 (m，1H)，2·26 (q，㈣ Hz，1H)，2.41 (m，2H)，2.88 (s，3 H)，3.04 (m，2H)，3.17 (m，lH)，3.31 (td，J=9, 3 Hz，1H)，7.64 (dd，J-9，2 Hz，1H)，7.69 (d，J=2 Hz，1H)，8.00 (t，J=8 Hz， 1H)，8·10 (m，2H)，8.25 (d，J=9 Hz，1H)，8.66 (d，J=9 Hz，1H)， 8.88 (dd，J=8, 1Hz，1H); (DCI/NH3) m/z 360 (M+H)+。 實例61 i:ig-{2d(2RM甲基小吡咯啶某1乙基丨_6_崦啉某）苽某教 1 生：i.3- {2-|~(2R)-2 -甲基-1 - ρ比哈咬基1乙基} - 6-4^株基）茉某氰 實例61A 4 -&gt;臭-1,2·笨二胺 取含4-溴-2-硝基苯胺（10 g，46 mmol)之丁HF (120 mL)經 1% Pt/C (1·〇 g)處理，於室溫下，於40 psi H2下氫化。2小 時後，反應過濾，濾液濃縮，產生標題化合物，未再純化 89248.doc -156- 200418454 即用於下一個步驟。MS 188 (M + H)+ ; 4 NMR (400 MHz， CDC13) δ 6.77-6.81 (m，2H)，6.54 (d，J=8.4 Hz，1H)，3.28 (br， 4H)。Hz, 1H), 8.46 (d J 2 9 Hz im 0, 1, 1H), 8.63 (d, J = 2 Hz, 1H), 8.66 (dd, 1H); (DCI / NH3) m / z 319 2 Hz? ih) 5 9.86 (d5 J ^ ih2? (M + H) +. '^ JH60 ethyl ethyl 2-4.yl) -2-pyridine ~ The method according to Example 57 Preparation, but in which 2,6-diethenyl group gas was used instead of iWL group. iH nMr (then mHz, CDC13) δ 1.14 (d, J = 6 Hz, 3 H), 1.48 (m, 1H), 1.78 (m, 2H), 1.95 (m, 1H), 2.26 (q , ㈣ Hz, 1H), 2.41 (m, 2H), 2.88 (s, 3 H), 3.04 (m, 2H), 3.17 (m, lH), 3.31 (td, J = 9, 3 Hz, 1H), 7.64 (dd, J-9, 2 Hz, 1H), 7.69 (d, J = 2 Hz, 1H), 8.00 (t, J = 8 Hz, 1H), 8.10 (m, 2H), 8.25 (d , J = 9 Hz, 1H), 8.66 (d, J = 9 Hz, 1H), 8.88 (dd, J = 8, 1Hz, 1H); (DCI / NH3) m / z 360 (M + H) +. Example 61 i: ig- {2d (2RM methyl small pyrrolidine 1 ethyl 丨 _6_pyridinium 1) 苽 certain teaching 1 students: i.3- {2- | ~ (2R) -2 -methyl -1-ρ biharyl 1 ethyl}-6-4 ^ strain) Example of a cyanogen 61A 4-&gt; odor-1,2 · benzyl diamine containing 4-bromo-2-nitroaniline ( 10 g, 46 mmol) of butane HF (120 mL) were treated with 1% Pt / C (1.0 g) and hydrogenated at room temperature under 40 psi H2. After 2 hours, the reaction was filtered and the filtrate was concentrated to give the title compound, which was used without purification 89248.doc -156- 200418454 for the next step. MS 188 (M + H) +; 4 NMR (400 MHz, CDC13) δ 6.77-6.81 (m, 2H), 6.54 (d, J = 8.4 Hz, 1H), 3.28 (br, 4H).

實例61B 7-溴-2-甲基p奎哼啉 6-溴-2-甲基4噚4 取含實例61A產物（9.4g，50 mmol)之乙腈（100 mL)，滴加 40%丙酮择（11 ·〇 mL，60 mmol)處理。於室溫下攪拌2小時 後，混合物濃縮，殘質懸浮於IPAc (100 mL)中，過濾。漉 液經20%鹽水洗滌，經硫酸鈉脫水，過漉，濾液濃縮。殘質 經管柱層析法純化，以庚烷：EtOH : MeOH (8 : 2 : 1)溶離 ，產生標題化合物。MS 224 (M+H) + ; 4 NMR (400 MHz， CDC13) δ 8.73 (s，1H)，8·72 (s，1H)，8·23 (d，J=2.2 Hz，1H)， 8.18 (d，J=2.1Hz，1H)，7.75-7.93 (m，4H)，2.78 (s，3H)，2.76 (s，3H); 13C NMR (400 MHz，CDC13) δ 154.32, 153.73, 146.34, 145.83, 142.28, 141·17, 140.45, 139.34, 133.17, 132.15, 131.15, 130.75, 130.16, 129.71，123.66, 122.38, 22.89。Example 61B 7-bromo-2-methyl p-quinoline 6-bromo-2-methyl 4 噚 4 Take acetonitrile (100 mL) containing the product of Example 61A (9.4 g, 50 mmol), and add 40% acetone dropwise to select (11.0 mL, 60 mmol). After stirring at room temperature for 2 hours, the mixture was concentrated, and the residue was suspended in IPAc (100 mL) and filtered. The mash was washed with 20% brine, dehydrated over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography and eluted with heptane: EtOH: MeOH (8: 2: 1) to give the title compound. MS 224 (M + H) +; 4 NMR (400 MHz, CDC13) δ 8.73 (s, 1H), 8.72 (s, 1H), 8.23 (d, J = 2.2 Hz, 1H), 8.18 ( d, J = 2.1Hz, 1H), 7.75-7.93 (m, 4H), 2.78 (s, 3H), 2.76 (s, 3H); 13C NMR (400 MHz, CDC13) δ 154.32, 153.73, 146.34, 145.83, 142.28, 141 · 17, 140.45, 139.34, 133.17, 132.15, 131.15, 130.75, 130.16, 129.71, 123.66, 122.38, 22.89.

實例61C 4-(2-甲基-6-崦噚啉某）宏 4-(3-甲基-6-崦哼啉某）苽H - 取4 -氰基苯基二酸（588 mg ’ 4· 0 mmol)、碳酸铯（2.2 g ，7.0 mmol)與氟化铯（608 mg，4·0 mmol)於 h2〇（15 mL)中 -157- 89248.doc 200418454 合併，以實例61B產物（446 mg，2.0 mmol)之甲苯（10 mL)處 理，於80°C下加熱3小時。使反應混合物冷卻至室溫，經寅 氏鹽墊過濾。濾液分溶於IPAc (60 mL)與H20 (50 mL)之間 。分離有機層，以20%鹽水洗滌，經硫酸鈉脫水，過濾，濾 液真空濃縮，產生標題化合物，未再純化即用於下一個步 驟。MS 246 (M+H)+ ; 4 NMR (400 MHz，CDC13) δ 8.71 (s， 1H)，8.69 (s，1H)，8.02-8.20 (m，4H)，7.84-7.90 (m，2H)， 7.70-7.76 (m，8H)，2.73 (s，6H) ; 13C NMR (400 MHz，CDC13) δ 154.34，154.10，146.47，147.17，143.80，142.93，141.74, 140.62, 140.39, 140.18, 139.16, 132.49, 130.16, 129.74, 129.25, 128.71，128.63, 128.06, 127·77, 127.74, 127.66, 127.59, 127.22, 126.73, 118.39, 118.37, 111.61，111.51，22.96。Example 61C 4- (2-methyl-6-pyridinoline) macro 4- (3-methyl-6-pyringoline) 苽 H-Take 4-cyanophenyl diacid (588 mg '4 · 0 mmol), cesium carbonate (2.2 g, 7.0 mmol) and cesium fluoride (608 mg, 4.0 mmol) in h2O (15 mL) -157- 89248.doc 200418454, and the product of Example 61B (446 mg, 2.0 mmol) in toluene (10 mL) and heated at 80 ° C for 3 hours. The reaction mixture was allowed to cool to room temperature and filtered through a Yin's salt pad. The filtrate was partitioned between IPAc (60 mL) and H20 (50 mL). The organic layer was separated, washed with 20% brine, dehydrated over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give the title compound, which was used in the next step without further purification. MS 246 (M + H) +; 4 NMR (400 MHz, CDC13) δ 8.71 (s, 1H), 8.69 (s, 1H), 8.02-8.20 (m, 4H), 7.84-7.90 (m, 2H), 7.70-7.76 (m, 8H), 2.73 (s, 6H); 13C NMR (400 MHz, CDC13) δ 154.34, 154.10, 146.47, 147.17, 143.80, 142.93, 141.74, 140.62, 140.39, 140.18, 139.16, 132.49, 130.16 , 129.74, 129.25, 128.71, 128.63, 128.06, 127.77, 127.74, 127.66, 127.59, 127.22, 126.73, 118.39, 118.37, 111.61, 111.51, 22.96.

實例61D 4二(2-{M(_2R)-2-甲某比咯啶基1乙某崎啉某）苯某氧Example 61D 4 Bis (2- {M (_2R) -2-methyl certain pyrrolidinyl 1 ethyl certain azolin) benzene certain oxygen

Uj_-12—-[(2R)-2-甲基-1^比咯啶基1乙某卜6-P杳噚啉基）苯某氨 (2R)-2-甲基p比哈咬鹽酸鹽5 (973 mg，.8.0 mmol)與37%甲 醛水溶液（0.57 mL，7.0 mmol)於EtOH (20 mL)中合併，於密 封η式€中’於8 5 C下加熱1小時。使混合物冷卻至室溫，以 實例61C產物（500 mg，2.0 mmol)處理，於85°C下加熱一夜 。使混合物冷卻至室溫，真空濃縮至乾。殘質分溶於IPAc (5〇 mL)與20%鹽水（40 mL)之間。分離有機層，經硫酸納脫水-， 過濾，濾液真空濃縮。殘質經管柱層析法純化，以庚燒： 丙酮：CH^C!2 : EtsN (60 : 40 : 3 : 1)溶離，產生標題化合 89248.doc -158- 200418454 物。MS 343 (M + H)+ ;咕 NMR (400 MHz，CDC13) δ 8.74 (s， 1H)，7.72 (s，1H)，8.16 (m，2H)，8.06 (m，2H)，7.85 (m，2H)， 7·70 (m，4H)，3.17 (m，8H)，2.52 (ni，2H)，2.31 (m，2H)，2,17 (m，2H)，1.83 (m，2H)，1.65 (m，4H)，1.32 (m，2H)。13c NMR (400 MHz，CDC13) 1 56.63，156·41，146.45，145.16，143.73, 143.70，141.75，141.53，140.81，Η0·60，139.89，139.04, 132.38，129.66，129.36，128.42，127.68，127.65，127.55, 137.13，126.86，118.29，111.48，111.40, 59.87, 53.93, 52.89, 35.83, 3;·90, 21.98, 19.25 ° 實例62 7-(2,6-二氣-3-口比淀基）-3-{2-|&quot;(2!0-2-甲基-1-1?比口各哈基1乙基} 異口奎口林Uj_-12 —- [(2R) -2-methyl-1 ^ pyrrolidinyl 1 ethyl molybdenum 6-Pfluorinyl) benzene ammonia (2R) -2-methyl p Salt 5 (973 mg, .8.0 mmol) was combined with a 37% aqueous formaldehyde solution (0.57 mL, 7.0 mmol) in EtOH (20 mL), and heated in a sealed solution at 8 5 C for 1 hour. The mixture was allowed to cool to room temperature, treated with the product of Example 61C (500 mg, 2.0 mmol), and heated at 85 ° C overnight. The mixture was allowed to cool to room temperature and concentrated to dryness in vacuo. The residue was dissolved in IPAc (50 mL) and 20% saline (40 mL). The organic layer was separated, dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography and dissolved in heptane: acetone: CH ^ C! 2: EtsN (60: 40: 3: 1) to give the title compound 89248.doc -158- 200418454. MS 343 (M + H) +; NMR (400 MHz, CDC13) δ 8.74 (s, 1H), 7.72 (s, 1H), 8.16 (m, 2H), 8.06 (m, 2H), 7.85 (m, 2H), 7.70 (m, 4H), 3.17 (m, 8H), 2.52 (ni, 2H), 2.31 (m, 2H), 2,17 (m, 2H), 1.83 (m, 2H), 1.65 (m, 4H), 1.32 (m, 2H). 13c NMR (400 MHz, CDC13) 1 56.63, 156.41, 146.45, 145.16, 143.73, 143.70, 141.75, 141.53, 140.81, Η60, 139.89, 139.04, 132.38, 129.66, 129.36, 128.42, 127.68, 127.65, 127.55, 127.55 , 137.13, 126.86, 118.29, 111.48, 111.40, 59.87, 53.93, 52.89, 35.83, 3; · 90, 21.98, 19.25 ° Example 62 7- (2,6-Digas-3-port ratio) {2- | &quot; (2! 0-2-Methyl-1-1? Bikouhaji 1ethyl} isokouline

實例62A 5-溴-2-碘茉甲酸甲酯 在含2-碘-苯甲酸甲酯（5.0 g，0.019 mol)與N-溴琥珀醯亞 胺（3.74 g ’ 0.021 mol)之乙酸（10 mL)揽拌漿狀物中滴加濃硫 酸（10 mL)，同時保持溫度在20-40°C。混合物於室溫下攪拌 8 8小時後，於5 0 °C下加熱4小時。混合物冷卻至1 〇 t，以 40 g冰水處理’以50 mL CH2C12萃取。有機相依序經2 X 50 mL 5% NaHC03、50 mL 10% Na2S203、50 mL水洗滌，濃縮 成無色油狀物。殘質經管柱層析法純化（矽膠，1 〇 : 90 Et0Ac •己 fe )，產生標題化合物。1H NMR (CDC13，400 MHz) δ 7.92 (d，J=4 Hz，1H)，7.83 (d，J=8 Hz，1H)，7.27 (dd，J二8，4 Hz， 1H)，3.92 (s，3H) ; MS (DCI/NH3) [M+NH4]+ 358, [M+NH3 ·ΝΗ4]+ 89248.doc -159- 200418454 375 〇 實例62Β (5-溴-2-碘笨墓）甲醢 於 5°C 下’在含 NaBH4 (11.18 g，0.296 mol)之 EtOH (200 mL)攪拌混合物中添加含實例62a產物（50.4 g，0.148 mol) 之THF (100 mL)。使混合物回升至室溫，攪拌18小時。混 合物再經NaBH4(8.4 g，0.222 mol)處理，攪拌22小時。混合 物冷卻至〇°C ’以1 〇〇 mL 15%檸檬酸水溶液慢慢處理，以600 mL CH2C；12萃取。有機相經20〇 mL 15% NaCl洗滌，濃縮， 產生標題化合物。1H NMR (CDCh，400 ΜΗζ) δ 7.64 (d，J=8 Hz，1H)，7·61 (d，J=4 Hz，1H)，7.12 (dd，J=4, 8 Hz，1H)，4·63 (d，J=8 Hz，2H)，1.98 (t，J=8 Hz, 1H)。MS (DCI/NH3) [M+NH4]+ 330, [M+NH4-H20]+ 312。Example 62A Methyl 5-bromo-2-iodojamate in acetic acid (10 mL containing methyl 2-iodo-benzoate (5.0 g, 0.019 mol) and N-bromosuccinimide (3.74 g '0.021 mol) ) Concentrated sulfuric acid (10 mL) was added dropwise to the slurry while maintaining the temperature at 20-40 ° C. After the mixture was stirred at room temperature for 8 8 hours, it was heated at 50 ° C for 4 hours. The mixture was cooled to 10 t, treated with 40 g of ice-water 'and extracted with 50 mL of CH2C12. The organic phase was sequentially washed with 2 X 50 mL of 5% NaHC03, 50 mL of 10% Na2S203, and 50 mL of water, and concentrated to a colorless oil. The residue was purified by column chromatography (silica gel, 10:90 Et0Ac • hexane fe) to give the title compound. 1H NMR (CDC13, 400 MHz) δ 7.92 (d, J = 4 Hz, 1H), 7.83 (d, J = 8 Hz, 1H), 7.27 (dd, J = 8, 4 Hz, 1H), 3.92 (s , 3H); MS (DCI / NH3) [M + NH4] + 358, [M + NH3 · ΝΗ4] + 89248.doc -159- 200418454 375 〇 Example 62B (5-Bromo-2-iodine tomb) formazan To a stirred mixture of NaBH4 (11.18 g, 0.296 mol) in EtOH (200 mL) at 5 ° C was added THF (100 mL) containing the product of Example 62a (50.4 g, 0.148 mol). The mixture was warmed to room temperature and stirred for 18 hours. The mixture was treated with NaBH4 (8.4 g, 0.222 mol) and stirred for 22 hours. The mixture was cooled to 0 ° C and treated slowly with 100 mL of a 15% citric acid aqueous solution and extracted with 600 mL of CH2C; 12. The organic phase was washed with 20 mL of 15% NaCl and concentrated to give the title compound. 1H NMR (CDCh, 400 MHz) δ 7.64 (d, J = 8 Hz, 1H), 7.61 (d, J = 4 Hz, 1H), 7.12 (dd, J = 4, 8 Hz, 1H), 4 · 63 (d, J = 8 Hz, 2H), 1.98 (t, J = 8 Hz, 1H). MS (DCI / NH3) [M + NH4] + 330, [M + NH4-H20] + 312.

實例62C 溴-2-碘苯甲醢 取含草醯氯（1.53 g，〇·〇ΐ2 mol)之 CH2C12 (15 mL)溶液冷 卻至-70°C，於-65至-70t：下添加含DMSO (1.41 g，0.018 mol) 之CH2C12 (15 mL)。混合物於氮蒙氣與_70°C下攪拌10分鐘 後’以含實例 62B 產物（2.35 g，7.5 mmol)之 60mL CH2C12處 理。漿狀物於-65°C下攪拌15分鐘，經三乙胺（3.8 g，0.037 mol)處理。使混合物以1小時時間回升至-1C)ac。混合物經2〇 mL水處理，使之回升至室溫。分離有機層，濃縮，產生標 題化合物。1H NMR (CDC13, 400 ΜΗζ) δ 9.97 (s，1H)，7.97 (d, J=4 Ηζ，1Η)，7·79 (d，J=8 Ηζ，1Η)，7.40 (dd，J=4, 8 Ηζ，1Η) 89248.doc -160- 200418454 。MS (DCI/NH3) [M+NH4]+ 328 〇Example 62C Bromo-2-iodobenzylacetate Chlorochloride (1.53 g, 0.002 mol) in CH2C12 (15 mL) was cooled to -70 ° C, and DMSO-containing (1.41 g, 0.018 mol) of CH2C12 (15 mL). The mixture was stirred under nitrogen blanket at -70 ° C for 10 minutes' and treated with 60 mL of CH2C12 containing the product of Example 62B (2.35 g, 7.5 mmol). The slurry was stirred at -65 ° C for 15 minutes and treated with triethylamine (3.8 g, 0.037 mol). The mixture was allowed to rise back to -1C) ac over a period of 1 hour. The mixture was treated with 20 mL of water and allowed to warm to room temperature. The organic layer was separated and concentrated to give the title compound. 1H NMR (CDC13, 400 ΜΗζ) δ 9.97 (s, 1H), 7.97 (d, J = 4 Ηζ, 1Η), 7.79 (d, J = 8 Ηζ, 1Η), 7.40 (dd, J = 4, 8 Ηζ, 1Η) 89248.doc -160- 200418454. MS (DCI / NH3) [M + NH4] + 328 〇

實例62D Ν-ΠΕ)-(5-溴-2-碘笨基）亞甲某三丁其）胺 取含實例62C產物（2.28 g，7.3 mmol)之THF (1〇 mL)經第 三丁基胺（1.61g，22 ·0 mmol)處理，於氮蒙氣與室溫下攪拌 40小時。混合物減壓濃縮，殘質溶於30mL二氯甲烷中。該 二氣甲烷溶液經10 mL水洗滌，濃縮，產生標題化合物，未 再純化即用於下一個步驟。4 NMR (CDC13，400 MHz) δ 8·29 (s，LH)，8·05 (d，J=4 Ηζ，1Η)，7.66 (d，J=8 Ηζ，1Η)，7.19 (dd，J=4, 8 Hz，1H)，1.34 (s，9H)。MS (DCI/NH3) 366 [M+H]+。 實例62E 2-(7-溴-3-異4啉基）乙醇 取實例 62D產物（1.3 g，3.6 mmol)、3_丁块-1-醇（〇.3 g，4.3 mmol)、CuI (0·04 g，0.2 mmol)與 PdCl2 (PPh3)2 (〇·〇8 g，0.1 mmol)於曱苯（15 mL)中合併。混合物經二異丙基胺（〇54 g， 5·3 mmol)處理’於室溫下攪掉4小時。混合物再經Cul (0.07 g，0.4 mmol)處理，於l〇〇°C·下加熱4小時。使混合物冷卻至 室溫，以30 mL CH2C12稀釋，過漉。漉液經2 X 1〇 mL 15% NaC 1洗滌’減壓濃縮。殘質經管柱層析法純化（秒膠，丄〇 :90 MeOH: CHC13)，產生標題化合物。1η NMR (CDCU，400 MHz) δ 9.08 (s，1Η)，8.09 (d，J=4 Ηζ，1Η)，7.73 (dd，J=8, 4 Hz，1H)，7·63 (d，J=8 Hz，1H)，7.48 (s，1H)，4.08 (t，J=4 Hz， 2H)，3.92 (s，1H)，3.15 (t，J=4 Hz，2H)。13C NMR (CDC13, 100 MHz) δ 153.8, 150.3, 134.5, 133.8, 129.4，127.6, 120.0, 118.6, 89248.doc -161 - 200418454 62.3, 39.4。MS (DCI/NH3) 252, 254 [M+H]+。Example 62D Ν-ΠΕ)-(5-bromo-2-iodobenzyl) methylene tributyrate) amine Take the THF (10 mL) containing the product of Example 62C (2.28 g, 7.3 mmol) over a third Treated with amine (1.61 g, 22.0 mmol) and stirred at room temperature under nitrogen blanket for 40 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in 30 mL of dichloromethane. This digas methane solution was washed with 10 mL of water and concentrated to give the title compound, which was used in the next step without further purification. 4 NMR (CDC13, 400 MHz) δ 8.29 (s, LH), 8.05 (d, J = 4 Ηζ, 1Η), 7.66 (d, J = 8 Ηζ, 1Η), 7.19 (dd, J = 4, 8 Hz, 1H), 1.34 (s, 9H). MS (DCI / NH3) 366 [M + H] +. Example 62E 2- (7-bromo-3-iso4olinyl) ethanol The product of Example 62D (1.3 g, 3.6 mmol), 3-butan-1-ol (0.3 g, 4.3 mmol), CuI (0 · 04 g, 0.2 mmol) and PdCl2 (PPh3) 2 (0.08 g, 0.1 mmol) in toluene (15 mL). The mixture was treated with diisopropylamine (0544 g, 5.3 mmol) 'and stirred off at room temperature for 4 hours. The mixture was treated with Cul (0.07 g, 0.4 mmol) and heated at 100 ° C for 4 hours. The mixture was allowed to cool to room temperature, diluted with 30 mL of CH2C12, and evaporated. The mash was washed with 2 × 10 mL of 15% NaC 1 ′ and concentrated under reduced pressure. The residue was purified by column chromatography (Second Gum, 100: 90 MeOH: CHC13) to give the title compound. 1η NMR (CDCU, 400 MHz) δ 9.08 (s, 1Η), 8.09 (d, J = 4 Ηζ, 1Η), 7.73 (dd, J = 8, 4 Hz, 1H), 7.63 (d, J = 8 Hz, 1H), 7.48 (s, 1H), 4.08 (t, J = 4 Hz, 2H), 3.92 (s, 1H), 3.15 (t, J = 4 Hz, 2H). 13C NMR (CDC13, 100 MHz) δ 153.8, 150.3, 134.5, 133.8, 129.4, 127.6, 120.0, 118.6, 89248.doc -161-200418454 62.3, 39.4. MS (DCI / NH3) 252, 254 [M + H] +.

實例62F 7- &gt;臭_ 3 - { 2 - f (2R) -2 _甲基-1 - p比嘻淀基1乙某}昇p争琳 於-15 C下’取貫例62E產物（0.5 g ’ 2.0 mmol)與三乙胺（0.5 g，4.9 mmol)於THF (15 mL)中合併。混合物經甲磺醯氯（〇.24 g，2· 1 mmol)處理，於0-10°C下攪拌2小時。混合物再經甲 橫醯氯（〇·2 mmol)處理’於室溫下攪拌16小時。混合物經含 (2R)-2 -甲基 p比嘻淀鹽酸鹽（0.72 g，6.0 mmol)與 K2C03 (0.27 g ，2.0 1111^01)之乙腈（25 mL)處理後，混合物於6〇°C下加熱20 小時。使混合物冷卻至室溫，減壓濃縮。殘質溶於2〇 mL CHAh，以5 mL水洗滌’減壓濃縮。殘質經管柱層析法純 化（矽膠，10 : 90 MeOH : CHC13)，產生標題化合物。1η NMR (CDC13, 400 MHz) δ 9.10 (s，1Η)，8·09 (d，J=4 Ηζ，1Η)，7.72 (dd，J=12，4 Ηζ，1Η)，7.64 (d，J=12 Ηζ，1Η)，7·58 (s，1Η)， 3.46-3.40 (m，2H), 3.34-3.29 (m，2H)，2.91-1.85 (m，1H)， 2.81-2.68 (m，1H)，2.59-2.49 (m，1H)，2.11-2.02 (m，1H)， 2·00-1.91 (m，1H)，1.88-1.79 (m，1H)，1.71-1.61 (m，1H)， 1.32 (d，J=8 Hz，3H)。13C NMR(CDC13，100 MHz) δ 152.5, 150.6，134·5，133.6，129.2，127.8，127.7，120.0，118.7, 61.7, 53.7，53.4，36.0，32·4，21.9，17·9。MS (DCI/NH3) 319，321 [M+H]+。 實例62G · 7-(2,6·二氣- 3-p比淀基）-3-{2-「（2R)-2 -甲基-1-p比p各淀基1乙基} 異喹啉 89248.doc -162- 200418454 取貫例 62F產物（〇·3〇 g，〇·9 mmol)、2,6-二氟- 3-p比淀二樂 硼酸（0.3 g，1.9 mmol)、2-(二環己基膦基）聯苯（66 mg，〇·2 mmol)與 PdCl2 (PPh3)2 (66 mg，0.1 mmol)於異丙醇（15 mL) 中合併。混合物經含Na2CO3(0.l5g，1.4111111〇1)之511^水溶 液處理，於6 5 C下加熱16小時。冷卻至室溫後，混合物經 20 mL CH2C12稀釋，過濾。濾液經1〇 mL 15% NaCi洗滌， 減壓濃縮。殘質經管柱層析法純化（碎膠，1 〇 : 9〇 : 1 MeOH :CHC13: Et3N)，產生標題化合物。1η NMR (CDC13, 400 MHz) δ 9.25 (s，1H)，8.11-8.05 (m，2H)，7.85 (d，J=10 Hz，1H)， 7·81-7·78 (m，1H)，7.58 (s，1H)，6.98 (dd，J=10 Hz，1H)， 3.34-3.27 (m，2H)，3.22-3.15 (m，2H)，2.65-2.56 (m，lH)， 2.45-2.40 (m，1H)，2.33-2.27 (m，1H)，2.01-1.91 (m，1H)， 1.87-1.80 (m，1H)，1.77-1.70 (m，1H)，1·52-1·42 (m，1H)， 1.16 (d，J=8 Hz，3H) ; 13C NMR (CDC13, 400 MHz) δ 158.9, 154.6，151.9，144.6，144.5，135.6，130.7，130.2，127.3，126.7, 126.6，118.1，1006.8，106.5，60.2，54.2，54.1，37.5，32.9, 22.0, 19.2。 . 實例63 3-{2-「（2R)-2 -甲基-1-口比洛淀基1乙基-口比咬基）異口奎口林Example 62F 7- &gt; Odor 3-{2-f (2R) -2 _Methyl-1-p than Heydoyl 1 B} liter p at -15 C 'take the product of Example 62E ( 0.5 g '2.0 mmol) and triethylamine (0.5 g, 4.9 mmol) in THF (15 mL). The mixture was treated with methanesulfonyl chloride (0.24 g, 2.1 mmol) and stirred at 0-10 ° C for 2 hours. The mixture was further treated with methylene chloride (0.2 mmol) 'and stirred at room temperature for 16 hours. The mixture was treated with acetonitrile (25 mL) containing (2R) -2-methylp-bihexidine hydrochloride (0.72 g, 6.0 mmol) and K2C03 (0.27 g, 2.0 1111 ^ 01), and the mixture was heated at 60 °. Heat at C for 20 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 20 mL of CHAh, washed with 5 mL of water 'and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10:90 MeOH: CHC13) to give the title compound. 1η NMR (CDC13, 400 MHz) δ 9.10 (s, 1Η), 8.09 (d, J = 4 Ηζ, 1Η), 7.72 (dd, J = 12, 4 Ηζ, 1Η), 7.64 (d, J = 12 Ηζ, 1Η), 7.58 (s, 1Η), 3.46-3.40 (m, 2H), 3.34-3.29 (m, 2H), 2.91-1.85 (m, 1H), 2.81-2.68 (m, 1H) , 2.59-2.49 (m, 1H), 2.11-2.02 (m, 1H), 2.00-1.91 (m, 1H), 1.88-1.79 (m, 1H), 1.71-1.61 (m, 1H), 1.32 ( d, J = 8 Hz, 3H). 13C NMR (CDC13, 100 MHz) δ 152.5, 150.6, 134.5, 133.6, 129.2, 127.8, 127.7, 120.0, 118.7, 61.7, 53.7, 53.4, 36.0, 32 · 4, 21.9, 17.9. MS (DCI / NH3) 319, 321 [M + H] +. Example 62G 7- (2,6 · Digas-3-p ratio yodoyl) -3- {2-"(2R) -2 -methyl-1-p ratio p each p-yl 1ethyl} isoquine Porphyrin 89248.doc -162- 200418454 Take the product of Example 62F (0.30 g, 0.9 mmol), 2,6-difluoro-3-p-pyridine diboronic acid (0.3 g, 1.9 mmol), 2 -(Dicyclohexylphosphino) biphenyl (66 mg, 0.2 mmol) and PdCl2 (PPh3) 2 (66 mg, 0.1 mmol) in isopropanol (15 mL). The mixture was subjected to Na2CO3 (0. 15g, 1.4111111〇1) of a 511 ^ aqueous solution, heated at 65 C for 16 hours. After cooling to room temperature, the mixture was diluted with 20 mL CH2C12, filtered. The filtrate was washed with 10 mL 15% NaCi, and concentrated under reduced pressure. The residue was purified by column chromatography (crushed gel, 10: 90: 1 MeOH: CHC13: Et3N) to give the title compound. 1η NMR (CDC13, 400 MHz) δ 9.25 (s, 1H), 8.11-8.05 ( m, 2H), 7.85 (d, J = 10 Hz, 1H), 7.81-7 · 78 (m, 1H), 7.58 (s, 1H), 6.98 (dd, J = 10 Hz, 1H), 3.34 -3.27 (m, 2H), 3.22-3.15 (m, 2H), 2.65-2.56 (m, 1H), 2.45-2.40 (m, 1H), 2.33-2.27 (m, 1H), 2.01-1.91 (m, 1H), 1.87-1.80 (m, 1H), 1.77-1.70 (m 1H), 1.52--14.2 (m, 1H), 1.16 (d, J = 8 Hz, 3H); 13C NMR (CDC13, 400 MHz) δ 158.9, 154.6, 151.9, 144.6, 144.5, 135.6, 130.7 , 130.2, 127.3, 126.7, 126.6, 118.1, 1006.8, 106.5, 60.2, 54.2, 54.1, 37.5, 32.9, 22.0, 19.2. Example 63 3- {2-"(2R) -2 -methyl-1-port Biloxidyl 1 ethyl-orbital

實例63A 2-{7-〇-吡啶基V3-異4啉某丨A _ 取實例62E產物（0·3 g，1·2 mmol)、3-吡啶二羥硼酸（0.22 g ，1 ·8 mmol)、2-(二環己基膦基）聯苯（80 mg，〇·2 mmol)與 PdCl2 (PPh3)2 (80 mg，0.1 mmol)於異丙醇（15 mL)中合併， 89248.doc -163 - 200418454 以含Na2C〇3 (0.19 g，1·8 mmol)之（5 mL)水溶液處理，於65°C 下加熱16小時。冷卻至室溫後，混合物經20 mL CH2C12稀 釋’過濾。濾液經10 mL 15% NaCl洗滌，減壓濃縮。殘質 經管柱層析法純化（矽膠，1〇 : 90 MeOH : CHC13)，產生標 題化合物。1H NMR (CDC13, 400 ΜΗζ) δ 9.24 (s，1H)，8.95 (d， J=4 Hz, 1H), 8.65 (dd5 J=2? 8Hz5 1H)? 8.13 (bs? 1H)5 7.98 (2 m，1H)，7.91-7.86 (m，2H)，7.55 (s，1H)，7.44-7.41 (2d，1H)， 4·11 (t，J=4 Hz，2H)，3.19 (t，J=4 Hz，2H) ; 13C NMR (CDC13, 400 MHz) δ 153.9, 151.7, 148.6, 148.0, 135.9, 135.5, 135.4, 134.2, 129.5, 127.2, 126.9, 125.4, 123.5, 118.5, 62.4, 39.4。Example 63A 2- {7-〇-pyridyl V3-iso4line, a certain A_ Take the product of Example 62E (0.3 g, 1.2 mmol), 3-pyridine dihydroxyboronic acid (0.22 g, 1.8 mmol ), 2- (dicyclohexylphosphino) biphenyl (80 mg, 0.2 mmol) and PdCl2 (PPh3) 2 (80 mg, 0.1 mmol) in isopropanol (15 mL), 89248.doc- 163-200418454 Treat with Na2CO3 (0.19 g, 1.8 mmol) (5 mL) in water and heat at 65 ° C for 16 hours. After cooling to room temperature, the mixture was filtered through 20 mL of CH2C12 diluted 'and filtered. The filtrate was washed with 10 mL of 15% NaCl and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10:90 MeOH: CHC13) to give the title compound. 1H NMR (CDC13, 400 ΜΗζ) δ 9.24 (s, 1H), 8.95 (d, J = 4 Hz, 1H), 8.65 (dd5 J = 2? 8Hz5 1H)? 8.13 (bs? 1H) 5 7.98 (2 m , 1H), 7.91-7.86 (m, 2H), 7.55 (s, 1H), 7.44-7.41 (2d, 1H), 4.11 (t, J = 4 Hz, 2H), 3.19 (t, J = 4 Hz, 2H); 13C NMR (CDC13, 400 MHz) δ 153.9, 151.7, 148.6, 148.0, 135.9, 135.5, 135.4, 134.2, 129.5, 127.2, 126.9, 125.4, 123.5, 118.5, 62.4, 39.4.

實例63B 吡咯啶某1乙基丨-7-(3-吡啶某）異p奋呲 於-5。(：下，取含實例63八產物（〇.25§，1.〇111111〇1)與三乙胺 (〇·15 g ’ 1.5 mmol)之二氯甲烷（10 mL)經甲磺醯氯g， 1.2 mmol)處理，於〇。〇下攪拌2小時後，於室溫下攪拌15小 時。混合物減壓濃縮，殘質經含K2C〇3 (0.21 g，i.5mm〇1) 與（2R)-2-甲基吡咯啶（〇·13 g，1.5 mmol)之乙腈（15 mL)處理 ’於60°C下加熱5小時。混合物減壓濃縮，殘質溶於3〇mL 二氯甲烷中，以1〇 mL 15% NaC1洗滌，減壓濃縮。殘質經 官枉層析法純化（石夕膠，10 : 90 ·· 1 MeOH : CHC13 ·· Et3N) ，產生標題化合物。NMR (CDC13, 400 ΜΗζ) δ 9.27 (S，1H)， 8.95 (m，1H)，8·64 (dd，J=2, 4 Hz，1H)，8·12 (s，1H)，7.98 (m， 1H)? 1.90-1.86 (m5 2H)? 7.56 (s5 1H)5 7.44-7.40 (m5 1H), 3.37-3.28 (m，2H)，3.26-3.18 (m，2H)，2.68-2.61 (m，2H)， 89248.doc -164- 200418454 2.51-2.46 (m，1Η)，2·38-2·31 (m，1H)，2.00-1.93 (m，1H)， 1.88-1.82 (m，1H)，1.80-1.72 (m，1H)，1.55-1.46 (m，1H)，1.14 (d，3H) ; 13C NMR (CDC13, 400 MHz) δ 9.27，153.8，151.9, 148.4, 147.9, 135.6, 135.5, 135.4, 134.1，129.1，127.0, 126.9, 125.2, 123.4, 118.2, 60.4, 54.1，54.0, 37.2, 32.8, 21.9, 19.0。 膏例64 3-(苯甲甲某-6-i2-IY2RV2-甲某-1-响咯啶基1乙基} 口奎？林 標題彳ζ合物係依實例57之方法製備，但其中改用1-(苯甲 氧基）丙酮替代1-(1，3-噻唑-2-基）乙酮。4 NMR (300 ΜΗζ， CDC13) δ 1.13 (d，J=6.1 Hz，3 Η)，1.46 (m，1Η)，1·75 (m，1Η)， 1.94 (m，1H)，2.23 (q，J=8.8 Hz，1H)，2.37 (m，2H)，2.70 (s5 3 H)，2.97 (m，2H)，3.11 (m，1H)，3.28 (m，ih)，5.20 (s，2H)， 7.31 (s，1H)，7.35-7.46 (m，5H)，7.50 (m，3H)，7·89 (d，j=8 5 Hz，1H); (DCI/NH3) m/z 361 (M+H)+。 實例65 li/!丙基—2_甲基小啶某·[乙基丨?奎啉 標題化合物係依實例57之方法製備，但其中改用丨_環丙 基乙酮替代1-(1，3_P塞唑_2_基）乙酮。iH nmr (3〇〇 MHz， CDC13) δ 1.02-1.16 (m, 4 Η), 1.12 (d, J=6&lt;1 Hz, 3 H), 1.45 (m, 1H), 1.76 (m, 2H), 1.93 (m, 1H), 2.23 (m, 2H), 2.37 (m, 2H), 2.98 (m, 2H), 3.10 (m, 1H), 3.28 (m, lH), 7.13 (d, J=8.5 Hz, 1H), 7.50-7.56 (m, 2H), 7.88 (d, J=8.5 Hz, 1H), 7.93 (d, J=8.5Example 63B Pyrrolidine 1-ethyl-7- (3-pyridine) isoprazine at -5. (: Below, dichloromethane (10 mL) containing the eighth product of Example 63 (.25 §, 1.〇111111〇1) and triethylamine (0.15 g '1.5 mmol) was passed through g of methanesulfonyl chloride g , 1.2 mmol). After stirring at 0 ° C for 2 hours, it was stirred at room temperature for 15 hours. The mixture was concentrated under reduced pressure, and the residue was treated with acetonitrile (15 mL) containing K2C03 (0.21 g, i.5mm〇1) and (2R) -2-methylpyrrolidine (0.13 g, 1.5 mmol). Heat at 60 ° C for 5 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in 30 mL of dichloromethane, washed with 10 mL of 15% NaC1, and concentrated under reduced pressure. The residue was purified by government chromatography (Shi Xijiao, 10: 90 ·· 1 MeOH: CHC13 ·· Et3N) to give the title compound. NMR (CDC13, 400 ΜΗζ) δ 9.27 (S, 1H), 8.95 (m, 1H), 8.64 (dd, J = 2, 4 Hz, 1H), 8.12 (s, 1H), 7.98 (m , 1H)? 1.90-1.86 (m5 2H)? 7.56 (s5 1H) 5 7.44-7.40 (m5 1H), 3.37-3.28 (m, 2H), 3.26-3.18 (m, 2H), 2.68-2.61 (m, 2H), 89248.doc -164- 200418454 2.51-2.46 (m, 1Η), 2.38-2 · 31 (m, 1H), 2.0-1.93 (m, 1H), 1.88-1.82 (m, 1H), 1.80-1.72 (m, 1H), 1.55-1.46 (m, 1H), 1.14 (d, 3H); 13C NMR (CDC13, 400 MHz) δ 9.27, 153.8, 151.9, 148.4, 147.9, 135.6, 135.5, 135.4, 134.1, 129.1, 127.0, 126.9, 125.2, 123.4, 118.2, 60.4, 54.1, 54.0, 37.2, 32.8, 21.9, 19.0. Paste Example 64 3- (benzyl-6-i2-IY2RV2-methyl-1-1-salrolidinyl 1ethyl} Kou Kui? Lin titled 彳 ζ compound was prepared according to the method of Example 57, but the modified Replace 1- (1,3-thiazol-2-yl) ethanone with 1- (benzyloxy) acetone. 4 NMR (300 MHz, CDC13) δ 1.13 (d, J = 6.1 Hz, 3 ，), 1.46 (m, 1Η), 1.75 (m, 1Η), 1.94 (m, 1H), 2.23 (q, J = 8.8 Hz, 1H), 2.37 (m, 2H), 2.70 (s5 3 H), 2.97 ( m, 2H), 3.11 (m, 1H), 3.28 (m, ih), 5.20 (s, 2H), 7.31 (s, 1H), 7.35-7.46 (m, 5H), 7.50 (m, 3H), 7 · 89 (d, j = 8 5 Hz, 1H); (DCI / NH3) m / z 361 (M + H) +. Example 65 li /! Propyl-2_methylpyrimidine · [ethyl 丨? The title compound of quinoline was prepared according to the method of Example 57 except that 丨 _cyclopropyl ethyl ketone was used instead of 1- (1,3_P thiazolyl-2-yl) ethyl ketone. IH nmr (300 MHz, CDC13 ) δ 1.02-1.16 (m, 4 Η), 1.12 (d, J = 6 &lt; 1 Hz, 3 H), 1.45 (m, 1H), 1.76 (m, 2H), 1.93 (m, 1H), 2.23 ( m, 2H), 2.37 (m, 2H), 2.98 (m, 2H), 3.10 (m, 1H), 3.28 (m, lH), 7.13 (d, J = 8.5 Hz, 1H), 7.50-7.56 (m , 2H), 7.88 (d, J = 8.5 Hz, 1H), 7.93 ( d, J = 8.5

Hz, 1H); (DCI/NH3) m/z 281 (M+H)+。 89248.doc -165- 200418454 ψ m 66 4-(6-{2-「（2R)-2-甲甚-卜外匕咯啶某1乙甚}-2-4啉某）苯基 標題化合物係依實例57之方法製備，但其中改用4-乙醯 基苯基氰替代1-(1，3-噻唑-2-基）乙酮。b NMR (400 ΜΗζ， CDC13) δ 1.13 (d，J=5.8 Ηζ，3 Η)，1·46 (m，1Η)，1·73 (m，1Η)， 1.83 (m，1H)，1·95 (m，1H)，2.25 (q，J=8.6 Hz，1H)，2·40 (m， 2H)，3.03 (m5 2H)，3.14 (m，1H)，3.29 (dt，J二8.4, 2·3 Hz，1H)， 7.66 (m，2H)，7.81 (d，J=8.6 Hz，2H)，7.86 (d，&gt;8·3 Hz，1H)， 8.09 (d，J=8.6 Hz，1H)，8.22 (d，J=8.29 Hz，1H)，8.29 (d， J=8.59 Hz，2H); (DCI/NH3) m/z 342 (M+H)、 實例67 基-5-(6J2-「（2RV2-甲基-1-吡咯啶甚 1乙某 基）菸基氨Hz, 1H); (DCI / NH3) m / z 281 (M + H) +. 89248.doc -165- 200418454 ψ m 66 4- (6- {2-"(2R) -2-methyl-pyrrolidazole 1-ethyl}}-2-4 phenyl) phenyl title compound system Prepared according to the method of Example 57 except that 4-ethylfluorenylphenyl cyanide was used instead of 1- (1,3-thiazol-2-yl) ethanone. B NMR (400 MHz, CDC13) δ 1.13 (d, J = 5.8 Ηζ, 3 Η), 1.46 (m, 1Η), 1.73 (m, 1Η), 1.83 (m, 1H), 1.95 (m, 1H), 2.25 (q, J = 8.6 Hz , 1H), 2.40 (m, 2H), 3.03 (m5 2H), 3.14 (m, 1H), 3.29 (dt, J 2 8.4, 2.3 Hz, 1H), 7.66 (m, 2H), 7.81 (d, J = 8.6 Hz, 2H), 7.86 (d, &gt; 8.3 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.22 (d, J = 8.29 Hz, 1H), 8.29 (d, J = 8.59 Hz, 2H); (DCI / NH3) m / z 342 (M + H), Example 67 radical-5- (6J2-"(2RV2-methyl-1-pyrrolidine and 1 ethyl) Nicotinyl ammonia

‘越化合物係依實例5 7之方法製備，但其中改用5 -乙龜 基-2,6-二曱基|f基氰替代l-(l，3-p塞嗤-2-基）乙酮。1HNMR (300 MHz，CDC13) δ 1.14 (d，J=6.1〇 Hz，3 H)，1.48 (m，1H)， 1.77 (m，2H)，1.95 (m，1H)，2·25 (q，J=8.70 Hz，1H)，2.40 (m， 2H)，2.69 (s，3 H)，2.82 (s，3 H)，3·1〇 (m，3 H)，3.30 (m，1H)， 7·50 (d，J=8.48 Hz，1H)，7.68 (dd，J=2.03, 8.48 Hz，1H)，7.71 (bs，1H)，8.06 (d，J=8.48 Hz，1H)，8.06 (s，1H)，8·22 (d， &gt;8.48 Hz，1H); (DCI/NH3) m/z 371 (M+H)+。 實例68 - 基）-6-{2二[_(2R)-2-甲某小毗，各 口奎琳 89248.doc -166- 200418454 標題化合物係依實例57之方法製備，但其中改叫3_甲 基-2則基）乙|同替代H ) ,3_4唉_2·基）乙鲷。iH舰_ MHz, CDC13) δ l.!4 (d? J-6.10 Hz 3 h^i 1 47 r ^2, 3 H), 1.47 (m? 1H)? 1.77 2H),1.95(m,1H)52.25(q5 1=8.81 Hz, 1H), 2.41 2-94 ^3H),3.1〇(m,3H),3.3l(td, J=8.39, 2.54 Hz, 1H), 7.66 (dd, 1=8.65, !.δ6 Hz, 1H), 7.70 (d, J=2.〇〇 Hz? 1Η)? § 〇2 (d? 1=8.48 Hz, 1H) 8 09 (d aq tt ),8.09 (d, J-8.48 Hz, 1H), 8.25 (d, 1=8.82'Yue compound was prepared according to the method of Example 5 7 but in which 5-ethylpyridyl-2,6-difluorenyl | f-cyano was used instead of l- (l, 3-pethen-2-yl) ethyl. ketone. 1HNMR (300 MHz, CDC13) δ 1.14 (d, J = 6.10 Hz, 3 H), 1.48 (m, 1H), 1.77 (m, 2H), 1.95 (m, 1H), 2.25 (q, J = 8.70 Hz, 1H), 2.40 (m, 2H), 2.69 (s, 3 H), 2.82 (s, 3 H), 3.10 (m, 3 H), 3.30 (m, 1H), 7 · 50 (d, J = 8.48 Hz, 1H), 7.68 (dd, J = 2.03, 8.48 Hz, 1H), 7.71 (bs, 1H), 8.06 (d, J = 8.48 Hz, 1H), 8.06 (s, 1H ), 8.22 (d, &gt; 8.48 Hz, 1H); (DCI / NH3) m / z 371 (M + H) +. Example 68-Base) -6- {2 二 [_ (2R) -2-A some small pi, Kui Lin 89248.doc -166- 200418454 The title compound was prepared according to the method of Example 57, but the name was changed to 3 _Methyl-2 is a radical) B | Same as the replacement H), 3_4 唉 _2. iH ship_ MHz, CDC13) δ l.! 4 (d? J-6.10 Hz 3 h ^ i 1 47 r ^ 2, 3 H), 1.47 (m? 1H)? 1.77 2H), 1.95 (m, 1H) 52.25 (q5 1 = 8.81 Hz, 1H), 2.41 2-94 ^ 3H), 3.1〇 (m, 3H), 3.3l (td, J = 8.39, 2.54 Hz, 1H), 7.66 (dd, 1 = 8.65, ! .δ6 Hz, 1H), 7.70 (d, J = 2.〇〇Hz? 1Η)? § 〇2 (d? 1 = 8.48 Hz, 1H) 8 09 (d aq tt), 8.09 (d, J- 8.48 Hz, 1H), 8.25 (d, 1 = 8.82

Hz，1H)，8.53 (m，2H); (DCI/NH3) _ 333 (m+h)+。Hz, 1H), 8.53 (m, 2H); (DCI / NH3) _ 333 (m + h) +.

:1 -吡咯錢1^1土勉土H 唑―叛酸 標題化合物係依實例57之方法製備，但其中改用5_乙酸 基-3-異呤唑羧酸乙醋替代1(13+坐_2_基）乙酮。ΐΗ (300 MHz, CDC13) δ 1.13 (d, J=6.1〇 Ηζ, 3 Η), 1.45 (m, 1Η), 1.46 (t, J=7.12 Hz, 3 Η), 1.77 (m, 2H), 1.95 (m, 1H), 2.24 (q! 1=8.48 Hz, 1H), 2.38 (m, 2H), 2.97-3.22 (m, 3 H), 3.29 (m, 1H), 4.50 (q, J=7.12 Hz, 2H), 7.46 (s, 1H), 7.68 (m, 2H), 8.02 (d, 1=8.48 Hz, 1H), 8.09 (d, 1=8.82 Hz, 1H), 8.25 (d,J=8.48 Hz，1H); (DCI/NH3) m/z 380 (M+H)十。 實例70 5-(6- {2」—(2R上基小ϋ 啶 啉某、 標題化合物係採用實例57之方法製備，但其中改用5_乙 醯基-2-噻吩腈替代噻唑-2-基）乙酮，呈主要產物製得 。4 NMR (300 MHz，CDC13) δ 1·13 (d，J=5.76 Hz，3 Η)，1·46 89248.doc -167- 200418454 (m，1H)，1.76 (m，2H)，1.95 (m，1H)，2.23 (q，J=8.59 Hz，1H)， 2.40 (m，2H)，3·01 (m，2H)，3.14 (m，1H)，3.28 (dt，1H)，7.64 (m，4 H)，7.77 (d，J=8.81 Hz，1H)，8.01 (d，J=9.15 Hz，1H)， 8.15 (d，J=9.15 Hz，1H); (DCI/NH3) m/z 348 (M+H)+。 實例71 5-(6-i2-「（2RV2-甲基-1-吡咯啶基1乙某某V2-邊吩·_ 羧亞胺酸乙酯: 1 -pyrrolidine 1 ^ 1 Tumotu Hazole-the title compound of amidoacid was prepared according to the method of Example 57, but the 5-acetic acid-3-isopyrazole carboxylic acid ethyl acetate was used instead of 1 _2_yl) ethyl ketone. ΐΗ (300 MHz, CDC13) δ 1.13 (d, J = 6.1〇Ηζ, 3 Η), 1.45 (m, 1Η), 1.46 (t, J = 7.12 Hz, 3 Η), 1.77 (m, 2H), 1.95 (m, 1H), 2.24 (q! 1 = 8.48 Hz, 1H), 2.38 (m, 2H), 2.97-3.22 (m, 3 H), 3.29 (m, 1H), 4.50 (q, J = 7.12 Hz , 2H), 7.46 (s, 1H), 7.68 (m, 2H), 8.02 (d, 1 = 8.48 Hz, 1H), 8.09 (d, 1 = 8.82 Hz, 1H), 8.25 (d, J = 8.48 Hz , 1H); (DCI / NH3) m / z 380 (M + H) ten. Example 70 5- (6- {2 "— (2R stilbenepyridinyl) The title compound was prepared by the method of Example 57 but using 5-acetamidine-2-thienilnitrile instead of thiazole-2- Methyl ethyl ketone, prepared as the main product. 4 NMR (300 MHz, CDC13) δ 1 · 13 (d, J = 5.76 Hz, 3 Η), 1.46 89248.doc -167- 200418454 (m, 1H) , 1.76 (m, 2H), 1.95 (m, 1H), 2.23 (q, J = 8.59 Hz, 1H), 2.40 (m, 2H), 3.01 (m, 2H), 3.14 (m, 1H), 3.28 (dt, 1H), 7.64 (m, 4 H), 7.77 (d, J = 8.81 Hz, 1H), 8.01 (d, J = 9.15 Hz, 1H), 8.15 (d, J = 9.15 Hz, 1H) (DCI / NH3) m / z 348 (M + H) +. Example 71 5- (6-i2-"(2RV2-Methyl-1-pyrrolidinyl 1) Sodium V2-Phenyl · _ Carboxylidene Urethane

標題化合物係採用實例5 7之方法製備，但其中改用5 _乙 醯基噻吩腈替代1-(1，3_噻唑基）乙酮，呈次要產物製得 。iH NMR (300 MHz，CDC13) δ 1.13 (d，J=6.10 Hz，3 H)，44 (t，J=7.12 Hz，3 H)，1.46 (m，1H)，1.77 (m，2H)，1.95 (m，1H) 2.24 (q，J=8.82 Hz，lH)，2.39 (m，2H)，3.00 (m，2H)，3.12 (m 1H)，3.29 (m，1H)，4.34 (q，J=7.46 Hz，2H)，7·60 (m，4 Ή) 7.77 (d，J=8.48 Hz，1H)，8·01 (d，J=9.16 Hz，1H)，8·1〇 (d J=8.48 Hz，1H); (DCI/NH3) m/z 394 (M+H)+。 ’ 實例72The title compound was prepared by the method of Example 5 7 but using 5- acetamidothiophenonitrile instead of 1- (1,3-thiazolyl) ethanone as the secondary product. iH NMR (300 MHz, CDC13) δ 1.13 (d, J = 6.10 Hz, 3 H), 44 (t, J = 7.12 Hz, 3 H), 1.46 (m, 1H), 1.77 (m, 2H), 1.95 (m, 1H) 2.24 (q, J = 8.82 Hz, lH), 2.39 (m, 2H), 3.00 (m, 2H), 3.12 (m 1H), 3.29 (m, 1H), 4.34 (q, J = 7.46 Hz, 2H), 7.60 (m, 4 Ή) 7.77 (d, J = 8.48 Hz, 1H), 8.01 (d, J = 9.16 Hz, 1H), 8.10 (d J = 8.48 Hz, 1H); (DCI / NH3) m / z 394 (M + H) +. ’Example 72

二甲 基 •甲某 基&quot;I乙基丨4 標題化合物係依實例57之方法製備，但其中改用i (2 4 二甲基-1，3-呤唑基）乙酮替代1-(1，夂嘍唑_2_基）乙酮。: NMR (300 MHz? CD3OD) δ 1.20 (d5 J=6.10 Hz? 3 H)5 ! 5〇 1H)? 1.85 (m5 2H)? 2.05 (m, 1H), 2.44 (m5 1H)? 2.55 (s? 3 ^ 2·56 (m，2H)，2·65 (s，3 H)，3.05 (m5 2H)，3·29 (m，2H)，7 幻 ⑽，J=8·65, U6 Hz，1H)，7·75 (d，J吐86 Hz，1H)，7 8〇 (: 89248.doc -168- 200418454 J=8.48 Hz, 1Η)，7·98 (d，J二8·48 Ηζ，1Η)，8·29 (d，J=8.81Hz， 1H); (DCI/NH3) m/z 336 (M+H)+。 實例73 3二见基- 5-(6 - -甲基-1-p比p各啶某1 6某} - 2-4： 4木某） -4-異噚唑羧酸乙酯 標題化合物係依實例57之方法製備，但其中改用5-乙醯 基-3 -甲基-4-異噚唑羧酸乙酯替代1_(丨，3_噻唑-2-基）乙酮。 'H NMR (300 MHz? CD3OD) δ 1.18 (d5 J=6.1〇 Hz5 3 H),1.19 (t，JW.UHz，3 H)，1.48 (m，1H)，1.82 (m，2H)，2.03 (m，1H)， 2·37 (m，1Η)，2·52 (m，2H)，2.53 (s，3 H)，3.07 (m，2H)，3.21 (m，1H)，3.31 (m，1H)，4.29 (q，J=7.12 Hz，2H)，7.78 (dd， J二8.82, 2.03 Hz，1H)，7.89 (d，J=1.36 Hz，1H)，7.98 (d，J=8.48 Hz，1H)，8.07 (d，J = 8.82 Hz，1H)，8·45 (d，J=8.82 Hz，1H); (DCI/NH3) m/z 394 (M+H)+。 實例74The title compound was prepared according to the method of Example 57 except that i (2 4 dimethyl-1,3-pyrazolyl) ethyl ketone was used instead of 1- ( 1, oxazole_2_yl) ethyl ketone. : NMR (300 MHz? CD3OD) δ 1.20 (d5 J = 6.10 Hz? 3 H) 5! 5〇1H)? 1.85 (m5 2H)? 2.05 (m, 1H), 2.44 (m5 1H)? 2.55 (s? 3 ^ 2.56 (m, 2H), 2.65 (s, 3 H), 3.05 (m5 2H), 3.29 (m, 2H), 7 maggots, J = 8.65, U6 Hz, 1H ), 7.75 (d, J spit 86 Hz, 1H), 7 80 (: 89248.doc -168- 200418454 J = 8.48 Hz, 1Η), 7.98 (d, J 2 8.48 Ηζ, 1Η ), 8.29 (d, J = 8.81Hz, 1H); (DCI / NH3) m / z 336 (M + H) +. Example 73 3-Diamino- 5- (6--methyl-1-p to p-pyridine 1 6-1-2-4: 4-2-4) -isoxazole carboxylic acid ethyl ester title compound system It was prepared according to the method of Example 57 except that 5-ethylfluorenyl-3-methyl-4-isoxazole carboxylic acid ethyl ester was used instead of 1- (3,3-thiazol-2-yl) ethanone. 'H NMR (300 MHz? CD3OD) δ 1.18 (d5 J = 6.1〇Hz5 3 H), 1.19 (t, JW.UHz, 3 H), 1.48 (m, 1H), 1.82 (m, 2H), 2.03 ( m, 1H), 2.37 (m, 1Η), 2.52 (m, 2H), 2.53 (s, 3 H), 3.07 (m, 2H), 3.21 (m, 1H), 3.31 (m, 1H) ), 4.29 (q, J = 7.12 Hz, 2H), 7.78 (dd, J = 8.82, 2.03 Hz, 1H), 7.89 (d, J = 1.36 Hz, 1H), 7.98 (d, J = 8.48 Hz, 1H ), 8.07 (d, J = 8.82 Hz, 1H), 8.45 (d, J = 8.82 Hz, 1H); (DCI / NH3) m / z 394 (M + H) +. Example 74

4-(7-(2-「（2R)-2-曱某-1-4咯啶基1乙基}-3-異崦啉基）苯某I4- (7- (2-"(2R) -2-fluorene-1-4pyridinyl 1ethyl} -3-isofluorinyl) benzene I

實例74A 4-(7-溴-3-異崦啉基）笨基氰 取實例62D產物（3.6 mmol)、4-氰基苯基乙块（4.3 mmol) 、0：111(0.2 111111〇1)、？(1(：12(??113)2(0.1111111〇1)與二異丙基胺（5.3 mmol)於甲苯（15 mL)中合併，依實例62E處理，產生標題化 合物。Example 74A 4- (7-bromo-3-isofluorinyl) benzyl cyanide Take the product of Example 62D (3.6 mmol), 4-cyanophenyl ethyl block (4.3 mmol), 0: 111 (0.2 111111〇1) ,? (1 (: 12 (?? 113) 2 (0.1111111〇1) was combined with diisopropylamine (5.3 mmol) in toluene (15 mL) and treated according to Example 62E to give the title compound.

實例74B 4-「7-(2-羥乙某V3-異4啉基1苯基氨 89248.doc -169- 200418454 取實例74A產物（4 mmol)溶於20 mL THF中，於氮蒙氣下 冷卻至-60 C。滴加n-BuLi (4.4 mmol)，混合物於-60°C再攪; 拌30分鐘。添加含環氧乙烷（2〇 mmol)之10 ml THF，使混合 物回升至10°C，攪拌至反應完成。混合物冷卻至〇°C，慢慢 添加2 N HC1至pH==3，以中止反應，真空排除溶劑，殘質溶 於20 mL二氯甲燒中，以水洗;;條，減壓濃縮。殘質經石夕膠層 析（5 ·· 95 MeOH ·· CHC13)，產生標題化合物。Example 74B 4- "7- (2-Hydroxyethyl, V3-iso4olinyl1phenylamino 89248.doc -169- 200418454 The product of Example 74A (4 mmol) was dissolved in 20 mL of THF under nitrogen atmosphere. Cool to -60 C. Add n-BuLi (4.4 mmol) dropwise and stir the mixture at -60 ° C; stir for 30 minutes. Add 10 ml THF containing ethylene oxide (20 mmol) to bring the mixture back to 10 ° C, stir until the reaction is complete. The mixture is cooled to 0 ° C, slowly add 2 N HC1 to pH == 3 to stop the reaction, remove the solvent in vacuo, the residue is dissolved in 20 mL of dichloromethane, and washed with water; Strip, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (5 ·· 95 MeOH ·· CHC13) to give the title compound.

實例74C 甲基-1-吡咯啶某1乙基丨—3-異崦嗷基）笨某教 取實例74B產物、甲磺醯氣與（2R)-2-甲基吡咯啶鹽酸鹽依 實例62F之方法處理，產生標題化合物。 實例75 豆-{2-「(2R)-2 -甲基- l-ΐ?比p各咬基1乙基丨-2-(4 -甲氣笨基V奎。号口林 2-{2-「（2 R)-2 -甲基- Ι- p比p各淀基1乙基丨- 2-(4 -甲氣笨基V奎。号淋Example 74C Methyl-1-pyrrolidine 1 ethyl 丨 3-isofluorenyl) Example of a 74B product, methanesulfonium gas and (2R) -2-methylpyrrolidine hydrochloride Treatment with 62F yielded the title compound. Example 75 Bean- {2-"(2R) -2 -methyl-l-fluorene? Ratio p 1 ethyl 1-2-(4-methylbenzyl V Kui. No. Lin 2- {2 -"(2 R) -2 -methyl-l-p-p-p-dodecyl 1-ethyl 2--2- (4-methylbenzyl V-quinone. No. leaching

實例75A N-(4二(2-f(2R)-2-甲基-1-吡咯啶基1乙某}苽某）乙醯胺 取含實例54B產物（0.47 g，2.3mmol)之乙酸：水（1 : 1)， 於0C下經乙酸肝（0.44 mL，4.6mmol)處理，於1 〇〇°C下加熱 45分鐘。使混合物冷卻至室溫，濃縮，殘質分溶於1M NaOH 與二氯甲烷之間。分相，水相經二氯甲烷萃取（3次）。取二 氯曱烷層合併，脫水（硫酸鎂），過濾，濾液濃縮，產生標題 化合物。1H NMR (300 MHz，CDC13) δ 1.10 (d，J=6 Hz，3 H)， 1.43 (m，1Η)，1·76 (m，2H)，1.92 (m，1H)，2.16 (s，3 H)，2·25 89248.doc -170- 200418454 (m，3H)，2.77 (m，2H)，2,99 (m，1Η)，3·23 (td，J=9, 3 Hz，1H)， 7.16 (d，J=8 Hz，2H)，7.40 (d，J=8 Hz，2H); (DCI/NH3) m/z 247 (M+H)+。Example 75A N- (4-bis (2-f (2R) -2-methyl-1-pyrrolidinyl 1 ethyl}}} acetamidine Acetic acid containing the product of Example 54B (0.47 g, 2.3 mmol): Water (1: 1), treated with liver acetate (0.44 mL, 4.6 mmol) at 0C, and heated at 1000 ° C for 45 minutes. The mixture was cooled to room temperature, concentrated, and the residue was dissolved in 1M NaOH and Between dichloromethane. The phases were separated and the aqueous phase was extracted with dichloromethane (3 times). The dichloromethane layers were combined, dehydrated (magnesium sulfate), filtered, and the filtrate was concentrated to give the title compound. 1H NMR (300 MHz, CDC13) δ 1.10 (d, J = 6 Hz, 3 H), 1.43 (m, 1Η), 1.76 (m, 2H), 1.92 (m, 1H), 2.16 (s, 3 H), 2.25 89248.doc -170- 200418454 (m, 3H), 2.77 (m, 2H), 2,99 (m, 1Η), 3.23 (td, J = 9, 3 Hz, 1H), 7.16 (d, J = 8 Hz, 2H), 7.40 (d, J = 8 Hz, 2H); (DCI / NH3) m / z 247 (M + H) +.

實例75B N-(4.:.j&gt;「（2R)-2-甲基比咯啶某1乙基卜2-硝某苯某）乙醯胺 取貫例75A產物（〇·58 g，2.4 mmol)之乙酸肝（2.2 mL)與濃 硫酸（0.16 mL)冷卻至〇。〇，滴加90%硝酸（0.115 mL，2.4 mmol)處理。於周溫下攪拌16小時，混合物加水稀釋，冷卻 至〇°C，像用1 M NaOH調整pH，以二氣甲烷萃取（3次）。合 併二氯甲烷層，脫水（硫酸鎂），過濾，濾液濃縮，產生標題 化合物。1H NMR (300 MHz，CDC13) δ 1.08 (d，J=6 Hz，3 H)， 1.43 (m，1H), 1.74 (m，2H)，1.92 (m，1H)，2.18 (q，J=9 Hz， 1H)，2.28 (s，3 H)，2·32 (m，1H)，2·84 (m，2H)，3.02 (m，1H)， 3.21 (td，J=8, 3 Hz，1H)，7.51 (dd，J=9, 2 Hz，1H)，8.07 (d， J二2 Hz，1H)，8.65 (d，J=9 Hz，1H)，10.23 (s，1H); (DCI/NH3) m/z 292 (M+H)+。Example 75B N- (4.:. J &gt; "(2R) -2-methylpyrrolidine 1 ethyl ethyl 2-nitro certain benzene) Acetylamine Take the product of Example 75A (0.58 g, 2.4 Hepatic acetate (2.2 mL) and concentrated sulfuric acid (0.16 mL) were cooled to 0.0%, and then treated with 90% nitric acid (0.115 mL, 2.4 mmol) dropwise. After stirring at ambient temperature for 16 hours, the mixture was diluted with water and cooled to At 0 ° C, the pH was adjusted with 1 M NaOH and extracted with methane (3 times). The dichloromethane layers were combined, dehydrated (magnesium sulfate), filtered, and the filtrate was concentrated to give the title compound. 1H NMR (300 MHz, CDC13 ) δ 1.08 (d, J = 6 Hz, 3 H), 1.43 (m, 1H), 1.74 (m, 2H), 1.92 (m, 1H), 2.18 (q, J = 9 Hz, 1H), 2.28 ( s, 3 H), 2.32 (m, 1H), 2.84 (m, 2H), 3.02 (m, 1H), 3.21 (td, J = 8, 3 Hz, 1H), 7.51 (dd, J = 9, 2 Hz, 1H), 8.07 (d, J 2 Hz, 1H), 8.65 (d, J = 9 Hz, 1H), 10.23 (s, 1H); (DCI / NH3) m / z 292 ( M + H) +.

實例75C 4-{2-「（2RV2-甲基-1-吡咯啶某1乙某卜2-硝基笨胺 取含實例 75B 產物（0.60 g，2.1mmol)之 3 M HC1 (12 mL) 於80°C下加熱2小時，冷卻至0°C，慢慢添加1 M NaOH調整 pH，以二氯甲烷萃取（4次）。合併之二氯甲烷層脫水（硫酸鎂） ，過漉，漉液濃縮，產生標題化合物。4 NMR (300 MHz， CDC13) δ 1.13 (d，J=6 Hz，3 Η)，1·47 (m，1H)，1.77 (m，2H)， 1.95 (m，1H)，2.29 (m，3 H)，2.76 (dd，J=9, 7 Hz，2H)，3.00 89248.doc -171 - 200418454 (m，1H)，3.25 (td，J=8, 3 Hz，1H)，5.97 (s，2H)，6.75 (d，J二9 Hz，1H)，7·26 (dd，J=9，2 Hz，1H)，7·96 (d，J=2 Hz，1H); (DCI/NH3) m/z 250 (M+H)+ 0Example 75C 4- {2-"(2RV2-methyl-1-pyrrolidine, 1 ethyl, 2 nitrobenzylamine, 3 M HC1 (12 mL) containing the product of Example 75B (0.60 g, 2.1 mmol) in Heated at 80 ° C for 2 hours, cooled to 0 ° C, slowly added 1 M NaOH to adjust the pH, and extracted with dichloromethane (4 times). The combined dichloromethane layers were dehydrated (magnesium sulfate). Concentrate to give the title compound. 4 NMR (300 MHz, CDC13) δ 1.13 (d, J = 6 Hz, 3 Η), 1.47 (m, 1H), 1.77 (m, 2H), 1.95 (m, 1H) , 2.29 (m, 3 H), 2.76 (dd, J = 9, 7 Hz, 2H), 3.00 89248.doc -171-200418454 (m, 1H), 3.25 (td, J = 8, 3 Hz, 1H) , 5.97 (s, 2H), 6.75 (d, J 2 9 Hz, 1H), 7.26 (dd, J = 9, 2 Hz, 1H), 7.96 (d, J = 2 Hz, 1H); (DCI / NH3) m / z 250 (M + H) + 0

實例75D 基-1-吡咯啶基1乙某丨-Hy -栌 標題化合物係依實例54Β之方法製備，但其中改用實例 75C產物替代實例54Α產物，產生標題化合物。NMR (300 MHz，CDC13) δ 1.15 (d，J:6 Hz，3 Η)，1·47 (m，1Η)，1·83 (m， 3 Η)，2·3β (m，3 η)，2.70 (m，2Η)，3·00 (m，1Η)，3.27 (m，5 H)，6·59 (m，3 H); (DCI/NH3) m/z 220 (M+H)+。Example 75D-I-1-pyrrolidinyl 1-Hy-Hy- 栌 The title compound was prepared according to the method of Example 54B, but the product of Example 75C was used instead of the product of Example 54A to give the title compound. NMR (300 MHz, CDC13) δ 1.15 (d, J: 6 Hz, 3 Η), 1.47 (m, 1 Η), 1.83 (m, 3 Η), 2.3β (m, 3 η), 2.70 (m, 2Η), 3.00 (m, 1Η), 3.27 (m, 5 H), 6.59 (m, 3 H); (DCI / NH3) m / z 220 (M + H) +.

實例75E - {2-「（2R)-2-甲基-1-叶1^各啶基1乙某丨4崎4 取實例 75D 產物（14·6 mg，0.067 mmol)經 〇·〇75 mL 1 Μ乙 一酸之乙醇溶液（由0.4 g 40重量％乙二酸之水溶液經乙醇 稀釋至總體積6.9 mL製成）處理，於80°C下加熱16小時。使 混合物冷卻至室溫，濃縮。殘質經矽膠層析法純化，以梯 度2%與3.5% (9 : 1 MeOH ··.濃NH4OH)之二氯甲烷溶液溶離 ，產生標題化合物。4 NMR (300 MHz，CD3OD) δ 1.15 (d， J=6 Hz，3 H)，1.47 (m，1H)，1.80 (m，2H)，2.03 (m，1H)，2.34 (q，J=9 Hz，1H)，2.48 (m，2H)，3.07 (m，2H)，3.25 (m，2H)， 7.80 (dd，J=9, 2 Hz，1H)，7.95 (d，J=2 Hz，1H)，8·04 (d，J=9 Hz，1H)，8.84 (d，J=2 Hz，1H)，8.86 (d，J=2 Hz，1H) ; (DCI/NH3) m/z 242 (M+H)+。Example 75E-{2-"(2R) -2-methyl-1-leaf 1 ^ each pyridyl 1 ethyl 4 Z 4 4 Take the product of Example 75D (14.6 mg, 0.067 mmol) through 0.075 mL A 1 M solution of glycolic acid in ethanol (made by diluting 0.4 g of a 40% by weight aqueous solution of oxalic acid with ethanol to a total volume of 6.9 mL) was treated and heated at 80 ° C for 16 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography and dissolved in a dichloromethane solution with a gradient of 2% and 3.5% (9: 1 MeOH .. concentrated NH4OH) to give the title compound. 4 NMR (300 MHz, CD3OD) δ 1.15 (d , J = 6 Hz, 3 H), 1.47 (m, 1H), 1.80 (m, 2H), 2.03 (m, 1H), 2.34 (q, J = 9 Hz, 1H), 2.48 (m, 2H), 3.07 (m, 2H), 3.25 (m, 2H), 7.80 (dd, J = 9, 2 Hz, 1H), 7.95 (d, J = 2 Hz, 1H), 8.04 (d, J = 9 Hz , 1H), 8.84 (d, J = 2 Hz, 1H), 8.86 (d, J = 2 Hz, 1H); (DCI / NH3) m / z 242 (M + H) +.

實例75F 89248.doc 172- 200418454 6- {2-「（2R)-2-甲某-1-说咯啶某1乙某丨-2-(4-甲氣笨基V杳哼啉 7- {2-「（21〇-2-甲某-1-吡咯啶某1匕某丨-2-(4-甲氧笨基&gt;套崎啉 取實例75D產物與氧代（4-甲氧苯基）乙醛（化學摘要編號 16208-17-6)依實例75E之方法處理，產生標題化合物。 實例76 6-{2-「（211)-2-甲基-1-吡咯啶篡1乙基}-2-笨基。套呤啉 mf(2R)-2 -甲基- Ι- p比p各症基1乙基}-2 -苯基峻琳 取實例75D產物與氧代（苯基）乙醛依實例75E之方法處理 ，產生標題化合物。 實例77 6二{2:__[.(2R)-2-尤基-吡咯啶基1乙某门-吡啶基v套唑啉Example 75F 89248.doc 172- 200418454 6- {2-"(2R) -2-methyl-1-1-said-pyridine-1 1-one 丨 -2- (4-methylbenzyl-V-phenanthroline 7- { 2-"(21〇-2-methyl-1-1-pyrrolidine-1, 1-2--1, 4-methoxybenzyl &gt; tarsazoline Example 75D product and oxo (4-methoxyphenyl ) Acetaldehyde (Chemical Abstract No. 16208-17-6) was treated according to the method of Example 75E to give the title compound. Example 76 6- {2-"(211) -2-methyl-1-pyrrolidine 1ethyl} -2-benzyl.Morphin mf (2R) -2-methyl-l-p ratio p each ethyl group 1 ethyl} -2-phenyl Junlin Take the product of Example 75D and oxo (phenyl) ethyl The aldehyde was treated according to the method of Example 75E to give the title compound. Example 77 6 bis {2: __ [. (2R) -2-Euyl-pyrrolidinyl 1-ethyl-pyridyl v-trozoline

實例77A 坠.(2_甲酿基-4_{2-「（2幻_?二甲基·比咯啶某1乙基}笨基）菸 醯胺 取實例54E產物（35 mg，0」5麵〇1)與三乙胺（〇·〇51 mL， 0.36 mmol)於二氯甲烷（0.5 mL)中合併，以菸醯氯鹽酸鹽（3〇 mg，0.17 mmol)處理。於周溫下攪拌ι6小時，混合物濃縮 ，殘質經矽膠層析法純化，以梯度2%與3·5% (9 : i Me〇H •;辰NH4〇H)之二氯甲烷溶液溶離，產生標題化合物。1h nmr (300 MHz，CDC13) δ 1.11 (d，J=6 Hz，3H)，1.45 (m，1H)，1.77 (m，2H)，1.94 (m，1H)，2.22 (q，J=9 Hz，1H)，2.35 (m，2H)， 2.90 (m，2H)，3·06 (m，1H)，3.25 (m，1H)，7.48 (dd，J=8, 5 Hz， 89248.doc -173 - 200418454 1H)，7.56 (dd，J=8, 2 Ηζ，1Η)，7·60 (d，J=2 Hz，1H)，8.34 (dt， J=8, 2 Hz，1H)，8.83 (m，2H)，9.32 (d，J=2 Hz，1H)，9.99 (s， 1H)，12.09 (s，1H); MS (DCI/NH3) m/z 338 (M+H)+。Example 77A. (2_Methylmethyl-4_ {2-"(2 幻 _? Dimethyl · pyrrolidine 1 ethyl} benzyl) nicotinamide Take the product of Example 54E (35 mg, 0" 5 Surface 01) was combined with triethylamine (0.051 mL, 0.36 mmol) in dichloromethane (0.5 mL) and treated with nicotine chloride hydrochloride (30 mg, 0.17 mmol). At ambient temperature After being stirred for 6 hours, the mixture was concentrated, and the residue was purified by silica gel chromatography, and was dissolved in a gradient of 2% and 3.5% (9: iMeOH • NHNH4OH) in dichloromethane to give the title compound. 1h nmr (300 MHz, CDC13) δ 1.11 (d, J = 6 Hz, 3H), 1.45 (m, 1H), 1.77 (m, 2H), 1.94 (m, 1H), 2.22 (q, J = 9 Hz , 1H), 2.35 (m, 2H), 2.90 (m, 2H), 3.06 (m, 1H), 3.25 (m, 1H), 7.48 (dd, J = 8, 5 Hz, 89248.doc -173 -200418454 1H), 7.56 (dd, J = 8, 2 Ηζ, 1Η), 7.60 (d, J = 2 Hz, 1H), 8.34 (dt, J = 8, 2 Hz, 1H), 8.83 (m , 2H), 9.32 (d, J = 2 Hz, 1H), 9.99 (s, 1H), 12.09 (s, 1H); MS (DCI / NH3) m / z 338 (M + H) +.

實例77B 6-{2-「（211)-2-甲某-1-吡咯啶基1乙基}-2-(3-吡啶基&gt;杳唑4 取含實例77A產物（25 mg，0.074 mmol)之飽和氯化銨水溶 液（3 mL)於80°C下加熱16小時。使混合物冷卻至室溫，使用 1 M NaOH調至pH 14，以二氯甲烷萃取（3次）。合併之二氯 甲烷層此水（硫酸鎂），過濾，濾液濃縮。殘質經矽膠層析法 純化，以梯度2%與3.5% (9 : 1 MeOH :濃NH4〇H)之二氯甲 烷溶液溶離，產生標題化合物。iHNMRpOOME^CDClJ δ 1.13 (d，J=6 Hz，3 H)，1.47 (m，1H)，1·75 (m，2H)，1·96 (m， 1H)，2.25 (q，J=9 Hz，1H)，2.41 (m，2H)，3.10 (m，3H)，3·29 (m，1H)，7.45 (dd，J=8, 5 Hz，1H)，7.78 (d，J=lHz，1H)，7·83 (dd，J=8, 2 Hz，1H)，8.03 (d，J=8Hz，1H)，8.73 (d，J=4 Hz， 1H)，8.85 (dt，J=8, 2 Hz，1H)，9.43 (d，J=lHz，1Η)，9·80 (s， 1H); MS (DCI/NH3) m/z 319 (M+H)+。 實例78 0 -甲基- 甲基-p比p各咬-1-基V乙基1-莫-2 -某 -2 Η - 口客？井-3 -酉同 標題化合物係依實例3 1F之方法製備，但其中改用 1-[2-(6-溴-莕-2-基）-乙基]-(2R)-2-甲基-吡咯啶（實例2Β，6〇 mg，0· 19 mmol)替代2-(6-溴-萘-2-基）-乙醇（實例31E)，及改 用6 -甲基- 2H-塔啡-3-酉同（41.5 mg，0.3 8 mmol，2當量）替代 89248.doc -174- 200418454 2H-嗒畊-3-酮。經管柱層析法純化（95 : 5 :微量之二氯曱燒 /甲醇/NHUOH)，產生游離鹼產物，其溶於Et2〇中。通入HC1 氣體至此溶液中，產生標題化合物之單鹽酸鹽（25 mg，收 率 34%)。4 NMR (CD3OD，300 ΜΗζ) δ 8.08 (d，J=2 Hz，1H)， 7.98 (s，1H)，7.95 (s，1H)，7.88画7.92 (m，1H)，7.67 (dd，J=2, 8 Hz，lH)，7.54 (dd，&gt;2, 8 Hz，1H)，7·48 (d，J二9 Hz，1H)，7·〇5 (d，J二9 Hz，1H)，3.85-3.70 (m，2H)，3.60-3.51 (m，1H)， 3.40-3.15 (m，4H)，2.42 (s，3H)，2.42-2.26 (m，lH)，2.25-1.99 (m，2H)，1^85-1.67 (m，1H)，1.49 (d，J二6 Hz，3H)。MS (DCI-NH3) [M+H] + 348。 實例79 U企J&gt;((2RV2-甲基-吡备^_1_基&gt; 乙基μ萁_2_基^嘧冷-?_崎Example 77B 6- {2-"(211) -2-methyl-1-pyrrolidinyl 1ethyl} -2- (3-pyridyl &gt; oxazole 4 Take the product containing Example 77A (25 mg, 0.074 mmol ) Of saturated ammonium chloride aqueous solution (3 mL) was heated at 80 ° C. for 16 hours. The mixture was cooled to room temperature, adjusted to pH 14 with 1 M NaOH, and extracted with dichloromethane (3 times). The combined dichloride The water (magnesium sulfate) in the methane layer was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography and dissolved in a gradient of 2% and 3.5% (9: 1 MeOH: concentrated NH4OH) in dichloromethane to give the title. Compound. IHNMRpOOME ^ CDClJ δ 1.13 (d, J = 6 Hz, 3 H), 1.47 (m, 1H), 1.75 (m, 2H), 1.96 (m, 1H), 2.25 (q, J = 9 Hz, 1H), 2.41 (m, 2H), 3.10 (m, 3H), 3.29 (m, 1H), 7.45 (dd, J = 8, 5 Hz, 1H), 7.78 (d, J = lHz , 1H), 7.83 (dd, J = 8, 2 Hz, 1H), 8.03 (d, J = 8Hz, 1H), 8.73 (d, J = 4 Hz, 1H), 8.85 (dt, J = 8 , 2 Hz, 1H), 9.43 (d, J = lHz, 1Η), 9.80 (s, 1H); MS (DCI / NH3) m / z 319 (M + H) +. Example 78 0 -methyl -Methyl-p to p-bite-1-yl Vethyl 1-mo-2-Some-2 Η-Oral? Well-3-酉 Same title The product was prepared according to the method of Example 3 1F, but 1- [2- (6-bromo-fluoren-2-yl) -ethyl]-(2R) -2-methyl-pyrrolidine was used instead (Example 2B, 60 mg, 0.19 mmol) in place of 2- (6-bromo-naphthalen-2-yl) -ethanol (Example 31E), and 6-methyl-2H-tarphin-3-pyridine (41.5 mg , 0.3 8 mmol, 2 equivalents) instead of 89248.doc -174- 200418454 2H-dagen-3-one. Purified by column chromatography (95: 5: trace amount of dichloromethane / methanol / NHUOH), producing free Alkali product, which was dissolved in Et20. HC1 gas was passed into this solution to produce the monohydrochloride salt of the title compound (25 mg, yield 34%). 4 NMR (CD3OD, 300 ΜΗζ) δ 8.08 (d, J = 2 Hz, 1H), 7.98 (s, 1H), 7.95 (s, 1H), 7.88, 7.92 (m, 1H), 7.67 (dd, J = 2, 8 Hz, lH), 7.54 (dd, &gt; 2, 8 Hz, 1H), 7.48 (d, J 2 9 Hz, 1H), 7.05 (d, J 2 9 Hz, 1H), 3.85-3.70 (m, 2H), 3.60-3.51 ( m, 1H), 3.40-3.15 (m, 4H), 2.42 (s, 3H), 2.42-2.26 (m, 1H), 2.25-1.99 (m, 2H), 1 ^ 85-1.67 (m, 1H), 1.49 (d, J 2 6 Hz, 3H). MS (DCI-NH3) [M + H] + 348. Example 79 U &J; ((2RV2-methyl-pyridine ^ _1_yl) &gt; ethyl μ 萁 _2_yl ^ pyrimidin-? _ Saki

實例79A U臭-•淀-2 -腈 取含 5-溴-2-埃嘧啶（1·85 g，6·49 mmol)與 CuCN (0.64 g， 7·14 mmol，1.1當量）之吡啶（13 mL)混合物於8〇它下攪拌3 小時後’再於▲溫下授拌15小時。減壓排除揮發物，殘質 分溶於二氯甲烷與鹽水之間。有機層脫水（硫酸鎂）與過漉。 濾液減壓濃縮，殘質經管柱層析法純化（95 : 5己烷/乙酸乙 酯），產生標題中間物之灰白色固體（〇 63g，收率53%)。M p. 119.6-121.5°C ^ NMR (CDC13, 300 MHz) δ 8.93 (s5 2H) 〇 MS (DCI-NH3) [M+H]+ 201。 -Example 79A Uzine- • Yodo-2 -nitrile was used to obtain pyridine (13 mL) The mixture was stirred at 80 ° C for 3 hours, and then was further stirred at ▲ temperature for 15 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in dichloromethane and brine. The organic layer is dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (95: 5 hexane / ethyl acetate) to give the title intermediate as an off-white solid (0.63 g, yield 53%). M p. 119.6-121.5 ° C ^ NMR (CDC13, 300 MHz) δ 8.93 (s5 2H) o MS (DCI-NH3) [M + H] + 201. -

t 例 79B 芝_;甲竭基-p密咬-2-月眚 89248.doc -175- 200418454 取含5-漠^密淀-2-腈（實例79a，276 mg，i 5〇 mm〇1)、六 甲基一錫（639 111§，1.95 111111〇1，13當量）與1^(1)1)113)4(551^ ，〇·15 mmol，0」當量）之甲苯（5 mL)混合物於回流下攪拌3 小時後，再於：C溫與無水氮蒙氣下丨5小時。減壓排除揮發 物，殘質分洛於二氯甲烷與KF水溶液（1〇 g含於1〇Q mL中） ^間。有機層脫水（¾酸鎂）與過濾。濾液減壓濃縮，殘質經 f柱層析法純化（100%二氯甲烷），產生標題中間物之白色 固體（219 11^’收率54%)。1^^1^11(€〇(^13,300]^1^)3 8.81 (s，2H)，Q.45 (s，9H)。MS (DCI-NH3)[M+H]+ 270，[M+NH4] + 287。t Example 79B Zhizhi; Methenyl-p dense bite-2-month 眚 89248.doc -175- 200418454 Take 5-mo ^ dense lake-2-carbonitrile (Example 79a, 276 mg, i 50mm) ), Hexamethyl monotin (639 111§, 1.95 111111〇1, 13 equivalents) and 1 ^ (1) 1) 113) 4 (551 ^, 0.15 mmol, 0 ″ equivalent) toluene (5 mL) After the mixture was stirred at reflux for 3 hours, it was further heated at: C temperature and anhydrous nitrogen for 5 hours. The volatiles were removed under reduced pressure, and the residue was taken up in dichloromethane and KF aqueous solution (10 g in 10 mL). The organic layer is dehydrated (¾magnesium) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by f-column chromatography (100% dichloromethane) to give the title intermediate as a white solid (219 11 ^ 'yield 54%). 1 ^^ 1 ^ 11 (€ 〇 (^ 13,300) ^ 1 ^) 3 8.81 (s, 2H), Q.45 (s, 9H). MS (DCI-NH3) [M + H] + 270, [M + NH4] + 287.

實例79C ϋ6·-(2二)_苯 _2_某 ％嘧啶 -睛 取含5-三甲錫烷基-嘧啶腈（實例79Β，2〇〇 mg，0.75 mmol，1·1 當量）、2-(6-溴-茬-2-基）-乙醇（實例 31E，171 mg ，0.679 mmol)、氟化铯（227 mg，1 49 mm〇1，2 2當量）與 Pd[P(t-Bu)3]2 (10·4 mg，〇.〇2 mmo卜 0.03 當量）之對-二 口咢烷 (10 mL)混合物於85 °c下攪拌72小時。減壓排除揮發物，殘 質分溶於乙酸乙醋與KF水溶液（10 g含於1〇〇 mL中）之間。有 機層脫水（硫酸鎂）與過濾。濾液減壓濃縮，殘質經管柱層析 法純化（70 : 30己烷/乙酸乙酯），產生標題中間物之白色固 體（35.5 mg，收率 19%)。咕 NMR (CDC13, 300 ΜΗζ) δ 9·33 (s， 2Η)，8.31 (d，J=2 Ηζ，1Η)，7·99 (t，J=9 Ηζ，1Η)，7.94 (s，1Η)， 7.86 (dd，J=2, 9 Hz，1H)，7.79 (brs，1H)，7·50 (dd，J=2, 9 Hz， 1H)，3.88 (t，J=7 Hz，2H)，3.02 (t，J=7 Hz，2H)。MS (DCI-NH3) 89248.doc -176- 200418454 [M+H]十 276, [M+NH4]+ 293。Example 79C ϋ6 ·-(2bis) _benzene_2_% pyrimidine-eye contains 5-trimethylstannyl-pyrimidinenitrile (Example 79B, 200 mg, 0.75 mmol, 1.1 equivalents), 2- (6-Bromo-stub-2-yl) -ethanol (Example 31E, 171 mg, 0.679 mmol), cesium fluoride (227 mg, 1 49 mm, 1.2 2 equivalents), and Pd [P (t-Bu) 3] 2 (10.4 mg, 0.02 mmo, 0.03 equivalent) of a p-dipoxane (10 mL) mixture was stirred at 85 ° C for 72 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in ethyl acetate and KF aqueous solution (10 g in 100 mL). The organic layer is dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (70:30 hexane / ethyl acetate) to give the title intermediate as a white solid (35.5 mg, yield 19%). NMR (CDC13, 300 ΜΗζ) δ 9.33 (s, 2Η), 8.31 (d, J = 2 Ηζ, 1Η), 7.99 (t, J = 9 Ηζ, 1Η), 7.94 (s, 1Η) , 7.86 (dd, J = 2, 9 Hz, 1H), 7.79 (brs, 1H), 7.50 (dd, J = 2, 9 Hz, 1H), 3.88 (t, J = 7 Hz, 2H), 3.02 (t, J = 7 Hz, 2H). MS (DCI-NH3) 89248.doc -176- 200418454 [M + H] 276, [M + NH4] + 293.

實例79D 比咯啶-1-基V乙基1-苯-2-某1-嘧啶-2-腈 標題化合物係依實例3B與3C之方法製備，但其中改用 5-[6-(2-#至乙基）-莕-2-基]-口密啶-2-腈（實例 79C，35·5 mg，0· 13 mmol)替代1-{3_[6-(2_羥乙基莕基]苯基）乙酮（實例μ) 形成甲續酸醋，及改用所形成之甲磺酸酯粗產物（約45 mg， 0·13 mmol)替代甲磺酸2-[6-(3 -乙醯基苯基）_2-萘基]乙酯（實 例3B)。緣管柱層析（97 : 3 :微量之二氯甲烷/甲醇/Nh4〇H) ，產生游離鹼產物，溶於扮2〇中。通入11(：1氣體至此溶液中 ，產生標題化合物之單鹽酸鹽（3·8 mg，兩步驟之收率9%) 。4 NMR(CD3〇D，300 MHz) s 9.33 (s，2H)，8.36 (d，J=2 Hz， 1H)，8.06 (dd，J=2, 8 Hz，2H)，8.07-7.90 (m，2H)，7·58 (dd， J=2,8Hz，lH)，3.85-3.69 (m，2H)，3.63-3.51(m，lH)，3.44-3.18 (m，4H)，2.43-2.31 (m，1H)，2.25-2.01 (m，2H)， 1.85-1.71 (m，1H)，1.5G (d，Hz，3H)。MS (DCI-NH3) [M+H]+ 343, [M+NH4]+ 360。 乙某 比啶 ^ΜΛ〇Α 羥乙基）-.盖^基-1H-吡啶-2-酮 ' 取含2-(6冬茶-2-基）_乙醇（實例31 E，i⑽mg，〇 4〇麵〇1) 、2-經基 4淀（57 mg，〇·6〇 _〇1，15 當量）、銅粉（25 叫 89248.doc ' 177. 200418454 ，〇·40 mmol)與 K2C〇3 (165 mg，；l20 mmol，3 當量）之吡啶 (2 mL)混合物於於無水氮蒙氣下回流攪拌丨8小時。反應混 合物冷卻至室溫，然後減壓濃縮。與甲苯重覆蒸發排除殘 留又咐淀。殘質分溶於乙酸乙酯與Nh4〇h水溶液（2 X50 mL) •^間，然後以鹽水洗滌。有機層脫水（硫酸鎂），過濾，濾液 減壓濃縮。殘質經管柱層析法純化（丨〇〇%乙酸乙酯），產生 標題中間物之白色固體（3〇 mg，收率28%)。4 NMR (CDC13, 300 MHz) δ 7.80 (d，J=9 Hz，1H)，7·72 (d，J=9 Hz，1H)，7.71 (s，1H)，163 (s, 1H)，7.42 (dd，J=2, 8 Hz，1Η)，7·39-7·30 (m, 3H)，6.62 (dd，J=l，l〇 Hz，1H)，6.20 (dt，J=l，6 Hz，1H)，3.84 (t，J=6Hz，2H)，2.95 (t，J=6 Hz，2H)。MS (DCI-NH3) [M+H] + 266, [M+NH4]+ 283。Example 79D Bipyridin-1-yl Vethyl 1-benzene-2-a 1-pyrimidine-2-carbonitrile The title compound was prepared according to the methods of Examples 3B and 3C, but 5- [6- (2- # To ethyl) -fluoren-2-yl] -oripyridine-2-carbonitrile (Example 79C, 35.5 mg, 0.13 mmol) instead of 1- {3_ [6- (2_hydroxyethylfluorenyl) ] Phenyl) ethyl ketone (example μ) to form mesylate, and use the crude mesylate product (about 45 mg, 0.13 mmol) instead of 2- [6- (3- Ethylfluorenyl) -2-naphthyl] ethyl ester (Example 3B). Edge column chromatography (97: 3: trace amount of dichloromethane / methanol / Nh4OH), resulting in the free base product, which was dissolved in 20%. 11 (: 1 gas was passed into this solution to produce the monohydrochloride salt of the title compound (3.8 mg, 9% yield in two steps). 4 NMR (CD3O, 300 MHz) s 9.33 (s, 2H ), 8.36 (d, J = 2 Hz, 1H), 8.06 (dd, J = 2, 8 Hz, 2H), 8.07-7.90 (m, 2H), 7.58 (dd, J = 2, 8Hz, lH ), 3.85-3.69 (m, 2H), 3.63-3.51 (m, 1H), 3.44-3.18 (m, 4H), 2.43-2.31 (m, 1H), 2.25-2.01 (m, 2H), 1.85-1.71 (m, 1H), 1.5G (d, Hz, 3H). MS (DCI-NH3) [M + H] + 343, [M + NH4] + 360. Ethylpyridine ^ ΜΛ〇Α hydroxyethyl) -. Capsyl-1H-pyridin-2-one 'Take 2- (6 winter tea-2-yl) -ethanol (Example 31 E, i⑽mg, 〇〇〇〇〇〇), 2- Jingji Lake (57 mg, 0.60-〇1, 15 equivalents), copper powder (25 called 89248.doc '177. 200418454, 0.40 mmol) and K2CO3 (165 mg, 120 mmol, 3 equivalents) The pyridine (2 mL) mixture was stirred at reflux under anhydrous nitrogen for 8 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. Evaporate repeatedly with toluene to remove the residue and order the precipitate. The residue was dissolved in ethyl acetate and Nh 4 0h aqueous solution (2 × 50 mL), and then washed with brine. The organic layer was dehydrated (magnesium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100% ethyl acetate) to give the title intermediate as a white solid (30 mg, yield 28%). 4 NMR (CDC13, 300 MHz) δ 7.80 (d, J = 9 Hz, 1H), 7.72 (d, J = 9 Hz, 1H), 7.71 (s, 1H), 163 (s, 1H), 7.42 (dd, J = 2, 8 Hz, 1Η), 7.39-7 · 30 (m, 3H), 6.62 (dd, J = 1, 10Hz, 1H), 6.20 (dt, J = 1, 6 Hz, 1H), 3.84 (t, J = 6Hz, 2H), 2.95 (t, J = 6 Hz, 2H). MS (DCI-NH3) [M + H] + 266, [M + NH4] + 283.

實例80B U^J&gt;(2(R)-甲某-吡咯啶-丨·某乙某μ革·2·基卜m_吡啶 -2-酮 利用針筒滴加甲磺醯氣（〇· 〇丨mL，0.136 mmol，1.2當量） 至-30°C之含1-[6-(2-衮乙基）-莕_2-基]-1H-吡啶-2-酮（實例 80Α ’ 30 mg，0.113 mmol)與 Et3N (0.024 mL，0·17 mmo卜 1·5當量）混合物中。於室溫下攪拌2小時後，反應混合物減 壓濃縮。殘質分溶於EtOAc與飽和Na2C03水溶液之間。有機 萃液脫水（硫酸鎂）與過濾。濾、液減壓濃縮，殘質自Et2〇/己 燒中結晶（20 mg，收率52%)。取含此甲磺酸酯（20 mg，0.058 mmol)、（2R)-2-甲基吡咯啶（14·9 mg，0.058mmol，3.0當量） 與碳酸铯（19 mg，0.058 mmol)之無水乙腈（3·5 mL)於密封試 89248.doc -178- 200418454 管中，於6 0 C下攪:掉1 8小時。反應混合物減壓濃縮。殘質分 溶於乙酸乙醋與飽和Na2C〇3水溶液之間。有機層脫水（硫酸 鎂:）與過遽。遽液減壓濃縮’殘質經管柱層析法純化（9 7 : 3 :微量之二氯甲虎/甲醇/NH4〇H)。取含產物之溶離份合併 ，減壓濃縮，產生游離驗。此游離驗溶於Et20中，通入HC1 氣體，使標題化合物之鹽酸鹽沉澱析出。1H NMR(CD3〇D， 300 MHz) δ 8.08-7.96 (m，2H)，7.93 (s，2H)，7.76-7.66 (m， 2H)，7.60-7.51 (m，2H)，6·70 (d，J=9 Hz，1H)，6.56 (dt，J=l，6 Hz，1Η)，3·83-3·68 (m，2H)，3.64-3.49 (m，1Η)，3·43-3·18 (m， 4H)，2.43-2.30 (m，1H)，2.22-2.02 (m，2H)，1.84-1.69 (m， 1H)，1.49 (d，J=6 Hz，3H)。MS (DCI-NH3)[M+H]+ 333。 實例81 5- {6-「2-(2(R) -甲基-P比p各淀-1-基V乙基革某卜於基氨Example 80B U ^ J &gt; (2 (R) -methyl-pyrrolidine --- · some-y-μμ- · 2 · kib m-pyridin-2-one using a syringe to drop methanesulfonium gas (〇 · 〇丨 mL, 0.136 mmol, 1.2 equivalents) 1- [6- (2-fluorethyl) -fluorene-2-yl] -1H-pyridin-2-one (Example 80A '30 mg, to -30 ° C, 0.113 mmol) and Et3N (0.024 mL, 0.17 mmol, 1.5 equivalents). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and a saturated aqueous Na2CO3 solution. The organic extract was dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure. The residue was crystallized from Et20 / hexane (20 mg, yield 52%). Take this mesylate (20 mg, 0.058) mmol), (2R) -2-methylpyrrolidine (14.9 mg, 0.058 mmol, 3.0 equivalents) and anhydrous acetonitrile (3.5 mL) in cesium carbonate (19 mg, 0.058 mmol) in a sealed test 89248.doc -178- 200418454 In a tube, stir at 60 ° C for 18 hours. The reaction mixture is concentrated under reduced pressure. The residue is dissolved between ethyl acetate and saturated aqueous Na2CO3 solution. The organic layer is dehydrated (magnesium sulfate :) The solution was concentrated under reduced pressure and the residue was purified by column chromatography. (97: 3: Trace amount of dichloromethyl tiger / methanol / NH4〇H). Take the product-containing fractions and combine, and concentrate under reduced pressure to produce a free test. This free test is dissolved in Et20, and HC1 gas is passed through to make The hydrochloride salt of the title compound precipitated. 1H NMR (CD3OD, 300 MHz) δ 8.08-7.96 (m, 2H), 7.93 (s, 2H), 7.76-7.66 (m, 2H), 7.60-7.51 (m , 2H), 6.70 (d, J = 9 Hz, 1H), 6.56 (dt, J = 1, 6 Hz, 1Η), 3.83-3 · 68 (m, 2H), 3.64-3.49 (m , 1Η), 3.43-3 · 18 (m, 4H), 2.43-2.30 (m, 1H), 2.22-2.02 (m, 2H), 1.84-1.69 (m, 1H), 1.49 (d, J = 6 Hz, 3H). MS (DCI-NH3) [M + H] + 333. Example 81 5- {6- "2- (2 (R) -methyl-P ratio p-Each-1-yl V B Kimono

實例81A 5_『6-(2-與乙基）一奈_2-基1_终某氣 取含5-(4,4,5,5-四甲基_[1，3,2]二氧硼戊環-2-基）-菸基氰 (220 mg，0.956 mmol，1.2 當量）、2-(6-溴-蕃-2-基）-乙醇（實 例 31E ’ 200 mg ’ 0.8 mmol)、Na2C〇3 (253 mg，2.39 mmol ，3當量）、聯苯-2-基-二環己基磷烧（7 mg，0.02 mm〇l，0.025 當量）與 PdCl2(PPh3)2 (27.9 mg，0.04 mmo 卜 〇·〇5 當量）之異 丙醇（20 mL)與水（8 mL)混合物於80°C下攪拌i小時。反應混 合物減壓濃縮，殘質分溶於乙酸乙酯與飽和Na2C〇3水溶液 之間。有機層脫水（硫酸鎂）與過濾。濾液減壓濃縮，產生之 粗產物固體經管柱層析法純化（1 : 1己燒/乙酸乙酯），產生 89248.doc -179- 200418454 標題中間物（166 mg，收率 76%)。4 NMR (CD3OD，300 MHz) δ 9‘19 (d，J=2 Ηζ，1Η)，8.88 (d，J=2 Hz，1H)，8·57 (t，J=2 Hz， 1H)，8·20 (d，J=2 Hz，1H)，7.99-7.90 (m，2H)，7.79 (dd，J=2, 9 Hz，1H)，7.76 (br s，1H)，7.48 (dd，J=2, 9 Hz，1H)，3·88 (t，J=7 Hz，2H)，3.02 (t，J=7 Hz，2H)。MS (DCI-NHOCM+H]. 275, [M+NH4]+ 292 °Example 81A 5_ 『6- (2- and ethyl) -naphthalene_2-yl 1-terminal gas extraction containing 5- (4,4,5,5-tetramethyl_ [1,3,2] dioxane Borapent-2-yl) -nicotinyl cyanide (220 mg, 0.956 mmol, 1.2 equivalents), 2- (6-bromo-fan-2-yl) -ethanol (Example 31E '200 mg' 0.8 mmol), Na2C 〇3 (253 mg, 2.39 mmol, 3 equivalents), biphenyl-2-yl-dicyclohexylphosphine (7 mg, 0.02 mm, 0.025 equivalents), and PdCl2 (PPh3) 2 (27.9 mg, 0.04 mmo) 0.005 equivalent) of a mixture of isopropanol (20 mL) and water (8 mL) was stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and a saturated aqueous Na2CO3 solution. The organic layer was dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude solid was purified by column chromatography (1: 1 hexane / ethyl acetate) to give 89248.doc -179- 200418454 as the title intermediate (166 mg, yield 76%). 4 NMR (CD3OD, 300 MHz) δ 9'19 (d, J = 2 Ηζ, 1Η), 8.88 (d, J = 2 Hz, 1H), 8.57 (t, J = 2 Hz, 1H), 8 20 (d, J = 2 Hz, 1H), 7.99-7.90 (m, 2H), 7.79 (dd, J = 2, 9 Hz, 1H), 7.76 (br s, 1H), 7.48 (dd, J = 2, 9 Hz, 1H), 3.88 (t, J = 7 Hz, 2H), 3.02 (t, J = 7 Hz, 2H). MS (DCI-NHOCM + H]. 275, [M + NH4] + 292 °

實例81B 甲磺酸2-16-(5-氰某-吡啶-3-基）_萁-2-基1-乙酯 添加 ％磺醯氯（0.056 mL，0.726 mmol，1.2 當量）至-30°C 與無水氮蒙氣下之5-[6-(2-羥乙基）-茬-2-基]-菸基氰（實例Example 81B Add 2-16- (5-cyano-pyridin-3-yl) _fluoren-2-yl 1-ethyl methanesulfonate to sulfonylurea chloride (0.056 mL, 0.726 mmol, 1.2 equivalent) to -30 ° 5- [6- (2-hydroxyethyl) -stub-2-yl] -nicotinyl cyanide in the presence of C and anhydrous nitrogen (example

81A，190 mg’ 0.53 9 mmol)攪拌溶液中，滴加三乙胺（0.13 mL81A, 190 mg ’0.53 9 mmol), and triethylamine (0.13 mL) was added dropwise.

，0.908 mmol，1.5當量）至該冷卻溶液中後，反應混合物於 室溫下攪拌18小時。反應混合物分溶於乙酸乙酯與飽和 Na2C〇3水溶液之間。有機層脫水（硫酸鎂）與過漉。濾液減 壓濃縮，產生標題中間物（192 mg，收率90%)。4 NMR (CDC13, 300 MHz) δ 9·22 (d，J=2 Hz，1H)，8.90 (d，J=2 Hz， 1H)，8.60 (t，J=2 Hz，1H)，8.25 (br s，1H)，8.00 (t，J=8 Hz， 2H)，7.87-7.81 (m，2Η)，7·52 (dd，J=2, 8 Hz，1H)，7.31-7.25 (m，1H)，4.55 (t，J = 6 Hz，2H)，3.25 (t，J=6 Hz，2H)，2.95 (s， 3H)。MS (DCI-NH3)[M+H]+ 353, [M+NH4]+ 370。(0.908 mmol, 1.5 equivalents) to the cooled solution, the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous Na2CO3 solution. The organic layer is dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure to give the title intermediate (192 mg, 90% yield). 4 NMR (CDC13, 300 MHz) δ 9 · 22 (d, J = 2 Hz, 1H), 8.90 (d, J = 2 Hz, 1H), 8.60 (t, J = 2 Hz, 1H), 8.25 (br s, 1H), 8.00 (t, J = 8 Hz, 2H), 7.87-7.81 (m, 2Η), 7.52 (dd, J = 2, 8 Hz, 1H), 7.31-7.25 (m, 1H) , 4.55 (t, J = 6 Hz, 2H), 3.25 (t, J = 6 Hz, 2H), 2.95 (s, 3H). MS (DCI-NH3) [M + H] + 353, [M + NH4] + 370.

實例81C 5-{6-「2_(2 (R)-甲基-p比洛淀-1-基）-乙基1-蕃-；2-某}-於基氰 取含甲磺酸2-[6-(5-氰基比啶-3-基）-莕-2-基]-乙酯（實例 8 1B，190 mg，0.54 mmol)、（2 R)-2 -甲基 ρ比略咬（138 mg，1.62 89248.doc -180- 200418454 mmol ’ 3.0當量）與碳酸铯（176 mg，〇·54 ^^οΐ)之無水乙腈（6 mL)於密封試管中，於5〇°C下攪拌18小時。反應混合物減壓 濃縮。殘質分溶於乙酸乙酯與飽*Na2C〇3水溶液之間。有 機層經鹽水洗滌後，脫水（硫酸鎂）與過濾。漉液減壓濃縮， 殘質經管柱層析法純化（98 : 2 :微量之二氯甲烷/甲醇 /NKUOH)。合併含產物之溶離份，減壓濃縮，產生標題化合 物之游離鹼，為白色固體（1〇5·9 mg，收率57%)。此游離鹼 溶於甲醇中，以過量二噚烷-11(：：1處理。添加醚謗使標題化 合物之、鹽酸鹽結晶。4 NMR (CD3〇D，300 ΜΗζ) δ 9.26 (br s，1H)，8·97 (br s，1H)，8.68 (s，lH)，8.29 (s，1H)，8.05 (s，m)， 8·02 (s，1H)，7.90 (br s，1H)，7.88 (dd，J=2, 9Hz，lH)，7.56 (d， J=8 Hz，1H)，3.84-3.49 (m，7H)，2.45-2.30 (m，1H)，2.27-1.99 (m，2Η)，1·84-1·69 (m，1H)，1.50 (d，J=6 Hz，3H)。MS (DCI-NH3) [M+H]+ 342。 實例82 甲基二(2(R)-甲基-p比吟症-1-某乙基&quot;μ莫 }Example 81C 5- {6- "2_ (2 (R) -methyl-p-bilodine-1-yl) -ethyl 1-fan-; 2-a}-in cyanocyanine containing methanesulfonic acid 2- [6- (5-Cyanopyridin-3-yl) -fluoren-2-yl] -ethyl ester (Example 8 1B, 190 mg, 0.54 mmol), (2 R) -2 -methylρ ratio slightly bite (138 mg, 1.62 89248.doc -180- 200418454 mmol '3.0 equiv.) And cesium carbonate (176 mg, 0.54 ^^ οΐ) anhydrous acetonitrile (6 mL) in a sealed test tube, and stirred at 50 ° C 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and saturated Na2CO3 aqueous solution. The organic layer was washed with brine, dehydrated (magnesium sulfate) and filtered. The mash was concentrated under reduced pressure, and the residue Purified by column chromatography (98: 2: trace amount of dichloromethane / methanol / NKUOH). The product-containing fractions were combined and concentrated under reduced pressure to give the free base of the title compound as a white solid (10.5 mg The yield was 57%). This free base was dissolved in methanol and treated with an excess of dioxane-11 (:: 1. Ether was added to crystallize the hydrochloride salt of the title compound. 4 NMR (CD30D, 300 ΜΗζ ) δ 9.26 (br s, 1H), 8.97 (br s, 1H), 8.68 (s, 1H), 8.29 (s, 1H ), 8.05 (s, m), 8.02 (s, 1H), 7.90 (br s, 1H), 7.88 (dd, J = 2, 9Hz, lH), 7.56 (d, J = 8 Hz, 1H) , 3.84-3.49 (m, 7H), 2.45-2.30 (m, 1H), 2.27-1.99 (m, 2Η), 1.84-1 · 69 (m, 1H), 1.50 (d, J = 6 Hz, 3H). MS (DCI-NH3) [M + H] + 342. Example 82 Methylbis (2 (R) -methyl-p Biyin syndrome-1-a certain ethyl group)

-1H-叶匕哈-2-綱 實例82A 1-「6-(2-巍乙基V茬-2-某1-4-甲基-1H-吡淀_2-酮 取含 2-(6·溴-莕-2-基）-乙醇（實例 3 1E，200 mg，0.796 mmol) 、2-备基-4-甲基比淀（130 mg，1.195 mmol，1·5當量）、銅 粉（50.6 mg，0.796 mmol)、與 K2C〇3 (330.2 mg，2.389 mmol ，3當量）之吡啶（5 mL)混合物於無水氮蒙氣下，回流攪拌62 小時。反應混合物冷卻至室溫後，減壓濃縮。與甲苯重覆 89248.doc -181 - 200418454 蒸發排除殘留之吡啶。殘質分溶於乙酸乙酯與NH4OH水溶 液之間後，以鹽水（3 X 50 mL)洗滌。有機層脫水（硫酸鎂） ’過滤’漉液減壓濃縮。殘質經管柱層析法純化（1 00%乙酸 乙酯），產生標題中間物之白色固體（70 mg，收率31%)。4 NMR (CD3OD? 300 MHz) δ 7.94 (d5 J=9 Hz, 1H)5 7.88 (d5 J-9-1H-Lepidoptera-2-class example 82A 1-``6- (2-Weiethyl V stub-2-a 1--4-methyl-1H-pyridine_2-one containing 2- (6 · Bromo-fluoren-2-yl) -ethanol (Example 3 1E, 200 mg, 0.796 mmol), 2-propyl-4-methyl ratio lake (130 mg, 1.195 mmol, 1.5 equivalents), copper powder ( 50.6 mg, 0.796 mmol), and a mixture of K2C03 (330.2 mg, 2.389 mmol, 3 eq.) Of pyridine (5 mL) was stirred at reflux under anhydrous nitrogen for 62 hours. After the reaction mixture was cooled to room temperature, the pressure was reduced. Concentrate. Repeat with 89248.doc -181-200418454 with toluene to remove the residual pyridine by evaporation. The residue is dissolved between ethyl acetate and NH4OH aqueous solution and washed with brine (3 X 50 mL). The organic layer is dehydrated (magnesium sulfate ） 'Filter' The mash was concentrated under reduced pressure. The residue was purified by column chromatography (100% ethyl acetate) to give the title intermediate as a white solid (70 mg, yield 31%). 4 NMR (CD3OD? 300 MHz) δ 7.94 (d5 J = 9 Hz, 1H) 5 7.88 (d5 J-9

Hz，1H)，7.84 (d，J=2 Hz，1H)，7.80 (br s，lH)，7.59 (d，J=7 Hz，1H)，7.49 (dd，J=2, 9 Hz，1H)，7·44 (dd，J=2, 9 Hz，1H)， 6.49 (br s，1H)，6.40 (dd，J二2, 7 Hz，1H)，3.87 (t，J=7 Hz，2H)， 3.04 (t，J37 Hz，2H)，2.32 (s，3H)。MS (DCI-NH3) [M+H]+ 280。Hz, 1H), 7.84 (d, J = 2 Hz, 1H), 7.80 (br s, lH), 7.59 (d, J = 7 Hz, 1H), 7.49 (dd, J = 2, 9 Hz, 1H) , 7.44 (dd, J = 2, 9 Hz, 1H), 6.49 (br s, 1H), 6.40 (dd, J = 2, 7 Hz, 1H), 3.87 (t, J = 7 Hz, 2H) , 3.04 (t, J37 Hz, 2H), 2.32 (s, 3H). MS (DCI-NH3) [M + H] + 280.

實例82B L甲基甲基-吡咯啶-1-某V乙基1-萁-2-某i 1Η - 口比咬-2 酉同 利用針筒滴加甲績驢氯（〇.〇3 mL，0.301 mmol，1.2當量） 至Ot：與無水氮蒙氣下之含1-[6-(2-羥基-乙基）-莕-2-基&gt;4-甲基-1Η-ρ比淀-2_酉同（實例82A，70 mg，0·25 1 mmol)之無水THF (10 mL)溶液中。添加三乙胺（ι·〇 mL，7,175 mmol，28·6當 量）。於0°C下攪拌2小時後，反應混合物減壓濃縮。殘質分 溶於EtOAc與飽和Na2C03水溶液之間。有機萃液脫水（硫酸 鎂）與過滤。滤液減壓濃縮。取含此甲績酸g旨粗產物（約89 mg ’ 0.249 mmol)、（2R)-2 -甲基 ρ比洛淀（64 mg，0.747 mmol，3.0 當量）與碳酸铯（81 mg，0.249 mmol)之無水乙腈（5 mL)於密 封試管中，於50°C下攪拌18小時。反應混合物減壓濃縮： 殘質分溶於乙酸乙酯與飽和Na2C〇3水溶液之間。有機層脫 水（硫酸鎂）與過濾。濾液減壓濃縮，殘質經管柱層析法純化 89248.doc -182· 200418454 (97 : 3 :微量之二氯甲烷/甲醇/NH4〇h)。取含產物之溶離 份合併’減壓濃縮，產生游離驗。此游離驗溶於Et2〇中， 溶液經HC1-二噚烷處理，使標題化合物之鹽酸鹽沉觀析出 (15 mg，收率 16%)。巾 NMR (CD3OD，3 00 ΜΗζ) δ 8.00 (d，Example 82B L methylmethyl-pyrrolidine-1-some V ethyl 1- 萁 -2-some i 1Η-mouth ratio bite-2 酉 Also use methyl syringe donkey chloride (0.03 mL, 0.301 mmol, 1.2 equivalents) to Ot: with 1- [6- (2-hydroxy-ethyl) -fluoren-2-yl> and 4-methyl-1fluorene-rhodo-2 under anhydrous nitrogen酉 Same (Example 82A, 70 mg, 0.25 1 mmol) in dry THF (10 mL). Triethylamine (ι · mL, 7,175 mmol, 28.6 equivalents) was added. After stirring at 0 ° C for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and saturated aqueous Na2C03. The organic extract is dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure. Take the crude product containing this formic acid g (about 89 mg '0.249 mmol), (2R) -2-methylpilolide (64 mg, 0.747 mmol, 3.0 equivalents) and cesium carbonate (81 mg, 0.249 mmol) ) Of anhydrous acetonitrile (5 mL) in a sealed test tube, and stirred at 50 ° C for 18 hours. The reaction mixture was concentrated under reduced pressure: the residue was dissolved in ethyl acetate and a saturated aqueous Na2CO3 solution. The organic layer was dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography 89248.doc -182 · 200418454 (97: 3: trace amount of dichloromethane / methanol / NH40h). The product-containing fractions were combined and concentrated under reduced pressure to produce a free assay. This free test was dissolved in Et20 and the solution was treated with HC1-dioxane to precipitate the hydrochloride salt of the title compound (15 mg, yield 16%). NMR (CD3OD, 3 00 ΜΗζ) δ 8.00 (d,

Hz，1H)，7.98 (d，J=9 Hz，1H)，7.93-7.89 (m，2H)，7.62 (d，j=7 Hz，1H)，7.56 (dd，J二2, 9 Hz，1H)，7·51 (dd，J二2, 9 Hz，1H) 6.52 (br s，1H)，6.45 (dd，J=2, 7 Hz，1H)，3.83-3.68 (m，2H) 3.61-3.49 (m，lH)，3.43-3.17 (m，4H)，2.43-2.30 (m，1H)，2.33 (s，3H)，2.24-1.99 (m，2H)，1.83-1.69 (m，1H)，1.49 (d，J=6Hz, 1H), 7.98 (d, J = 9 Hz, 1H), 7.93-7.89 (m, 2H), 7.62 (d, j = 7 Hz, 1H), 7.56 (dd, J-2, 9 Hz, 1H ), 7.51 (dd, J-2, 9 Hz, 1H) 6.52 (br s, 1H), 6.45 (dd, J = 2, 7 Hz, 1H), 3.83-3.68 (m, 2H) 3.61-3.49 (m, lH), 3.43-3.17 (m, 4H), 2.43-2.30 (m, 1H), 2.33 (s, 3H), 2.24-1.99 (m, 2H), 1.83-1.69 (m, 1H), 1.49 (d, J = 6

Hz，3H)。MS (DCI-NH3) [M+H]+ 347 o 實例83 g二L6-「2_((2R)-2-甲基·说咯啶-i-基乙基基丨』^Hz, 3H). MS (DCI-NH3) [M + H] + 347 o Example 83 g of di-L6- "2 _ ((2R) -2-methyl · sallidine-i-ylethyl group 丨" ^

實例83A K6-吡畊-2-某-蕃-2-某V乙醇 取含2-三丁錫烷基-吡畊（323 mg，0.876 mmol，1.1當量） 、2-(6-溴-莕-2-基）-乙醇（實例 31E，200 mg，〇 796 mmol)、氟 化铯（266 11^，1.75 111111〇1，2.2當量）與？(1[?(1：811)3]2(12.2 11^Example 83A: K6-Pycnogenol-2-A-Fan-2-V ethanol containing 2-tributinyl-Pycnogenol (323 mg, 0.876 mmol, 1.1 equivalents), 2- (6-Bromo-fluorene-2- Group)-ethanol (example 31E, 200 mg, 0796 mmol), cesium fluoride (266 11 ^, 1.75 111111〇1, 2.2 equivalents) and? (1 [? (1: 811) 3] 2 (12.2 11 ^

，0.024 mmol，〇·〇3當量）之對-二噚烷（10rnL)混合物於85°C, 0.024 mmol, 0.03 equivalent) of a mixture of p-dioxane (10rnL) at 85 ° C

下稅拌2.5小時。減壓排除揮發物，殘質分溶於乙酸乙酯與 KF水’谷液（l〇g含於1〇〇 mL中）之間。有機層依序經飽和 NaaCO3水溶液與鹽水洗滌後，脫水（硫酸鎂）與過濾。濾液 減壓濃縮，殘質經管柱層析法純化（1 : 1己烷/乙酸乙酯）' 產生&amp;遞中間物之米色固體（42·5 mg，收率21 %)。NMR (CD3〇D，300 MHz) δ 9.25 (d，J=1 Hz，1H)，8.72-8.70 (m， 89248.doc -183- 200418454 1H)，8.58 (d，J=2 Hz，1H)，8.54 (d，J=3 Hz，1H)，8.17 (dd， J=2, 9 Hz，1H)，7.97 (d，J=2 Hz，1H)，7.94 (d，J二2 Hz，1H)， 7.77 (br s，1H)，7.48 (dd，J=2, 8 Hz，1H)，3.88 (t，J=7 Hz，2H)， 3·02 (t，J=7 Hz，2H)。MS (DCI-NH3) [M+H]+ 251，[M+NH4] + 268 °Mix for 2.5 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in ethyl acetate and KF water 'cereal (10 g in 100 mL). The organic layer was washed sequentially with a saturated aqueous NaaCO3 solution and brine, and then dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (1: 1 hexane / ethyl acetate) 'to give a beige solid (42 · 5 mg, yield 21%). NMR (CD3OD, 300 MHz) δ 9.25 (d, J = 1 Hz, 1H), 8.72-8.70 (m, 89248.doc -183- 200418454 1H), 8.58 (d, J = 2 Hz, 1H), 8.54 (d, J = 3 Hz, 1H), 8.17 (dd, J = 2, 9 Hz, 1H), 7.97 (d, J = 2 Hz, 1H), 7.94 (d, J = 2 Hz, 1H), 7.77 (br s, 1H), 7.48 (dd, J = 2, 8 Hz, 1H), 3.88 (t, J = 7 Hz, 2H), 3.02 (t, J = 7 Hz, 2H). MS (DCI-NH3) [M + H] + 251, [M + NH4] + 268 °

實例83B 2-{6-「2-((2R)-2 -甲基-p比p各淀-l-基乙某&quot;μ富：-2-基}-叶匕呼 於無水於氮蒙氣下，利用針筒滴加曱磺醯氯（0.005 mL， 0.067 mrsol，1.2 當量）至 〇°C 之含 2-(6-吡畊-2-基-莕-2-基）-乙醇（實例 83 A，14 mg，0.056 mmol)之無水 THF (10 mL)攪 掉落液中。添加二乙胺（0.023 mL，0· 167 mmol，3當量）。 於-20°C下18小時後，反應混合物脫水（硫酸鎂），過濾。濾 液減壓濃縮。取含此甲績酸g旨粗產物（約18mg，0.056mmol) 、（2R)-2-曱基吡咯啶（190 mg，2.237 mmol，40當量）與碳酸 铯（182 mg，0· 5 59 mmol，10當量）之無水乙月膏（5 mL)於密封 試管中，於40 °C下攪拌62小時。反應混合物減壓濃縮。殘質 分溶於乙酸乙酯與飽.和Na2C03水溶液之間。有機層脫水（硫 酸鎂）與過濾。濾液減壓濃縮，殘質經管柱層析法純化（97 ·· 3 :微量之二氯甲烷/甲醇/NH4OH)。取含產物之溶離份合 併’減壓濃縮，產生游離驗。此游離驗溶於甲醇中，溶液 經HC1氣體處理。蒸發溶劑後，得到標題化合物之鹽酸鹽 (4.5 mg，收率 23%)。4 NMR (CD3OD，300 ΜΗζ) δ 9.29 (br s， 1H)，8.79-8.74 (m，1H)，8·64 (br s，1H)，8·58 (d，J=2 Hz，1H)， 8.24 (dd，J=2, 9 Hz，1H)，8·03 (t，J=9 Hz，2H)，7.90 (br s，1H)， 89248.doc -184- 200418454 7.55 (dd，J 2，9 Hz，1H)，3.84-3.68 (m，2H)，3.64-3.49 (m， 1H)5 3.44-3.17 (m5 4H)? 2.43-2.30 (m? 1H)? 2.27-2.00 (m? 2H)，1.84-1.68 (m，1H)，1.50 (d，J=7 Hz，3H)。MS (DCI-NH3) [M+H]+ 318。 實例84 i!H_ 口答口井'3-西同 t Μ 84Α 位幻-2·羥甲基酸第三丁酯 標題中間物可由相應之羧酸或其甲酯還原製得。 由竣酸之製法：採用文獻（R〇driguez，M.，et. ai.，Example 83B 2- {6- "2-((2R) -2 -methyl-p to p each y-l-yl ethyl" &quot; μ rich: -2-yl} -leaf drowsing in the absence of water in nitrogen Under air, add sulfasulfonium chloride (0.005 mL, 0.067 mrsol, 1.2 equivalents) to 0 ° C containing 2- (6-pyracin-2-yl-fluoren-2-yl) -ethanol (example 83 A, 14 mg, 0.056 mmol) of anhydrous THF (10 mL) was stirred off the falling liquid. Diethylamine (0.023 mL, 0.167 mmol, 3 equivalents) was added. After 18 hours at -20 ° C, the reaction The mixture was dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure. The crude product containing this formic acid g (approximately 18 mg, 0.056 mmol) and (2R) -2-fluorenylpyrrolidine (190 mg, 2.237 mmol, 40 (Equivalent) and cesium carbonate (182 mg, 0.559 mmol, 10 equivalents) in anhydrous ethyl month cream (5 mL) in a sealed test tube and stirred at 40 ° C for 62 hours. The reaction mixture was concentrated under reduced pressure. The residue was concentrated Dissolved in ethyl acetate and saturated Na2C03 aqueous solution. The organic layer was dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (97 ·· 3: trace dichloromethane / methanol / NH4OH). Take the product-containing fractions and combine 'reduced pressure Concentration gave a free test. This free test was dissolved in methanol and the solution was treated with HC1 gas. After evaporation of the solvent, the hydrochloride salt of the title compound (4.5 mg, yield 23%) was obtained. 4 NMR (CD3OD, 300 ΜΗζ) δ 9.29 (br s, 1H), 8.79-8.74 (m, 1H), 8.64 (br s, 1H), 8.58 (d, J = 2 Hz, 1H), 8.24 (dd, J = 2, 9 Hz, 1H), 8.03 (t, J = 9 Hz, 2H), 7.90 (br s, 1H), 89248.doc -184- 200418454 7.55 (dd, J 2, 9 Hz, 1H), 3.84-3.68 (m, 2H), 3.64-3.49 (m, 1H) 5 3.44-3.17 (m5 4H)? 2.43-2.30 (m? 1H)? 2.27-2.00 (m? 2H), 1.84-1.68 (m, 1H), 1.50 (d, J = 7 Hz, 3H). MS (DCI-NH3) [M + H] + 318. Example 84 i! H_ 口 口 口 井 '3- 西 同 t Μ 84Αposition phantom-2 · hydroxymethyl The title intermediate of the acid third butyl ester can be prepared by the reduction of the corresponding carboxylic acid or its methyl ester. Production method from the acid: using the literature (Rodriguez, M., et. Ai.,

Tetrahedron Letters，1991，32 (7)，923-926)之方法；取2,5- 一 iL -ρΛ ^ -l,(2R)-2-一 幾 1-弟二 丁酉旨（970 mg，4·549 mmol)溶 於無水DME (5 mL)中。此溶液於無水氮蒙氣下冷卻至_2〇°C 。在此攪拌溶液中依序慢慢添加4-甲基-嗎淋（0.5 mL，4.549 mmol)及氣甲酸異丁酉旨（〇·6 mL，4.549 mmol)。於-20 °C下攪: 拌一分鐘後，快速添加含氫硼化鈉（516 mg，13.647 mmol ，3當量）之水（5 mL)溶液，繼續攪拌，同時使反應混合物回 升至-5°C，並保持25分鐘。反應混合物加水稀釋，以乙酸 乙酯萃取。有機層經鹽水洗滌，脫水（硫酸鎂），過濾。濾液 減壓濃縮，殘質經管柱層析法純化（4 : 1己烷/乙酸乙酯）， 產生標題中間物（3 86 mg，收率42%)。1HNMR(CDCl3,300 ΜΗζ) δ 5.90-5.72 (m，1H)，5.69-5.56 (m，1H)，4.80-4.60 (m， 1H)3 4.28-3.99 (m? 2H), 3.78 (dd? J=2, 9 Hz, 1H), 3.65-3.51 89248.doc -185 - 200418454 (m，1Η)，ι·49 (s，9H)。MS (DCI-NH3) [M+H]+ 200, [M+NH4] + 217 〇 由羧酸甲酯之製法：一次添加全量氫硼化鈉（333 mg，8.80 mm〇l，2當量）至0°c之含2,5-二氫-吡咯-l，（2R)-2-二羧酸1-第三丁酯 2-甲酯（1.0 g，4.40 mmol)之丁HF (3 mL)與甲醇（2 mL)攪拌溶液中。反應混合物於〇°C下攪拌15分鐘後，於室 溫下18小時。依上述操作水相後，依上述經管柱層析法純 化’得到標題中間物（524 mg，收率60%)。Tetrahedron Letters, 1991, 32 (7), 923-926); take 2,5-a iL -ρΛ ^ -l, (2R) -2-a-chi 1-di-dibutrazine (970 mg, 4. · 549 mmol) was dissolved in anhydrous DME (5 mL). This solution was cooled to -20 ° C under anhydrous nitrogen. To this stirring solution, 4-methyl-morphine (0.5 mL, 4.549 mmol) and isobutyric acid formic acid (0.6 mL, 4.549 mmol) were slowly added sequentially. Stir at -20 ° C: After stirring for one minute, quickly add a solution of sodium borohydride (516 mg, 13.647 mmol, 3 eq.) In water (5 mL), continue to stir, while raising the reaction mixture to -5 ° C and hold for 25 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated (magnesium sulfate), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (4: 1 hexane / ethyl acetate) to give the title intermediate (3 86 mg, yield 42%). 1HNMR (CDCl3,300 ΜΗζ) δ 5.90-5.72 (m, 1H), 5.69-5.56 (m, 1H), 4.80-4.60 (m, 1H) 3 4.28-3.99 (m? 2H), 3.78 (dd? J = 2, 9 Hz, 1H), 3.65-3.51 89248.doc -185-200418454 (m, 1Η), ι · 49 (s, 9H). MS (DCI-NH3) [M + H] + 200, [M + NH4] + 217 〇 Production method of methyl carboxylate: add a full amount of sodium borohydride (333 mg, 8.80 mm, 2 equivalents) to 0 ° c butyl HF (3 mL) containing 2,5-dihydro-pyrrole-l, (2R) -2-dicarboxylic acid 1-third butyl ester 2-methyl ester (1.0 g, 4.40 mmol) and Methanol (2 mL) was stirred in the solution. The reaction mixture was stirred at 0 ° C for 15 minutes and then at room temperature for 18 hours. After operating the water phase as described above, it was purified by column chromatography 'as described above to obtain the title intermediate (524 mg, yield 60%).

, 實例84B (2幻-2_甲基_2,5_二氣-吡咯-1_羧酸第芑丁酯 滴加甲績酿氯（0.24 mL，3.13 mmol，1·2當量）至〇。〇與無 水氮蒙氣下，含（2S)-2-羥甲基-2,5-二氫-吡咯-丨-羧酸第三丁 酯（貫例 84A。520 mg，2.61 mmol)與三乙胺（11 mL，7.83 mmol，3當量）之無水THF (50 mL)攪拌溶液中。反應混合物 於〇°C下攪拌15分鐘後，於室溫下攪拌18小時。反應混合物 減壓濃縮，殘質分溶於乙酸乙酯與水之間。有機層經飽和 Na2C03水溶液洗:條’然後脫水（硫酸錢），過漉。滤液減壓 濃縮’甲績酸醋粗產物（約660 mg，收率91 %)立即進行還原 反應： 取含甲磺酸酯粗產物（約660 mg，2.3 8 mmol)之丁 HF (10 mL)溶液於0°C與無水氮蒙氣下攪拌。滴加三乙基氫硼化鋰 (1.0 Μ 之 THF 溶液，7_14 mL，7.14 mmM，3 當量）。添加後 績於0 C下授掉2 0分鐘’反應混合物再於室溫下揽掉1 $小時 。小心依序添加水（1.38 mL)、3N NaOH (2.75 mL)與30%過 89248.doc -186- 200418454 氧化氫水溶液（2 · 75 mL)中止反應。攪拌30分鐘後，反應經 飽和NkSO3水溶液處理，激烈攪拌一夜。有機層脫水（硫酸 鎂）與過濾。漉液減壓濃縮，殘質經管柱層析法純化（梯度： 100%己烷至95 : 5己烷/乙酸乙酯），產生標題中間物（282 mg ’收率 65%)。咕 NMR (CDC13, 300 MHz) δ 5.77-5.62 (m，2H)， 4.63-4.42 (m，1H)，4.27-3.98 (m，2H)，1.48 (s，9H)，1.34-1.19 (m，3H)。MS (DCI-NH3) [M+H]+184, [Μ+ΝΗ4Γ 201。Example 84B (2-Hydroxy-2_methyl_2,5_digas-pyrrole-1_dicarboxylic acid dibutyl ester was dripped with methyl chloride (0.24 mL, 3.13 mmol, 1.2 equivalents) to 0. 〇In the presence of anhydrous nitrogen, containing (2S) -2-hydroxymethyl-2,5-dihydro-pyrrole- 丨 -carboxylic acid tert-butyl ester (84A. 520 mg, 2.61 mmol) and triethyl Amine (11 mL, 7.83 mmol, 3 eq) in a stirred solution of anhydrous THF (50 mL). The reaction mixture was stirred at 0 ° C for 15 minutes and then stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was Separated in ethyl acetate and water. The organic layer was washed with a saturated aqueous Na2C03 solution: strips, then dehydrated (sulfate), and filtered. The filtrate was concentrated under reduced pressure to a crude formic acid vinegar (about 660 mg, yield 91). %) Immediate reduction reaction: Take a solution of the crude mesylate product (about 660 mg, 2.38 mmol) in butyl HF (10 mL) at 0 ° C and stir under anhydrous nitrogen. Add triethyl hydrogen dropwise. Lithium boride (1.0 M solution in THF, 7_14 mL, 7.14 mmM, 3 eq.). After addition, teach for 20 minutes at 0 C. The reaction mixture was then taken out at room temperature for 1 $ hour. Carefully add sequentially Water (1.38 mL), 3N N aOH (2.75 mL) and 30% over 89248.doc -186- 200418454 hydrogen oxide aqueous solution (2 · 75 mL) to stop the reaction. After stirring for 30 minutes, the reaction was treated with a saturated NkSO3 aqueous solution and stirred vigorously overnight. The organic layer was dehydrated (magnesium sulfate ) And filtered. The mash was concentrated under reduced pressure, and the residue was purified by column chromatography (gradient: 100% hexane to 95: 5 hexane / ethyl acetate) to give the title intermediate (282 mg 'yield 65%) NMR (CDC13, 300 MHz) δ 5.77-5.62 (m, 2H), 4.63-4.42 (m, 1H), 4.27-3.98 (m, 2H), 1.48 (s, 9H), 1.34-1.19 (m, 3H). MS (DCI-NH3) [M + H] +184, [Μ + ΝΗ4Γ 201.

實例84C , (2R)_2-甲某-2,5-二 i.-ΙΗ-说吟 滴加三氟乙酸（1.8 mL，22·92 mmol，15當量）至室溫下， 含（2R)-2-曱基-2,5-二氫-吡洛-1-叛酸第三丁酯（實例84B， 280 mg，1.528 mmol)之二氯甲烷（5 mL)攪拌溶液中。反應 混合物於室溫與無水氮蒙氣下攪拌1 8小時。反應混合物減 壓濃縮，產生標題中間物之三氟乙酸鹽粗產物（約300 mg， 收率 100%)。4 NMR (CD3OD，300 MHz) δ 5.92 (s，2H)， 4.9-4.49 (m，1Η)，4.12-3.97 (m，2Η)，1.44 (d，J=7 Ηζ，3Η)。 MS (ϋ(：Ι-ΝΗ3)[Μ+Η] + 84。Example 84C, (2R) _2-methyl-2,5-di-i.-ΙΗ-Suo Yin added trifluoroacetic acid (1.8 mL, 22.92 mmol, 15 equivalents) dropwise to room temperature, containing (2R)- 2-Methenyl-2,5-dihydro-pyrrol-1-metanoic acid tert-butyl ester (Example 84B, 280 mg, 1.528 mmol) in a stirred solution of dichloromethane (5 mL). The reaction mixture was stirred at room temperature under anhydrous nitrogen for 18 hours. The reaction mixture was concentrated under reduced pressure to give the crude trifluoroacetate salt of the title intermediate (about 300 mg, 100% yield). 4 NMR (CD3OD, 300 MHz) δ 5.92 (s, 2H), 4.9-4.49 (m, 1Η), 4.12-3.97 (m, 2Η), 1.44 (d, J = 7 Ηζ, 3Η). MS (VII (: 1-NIX3) [M + VII] +84.

實例84D 2-{6-「2-q2RV2-甲基-2,5-二氤_说咯-1-基）-乙某1-苯-2-基} -2 Η - 口答口井-3 -酉同 取含甲磺酸2-[6-(6-氧代-6Η-嗒畊-1-基)-萘-2-基]-乙酯（實 例 31G，205 mg，0.595 mmol)、（2R)-2-甲基-2,5-二氫-1Η-叶匕洛三氟乙酸鹽（實例84C，約300 mg，1.52 mm〇l ’ 2.55當 量）與碳酸铯（1.49 g，4.56 mmol，3當量）之無水乙腈（1〇 mL) 89248.doc -187- 200418454 混合物於密封試管中，於室溫下攪拌90小時後，於45°C下 再抵拌1 8小時。反應混合物減壓濃縮。殘質分溶於乙酸乙 酉曰與飽和NasCO3水落液之間。水層經乙酸乙酯洗滌，合併 之有機萃液脫水（硫酸鎂）與過濾。濾液減壓濃縮，殘質經管 枉層析法純化（98 : 2 :微量之二氯甲烷/甲醇/ΝΗ4〇Η)。取 含產物足落離份合併，減壓濃縮，產生游離鹼產物（69 mg ’收率 35%)。巾 NMR (CD3〇D，3〇〇 ΜΗζ) δ 8 〇4 (dd，J=2, 4Example 84D 2- {6- "2-q2RV2-Methyl-2,5-difluorenyl_suple-1-yl) -Ethyl-1-phenyl-2-yl} -2 Η-口 口 井 -3-酉 The same is taken with 2- [6- (6-oxo-6Η-dagen-1-yl) -naphthalene-2-yl] -ethyl methanesulfonate (Example 31G, 205 mg, 0.595 mmol), (2R ) -2-Methyl-2,5-dihydro-1H-pyrazol trifluoroacetate (Example 84C, about 300 mg, 1.52 mm ′ 2.55 equivalent) and cesium carbonate (1.49 g, 4.56 mmol, 3 Equivalent) of anhydrous acetonitrile (10 mL) 89248.doc -187- 200418454 The mixture was placed in a sealed test tube, stirred at room temperature for 90 hours, and then stirred at 45 ° C for another 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved between ethyl acetate and saturated NasCO3 water. The aqueous layer was washed with ethyl acetate, and the combined organic extracts were dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by tube chromatography. (98: 2: trace amount of dichloromethane / methanol / ΝΗ4〇Η). The product containing the product was separated and combined, and concentrated under reduced pressure to produce a free base product (69 mg 'yield 35%). NMR (CD3. D, 300MΗζ) δ 8 〇4 (dd, J = 2, 4

Hz，1H)，8.04 (d，1=2 Hz，1H)，7.92 (d，&gt;9 Hz，1H)，7.88 (d， J-9 Hz，kH)，7.79 (br s，1H)，7·62 (dd，J=2, 9 Hz，1H)，7.51 (dd，J=3, 9 Hz，1H)，7·48 (dd，J=2, 9 Hz，1H)，7.12 (dd，J=2, 9 Hz，1H)，5.83-5.68 (m，2H)，3.91-3.81 (m，1H)，3.66-3.54 (m， 1H)，3.40-3.30 (m，1H)，3.21-3.08 (m，iH)，3 08-2.91 (m，2H)， 2.86-2.73 (m，1H)，1.22 (d，Hz，3H)。MS (DCI-NH3) [M+H]+ 332。 實例 士—甲基胺基-乙某）胺某^某卜茗_2-基）· 笨基t 實例Hz, 1H), 8.04 (d, 1 = 2 Hz, 1H), 7.92 (d, &gt; 9 Hz, 1H), 7.88 (d, J-9 Hz, kH), 7.79 (br s, 1H), 7 62 (dd, J = 2, 9 Hz, 1H), 7.51 (dd, J = 3, 9 Hz, 1H), 7.48 (dd, J = 2, 9 Hz, 1H), 7.12 (dd, J = 2, 9 Hz, 1H), 5.83-5.68 (m, 2H), 3.91-3.81 (m, 1H), 3.66-3.54 (m, 1H), 3.40-3.30 (m, 1H), 3.21-3.08 (m , IH), 3 08-2.91 (m, 2H), 2.86-2.73 (m, 1H), 1.22 (d, Hz, 3H). MS (DCI-NH3) [M + H] + 332. Example ——Methylamino-Ethyl) Amine (A certain ^ _2-yl) · Benzot Example

Ul：酿「卜（4_氰基'篆產上名_2_某·[•乙酯 取0 C之含4-[6-(2-羥乙基）-2-萘基]苯基氰（實例1F，46〇 mg，1.683 mmol)與三乙胺（〇·94 mL，6·732 mm0卜 4當量） 之無水THF( 10 mL)攪掉溶液，於無水氮蒙氣下經甲磺醯氣 (0.17 mL·，2.188 mmol，1.3當量）處理。反應混合物於室溫 下攪拌1小時後’反應混合物加水稀釋，以乙酸乙g旨（3 X 20 89248.doc -188- 200418454 mL)萃取。合併之有機萃液經飽和Na2C03水溶液洗滌，然後 以鹽水洗滌。有機層脫水（硫酸鎂）與過濾。濾液減壓濃縮， 產生標題中間物（305 mg，收率52%)。4 NMR (CDC13, 300 MHz) δ 8.04 (d，J=2 Hz，1H)，7.94-7.87 (m，2H)，7.84-7.69 (m， 6H)，7.43 (dd，J=2, 8 Hz，1H)，4.54 (t，J:7 Hz，2H)，3.26 (t， J=7 Hz，2H)，2.88 (s，3H)。MS (DCI-NH3) [M+NH4]+ 369。Ul: "4- (6- (2-hydroxyethyl) -2-naphthyl) phenylcyanide containing 4- [6- (2-hydroxyethyl) -2-naphthyl] phenyl cyanide" (Example 1F, 46.0 mg, 1.683 mmol) and triethylamine (0.94 mL, 6.732 mm 0.44 eq.) In anhydrous THF (10 mL) was used to stir off the solution, and the solution was subjected to methanesulfonium under anhydrous nitrogen. Gas (0.17 mL ·, 2.188 mmol, 1.3 eq.). After the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was diluted with water and extracted with ethyl acetate (3 X 20 89248.doc -188- 200418454 mL). The combined organic extracts were washed with saturated aqueous Na 2 CO 3 solution and then with brine. The organic layer was dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure to give the title intermediate (305 mg, yield 52%). 4 NMR (CDC13, 300 MHz) δ 8.04 (d, J = 2 Hz, 1H), 7.94-7.87 (m, 2H), 7.84-7.69 (m, 6H), 7.43 (dd, J = 2, 8 Hz, 1H), 4.54 ( t, J: 7 Hz, 2H), 3.26 (t, J = 7 Hz, 2H), 2.88 (s, 3H). MS (DCI-NH3) [M + NH4] + 369.

實例85B iz.(6-{2二[(2二二甲基乙基甲基-胺基乙基 ^ 苯基氰 取含甲％酸2-[6_(4_氰基-苯基）_莕1基]-乙酯（實例85A ，150 mg，0.427 mmol)與N，N，N，-三甲基乙二胺（〇 17 ， 1.280 mmol，3當量）之無水乙腈（1 mL)混合物於室溫下，於 被封試管中攪拌66小時。反應混合物分溶於乙酸乙酯與飽 和NazCO3水溶液之間。有機層脫水（硫酸鎂）與過濾。濾液 減壓濃縮，殘質經管柱層析法純化（梯度：98 : 2至97 : 3 : 微量之二氯曱烷/甲醇/nH4〇H)，產生游離鹼產物（28 7 mg ’收率19%)。游離驗.溶於甲醇中，以含―當量^酒石酸之 甲醇處理。標題化合物之酒石酸鹽自甲醇溶液中結晶。lH NMR (CD3OD, 300 MHz) δ 8.17 (d, J=2 Hz, 1H), 7.97-7.82 (m, 4H), 7.86-7.77 (m, 4H), 7.48 (dd, J=2, 8 Hz, 1H), 4.39 (s, 酒石酸鹽，2H)，3.Π-2.90 (m，8H)，2.69 (s, 6h), 2 M(s, 3H) 。MS (DCI-NH3) [M+H]+ 358。 - 實例86 基丨-苯某氣 4-{6-[&quot;2-(4 -甲基-六氫p比p井-i-基莘 89248.doc -189- 200418454 取含甲磺酸2-[6-(4-氰基-苯基）_茬-2-基]-乙酯（15〇 mg， 0.427 mmol)與 1-甲基六氫吡啩（0.14 mL，1.280 mmol，3當 量）之無水乙腈（1 mL)混合物於室溫下，於密封試管中搅 拌66小時。反應混合物分溶於乙酸乙酯與飽和Na2C〇3水溶 液之間。有機層脫水（硫酸鎂），過濾。濾液減壓濃縮，殘質 經管柱層析法純化（97 · 3 ·微量之二氯甲燒/甲醇/nh4〇h) ，產生游離鹼產物。4 NMR(CD3OD，300 MH4 δ 1H)，7.97-7.89 (m，4H)，7·86-7·81 (m，2H)，7.79 (dd，&gt;2, 8 Hz，2H)，，7.74 (br s，1H)，7.44 (dd，J=2，8 Hz，1H)，3.05-2.97 (m，2H)，2.77-2.43 (m，10H)，2·31 (s，3H)。MS (DCI_NH3) [M+H]+ 356。 游離鹼溶於甲醇中，以含一當量L_酒石酸之甲醇溶液處 理。標題化合物之酒石酸鹽自甲醇溶液中結晶（i〇i ，收 率 66%)。 實例87； g二（2,5-二甲基二^^^^二基甲某小赴呔冷葚1 乙基]· - 口套说― 標題化合物係依實例57之方法製備，但其中改用^(21 二〒基-吱喃-3-基）_乙酮替代丨从3”塞唑：基）_乙酮。咕 NMR (300 MHz，CD3〇D) δ i 19 (d，j=6 Hz，3 h)，i 5i ㈣ 1H), 1.84 (m, 2H), 2.06 (m, 1H), 2.31 (s, 3 H), 2.48 (m, 3 H), 2.63 (s，3 H)，3.06 (m, 3 H) 3 21 (m，ih), 7 33 ⑷㈣ Hz， )’ (d5 J 3 Hz, 1H), 7.72 (dd, J=9 hz, J=3Hz, 1H), 7.82 (s, 1H), 8.16 (d, J=9 Hz, 1H), 8.39 (d, J=3 Hz&gt; 1H); (DCI/NH3) m/z 89248.doc -190- 200418454 335 (M+H)+ 〇 實例88 6_ {2-「（2RV2^^._吡咯啶基丄乙甲硫烷某-宏甚 口奎琳 標題化合物係依實例57之方法製備，但其中改用丨_(4_甲 硫烷基-苯基）-乙酮替代^^嘧唑_2_基）_乙酮。4 nmr (300 MHz, CD3〇D) δ 1.17 (d, J=6 Hz, 3 H), 1.48 (m, 1H), 1.84 (m, 2H), 2.〇5 (m, m), 2.49 (m, 3 H), 2.55 (s, 3 H), 2.63 (s, 3 H)„3.06 (m, 2H),3.17 (m, 1H), 3.21 (m, m), 7.41 (d, J=9 Hz, 2H), 7.68 (dd, J=9 Hz, J=3 Hz, 1H),7.77 (d, J=3 Hz, 1H), 7.94 (d, J=9 Hz, 1H), 8.03 (d, J=9 Hz, 1H), 8.05 (d, J=9 Ηζ,ΙΗ), 8.33 (d, J=9 Hz, 1H); (DCI/NH3) m/z 363 (M+H)+ 〇 實例89 甲基-峨g吡咯咗甚l λ其l 麵口奎琳 標題化合物係依實例π之方法製備，但其中改用^(^甲 基4淀-3-基）-乙酮（參考文獻：s. ρ· l編·Example 85B iz. (6- {2-Di [(2-Dimethylethylmethyl-aminoethyl ^^ phenyl cyanide is based on a methyl acid containing 2- [6_ (4_cyano-phenyl) _ 荇A mixture of 1-yl] -ethyl ester (Example 85A, 150 mg, 0.427 mmol) and N, N, N, -trimethylethylenediamine (〇17, 1.280 mmol, 3 equivalents) in anhydrous acetonitrile (1 mL) was mixed in the chamber. Stir in a sealed test tube for 66 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and saturated NazCO3 aqueous solution. The organic layer was dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography. (Gradient: 98: 2 to 97: 3: trace amount of dichloromethane / methanol / nH4OH) to produce a free base product (28 7 mg 'yield 19%). Free test. Dissolved in methanol to contain ―Equivalent ^ tartaric acid in methanol. The tartaric acid salt of the title compound was crystallized from a methanol solution. LH NMR (CD3OD, 300 MHz) δ 8.17 (d, J = 2 Hz, 1H), 7.97-7.82 (m, 4H), 7.86 -7.77 (m, 4H), 7.48 (dd, J = 2, 8 Hz, 1H), 4.39 (s, tartrate, 2H), 3.Π-2.90 (m, 8H), 2.69 (s, 6h), 2 M (s, 3H). MS (DCI-NH3) [M + H] + 358.-Example 86 radical 丨 -benzene certain gas 4- {6-[&quot; 2- (4-甲-Hexahydro p ratio p well-i-based 莘 89248.doc -189- 200418454 Take 2- [6- (4-cyano-phenyl) _stub-2-yl] -ethyl ester containing methanesulfonic acid (15 0 mg, 0.427 mmol) and 1-methylhexahydropyridine (0.14 mL, 1.280 mmol, 3 eq.) In anhydrous acetonitrile (1 mL) was stirred at room temperature in a sealed test tube for 66 hours. The reaction mixture was partitioned. Between ethyl acetate and saturated aqueous Na2CO3 solution. The organic layer was dehydrated (magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (97 · 3 · amount of dichloromethane / methanol / nh4〇h) to produce a free base product. 4 NMR (CD3OD, 300 MH4 δ 1H), 7.97-7.89 (m, 4H), 7.86-7 · 81 (m, 2H), 7.79 (dd, &gt; 2 , 8 Hz, 2H), 7.74 (br s, 1H), 7.44 (dd, J = 2, 8 Hz, 1H), 3.05-2.97 (m, 2H), 2.77-2.43 (m, 10H), 2 · 31 (s, 3H). MS (DCI_NH3) [M + H] + 356. The free base was dissolved in methanol and treated with a methanol solution containing one equivalent of L-tartaric acid. The tartrate salt of the title compound was crystallized from a methanol solution (ioi, yield 66%). Example 87; g bis (2,5-dimethyl bis ^^^^ dimethyl a cold go to the cold 1 ethyl] ·-mouth to say-the title compound was prepared according to the method of Example 57 but modified Substitute ^ (21 diamidino-crean-3-yl) _ethanone 丨 from 3 "sedazol: yl) _ethanone. NMR (300 MHz, CD3OD) δ i 19 (d, j = 6 Hz, 3 h), i 5i ㈣ 1H), 1.84 (m, 2H), 2.06 (m, 1H), 2.31 (s, 3 H), 2.48 (m, 3 H), 2.63 (s, 3 H) , 3.06 (m, 3 H) 3 21 (m, ih), 7 33 ⑷㈣ Hz,) '(d5 J 3 Hz, 1H), 7.72 (dd, J = 9 hz, J = 3Hz, 1H), 7.82 ( s, 1H), 8.16 (d, J = 9 Hz, 1H), 8.39 (d, J = 3 Hz &gt;1H); (DCI / NH3) m / z 89248.doc -190- 200418454 335 (M + H) + 〇 Example 88 6_ {2- "(2RV2 ^^ ._ pyrrolidinyl acetomethanine)-The title compound was prepared according to the method of Example 57 but changed to 丨 (4_ 甲Sulfanyl-phenyl) -ethanone replacement ^^ pyrazol_2_yl) _ethanone. 4 nmr (300 MHz, CD30D) δ 1.17 (d, J = 6 Hz, 3 H), 1.48 ( m, 1H), 1.84 (m, 2H), 2.〇5 (m, m), 2.49 (m, 3 H), 2.55 (s, 3 H), 2.63 (s, 3 H), 3.06 (m, 2H), 3.17 (m, 1H), 3.21 (m, m), 7.41 (d, J = 9 Hz, 2H), 7.68 (dd, J = 9 Hz, J = 3 Hz, 1H), 7.77 (d, J = 3 Hz, 1H), 7.94 (d, J = 9 Hz, 1H), 8.03 (d, J = 9 Hz, 1H), 8.05 (d, J = 9 Ηζ, ΙΗ), 8.33 (d, J = 9 Hz, 1H); (DCI / NH3) m / z 363 (M + H) + 〇 Example 89 methyl -Eg pyrrolidine and λ and its l facet quelin's title compound was prepared according to the method of Example π, but in which ^ (^ methyl-4-ammon-3-yl) -ethanone (Reference: s. Ρ · Editing ·

Chem. 39, 1996, 5053-5063)替代 1-(1，3-p塞嗤 _2·基）-乙酮。4 NMR (300 MHz，CD3〇D) δ1·17 (d，Hz，3 H)，1.48 (m， 1H)，1.84 (m，2H)，2.04 (m，1H)，2·38 (m，1H)，2.49 (m，3 H)， 2.63 (s，3 H)，3.06 (m5 2H)，3·19 (m，1H)，7.47 (d，J=9 Hz， 1H)，7·70 (dd，㈣ Hz，J = 3 Hz，1H)，7·80 (d，JN3 Hz，1H)， 8.00 (d, J-9 Hz，1H)，8.07 (d，J=9 Hz，1H)，8.37 (d，J=9 Hz， 1H)? 8.47 (dd5 J=9 Hz5 J=3Hz5 1H)? 9.17 (d5 J=3 Hz, 1H); 89248.doc -191 - 200418454 (DCI/NH3) m/z 332 (M+H)+。 —實例90 乙基1 - 口务口棟 標題化合物係依實例57之方法製備，但其中改用1_(1夂 二甲基-1Η-吡唑_4_基）_乙酮（參考文獻：ρ·以匕印。^以ai，了 Heterocyd· Chem· 19, 1982, 1355_1361)替代 -嘍唑 基）-乙酮。咕 NMR (300 MHz, CD3〇D) δ 1.32 (d, J=6 Hz 3 H), 1.63 &lt;m, 1H),1.97 (m, 2H), 2.17 (m, 1H), 2.60 (s, 3 h), 2.85 (m, 2H), 3.12 (m, 3 H), 3.47 (m, 2H), 3.90 (Sj 3 Η), η 66 (dd, J=9 Hz, J=3 Hz, 1H), 7.69 (d, J=9 Hz, 1H), 7.76 (d, J=2 Hz, 1H), 7.96 (d, J=9 Hz, 1H), 8.12 (s, 1H), 8.22 (d, J=9 Hz, 1H); (DCI/NH3) m/z 335 (M+H)+。 實例91Chem. 39, 1996, 5053-5063) in lieu of 1- (1,3-p-sedino-2-yl) -ethanone. 4 NMR (300 MHz, CD3OD) δ 1.17 (d, Hz, 3 H), 1.48 (m, 1H), 1.84 (m, 2H), 2.04 (m, 1H), 2.38 (m, 1H ), 2.49 (m, 3 H), 2.63 (s, 3 H), 3.06 (m5 2H), 3.19 (m, 1H), 7.47 (d, J = 9 Hz, 1H), 7.70 (dd , ㈣ Hz, J = 3 Hz, 1H), 7.80 (d, JN3 Hz, 1H), 8.00 (d, J-9 Hz, 1H), 8.07 (d, J = 9 Hz, 1H), 8.37 ( d, J = 9 Hz, 1H)? 8.47 (dd5 J = 9 Hz5 J = 3Hz5 1H)? 9.17 (d5 J = 3 Hz, 1H); 89248.doc -191-200418454 (DCI / NH3) m / z 332 (M + H) +. —Example 90 Ethyl 1-Kouwukoudong The title compound was prepared according to the method of Example 57, but 1_ (1 夂 dimethyl-1Η-pyrazole_4_yl) _acetone was used instead (Reference: ρ • With a dagger. ^ With ai, Heterocyd · Chem · 19, 1982, 1355_1361) instead of -oxazolyl)-ethyl ketone. NMR (300 MHz, CD3〇D) δ 1.32 (d, J = 6 Hz 3 H), 1.63 &lt; m, 1H), 1.97 (m, 2H), 2.17 (m, 1H), 2.60 (s, 3 h), 2.85 (m, 2H), 3.12 (m, 3 H), 3.47 (m, 2H), 3.90 (Sj 3 Η), η 66 (dd, J = 9 Hz, J = 3 Hz, 1H), 7.69 (d, J = 9 Hz, 1H), 7.76 (d, J = 2 Hz, 1H), 7.96 (d, J = 9 Hz, 1H), 8.12 (s, 1H), 8.22 (d, J = 9 Hz, 1H); (DCI / NH3) m / z 335 (M + H) +. Example 91

Li.gr「(2 R1U^基-卜吡咯啶基丄^基卜2 _ 標題化合物係依實例57之方法製備，但其中改用丨_嘧吩 -3_基-乙酮（參考文獻：E· Campaigne et al，了細以 S〇c· 70, 1948, 1555)替代 1-(1，34 唑-2-基）-乙酮。巾 NMR (300 MHz，CD3〇D) δ 1.27 (d，J=6 Hz，3 H)，1·61 (m，1H)， 1.92 (m，2H)，2.12 (m，lH)，2·70 (m，2H)，3·06 (m，3 H)，3·24 (m，1H)，3.45 (m，1H)，7.56 (dd，J=9 Hz，J=9 Hz，1H)，7.68 (dd，J=9 Hz，J=3 Hz，1H)，7.78 (s，1H)，7.88 (d，J=6 Hz，1H)， 7.94 (d，J=9 Hz，1H)，8.03 (d，J=9 Hz，1H)，8.18 (m，m)，8.28 (d，J=9 Hz，1H); (DCI/NH3) m/z 323 (M+H)+。 -192 - 89248.doc 200418454 實例92 ϋυ；(2ΙΙ)-2-甲基-1-吡咯啶基1乙甚卜2-嘧啶-5-基-崦啉 標題化合物係依實例57之方法製備，但其中改用丨_嘧啶 -5-基-乙酮（參考文獻：L r Naumenko et al.，Chem· Heterocycl. Compd·(英文版）π，1981，710_714)替代1-(1，3_ 噻唑-2-基卜 乙酮。iH NMR (300 MHz，CD3〇D) δ 1·16 (d，J=6 Hz，3 H)， 1.50 (m，1H)，1·84 (m，2H)，2.04 (m，1H)，2·35 (m，1H)，2.46 (m，2H)，3.12 (m，3 H)，3.21 (m，lH)，7.74 (dd，J=9 Hz，J=3 Hz，1H)，;7·82 (d，J=3 Hz，1H)，8·1〇 (d，J=6 Hz，2H)，8.43 (d， J=9 Hz，1H)，9.25 (s，1H)，9.56 (s，2H); (DCI/NH3) m/z 319 (M+H)+。 實例93 2-0二甲基二虛淀-3二基）-6-{2-「（2以-2-甲基-1-吡咯啶基1 乙基卜口杏说 標題化合物係依實例57之方法製備，但其中改用丨_(2,6_ 一甲基？比淀基）-乙酮（參考文獻k. Franke Angew. Chem. 67，1955，395)替代 ΐ，（ι，3_Ρ 塞唑 _2-基）_ 乙酮。iH NMR (300 MHz，CD3OD) δ 1.17 (d，J=6 Hz，3 H)，1.48 (m，1H)，1.82 (m， 2H)，2.01 (m，1Η)，2·35 (m，ih)，2.47 (m，2H)，2.54 (s，3 H)， 2.59 (s，3 H)，3.07 (m，3 H)，3.19 (m，1H)，7.29 (d，J=9 Hz， 1H)，7.63 (d，J=9 Hz，1H)，7·73 (dd，J=9 Hz，J=3 Hz，1Η)，7·81 (d, J-6 Hz3 1H)? 7.84 (d3 J=3 Hz3 1H)? 8.00 (d3 J=9 Hz, 1H)? 8.40 (d，J-9 Hz，lH); (DCI/NH3) m/z 346 (M+H)+。 f例94 89248.doc -193 - 200418454 比咯啶某 1 乙某卜4 4木-2-基比症-3-美酮 標題化合物係依實例57之方法製備，但其中改用3,5_二乙 醯基-2,6_二甲基吡啶替代丨气1，3-噻唑-2-基）乙酮。產物溶於 水中，以2當量^酒石酸處理。冷凍乾燥排除溶劑，產生產 物（二酒石酸鹽’為白色泡沫狀物。1H NMR (CD3OD) δ ppm 1.49 (d? J^6.78 Hz?3 H)5 1.81 (m? 1H)? 2.13 (m? 2H)? 2.35 (m, 1H), 2.60 (s5 3 H)) 2.64 (s5 3 H)5 2.76 (S) 3 H)3 3.36 (m? 4 H)? 3.59 (m5 iH)? 3.74 (m? 2H)5 4.47 (s? 4 H)5 7.77 (d? 1=8.48 Hz? 1H)，7.82 (dd，J—8.65, 1·87 Hz，1H)，7·99 (d，J==1 7〇 Hz，1H)， 8.10 (d, J 8·82 Hz，1H)，8.32 (s，1H)，8.47 (d，J=8.48 Hz，1H) 。MS (DCI-NH3) [m+H]+ 388。 6-[2-f(gR)-2-甲基-1 -吨 p各症某 i r ^ Ί -吡唑冬某 W杏 4 標題化合物係依實例57之方、本制 •貝J &lt;万去製備，但其中改用1-(1H- 吡唑-5-基）乙-1-酮鹽酸鹽替代丨 (1，3-p塞峻-2-基）乙酮，及使 用5滴飽和氫氧化鉀之乙醇溶液 /從進仃。iH NMR (CDC13) δ ppm 1.14 (d，J=6.1〇 Ηζ，3 Η) ι ,〇 , ’，148 (m，1H)，1.77 (m，2H)， 1.93 (m，1H)，2.25 (q，J=8.82 H2 im n2, 1H)，2.40 (m，2H)，3.01 (m， 2H)，3.14 (m，1H)，3.30 (m，1H) 6 m / 6·92 (s，1H)，7.61 (m，1H)， 7.63 (s，1H)，7.70 (d，J=2.03 Hz m、’ ，iH)，7.81 (d，J=8.82 Hz，1H)， 8.02 (d，J=8.48 Hz，1H)，8 14 m -Li.gr "(2 R1U ^ yl-pyrrolidinylpyridinyl ^^ b 2 _ The title compound was prepared according to the method of Example 57 but using 丨 _pyrimidine-3_yl-ethanone (Reference: E · Campaigne et al, replaced 1- (1,34 azol-2-yl) -ethanone with Soc · 70, 1948, 1555. NMR (300 MHz, CD3D) δ 1.27 (d, J = 6 Hz, 3 H), 1.61 (m, 1H), 1.92 (m, 2H), 2.12 (m, 1H), 2.70 (m, 2H), 3.06 (m, 3 H) , 3.24 (m, 1H), 3.45 (m, 1H), 7.56 (dd, J = 9 Hz, J = 9 Hz, 1H), 7.68 (dd, J = 9 Hz, J = 3 Hz, 1H) , 7.78 (s, 1H), 7.88 (d, J = 6 Hz, 1H), 7.94 (d, J = 9 Hz, 1H), 8.03 (d, J = 9 Hz, 1H), 8.18 (m, m) , 8.28 (d, J = 9 Hz, 1H); (DCI / NH3) m / z 323 (M + H) +. -192-89248.doc 200418454 Example 92 ϋυ; (2ΙΙ) -2-methyl-1 -Pyrrolidinyl 1 ethyl thiophene 2-pyrimidin-5-yl-pyridoline The title compound was prepared according to the method in Example 57 but using 丨 _pyrimidin-5-yl-ethanone (Reference: L r Naumenko et al., Chem. Heterocycl. Compd. (English, π, 1981, 710_714) instead of 1- (1,3_thiazol-2-ylbuthionone. iH NMR (300 MHz, CD3OD) δ 1.16 (d, J = 6 Hz, 3 H), 1.50 (m, 1H), 1.84 (m, 2H), 2.04 (m, 1H), 2.35 (m, 1H ), 2.46 (m, 2H), 3.12 (m, 3 H), 3.21 (m, 1H), 7.74 (dd, J = 9 Hz, J = 3 Hz, 1H), 7.82 (d, J = 3 Hz, 1H), 8.10 (d, J = 6 Hz, 2H), 8.43 (d, J = 9 Hz, 1H), 9.25 (s, 1H), 9.56 (s, 2H); (DCI / NH3) m / z 319 (M + H) +. Example 93 2-0 Dimethyldioxo-3diyl) -6- {2-"(2 to 2-methyl-1-pyrrolidinyl 1 Ethylbuccin said that the title compound was prepared according to the method of Example 57, but 丨 _ (2,6_monomethyl? Bitoyl) -ethyl ketone was used instead (Reference k. Franke Angew. Chem. 67, 1955, 395) instead of hydrazone, (ι, 3-P thiazol-2-yl)-ethyl ketone. iH NMR (300 MHz, CD3OD) δ 1.17 (d, J = 6 Hz, 3 H), 1.48 (m, 1H), 1.82 (m, 2H), 2.01 (m, 1Η), 2.35 (m, ih ), 2.47 (m, 2H), 2.54 (s, 3 H), 2.59 (s, 3 H), 3.07 (m, 3 H), 3.19 (m, 1H), 7.29 (d, J = 9 Hz, 1H ), 7.63 (d, J = 9 Hz, 1H), 7.73 (dd, J = 9 Hz, J = 3 Hz, 1Η), 7.81 (d, J-6 Hz3 1H)? 7.84 (d3 J = 3 Hz3 1H)? 8.00 (d3 J = 9 Hz, 1H)? 8.40 (d, J-9 Hz, lH); (DCI / NH3) m / z 346 (M + H) +. f Example 94 89248.doc -193-200418454 Bipyridine 1 Ethyl 4 4 xylan-2-ylbiosis-3-methanone The title compound was prepared according to the method of Example 57 but 3,5_ was used instead. Diethylamido-2,6-dimethylpyridine replaces 1,3-thiazol-2-yl) ethanone. The product was dissolved in water and treated with 2 equivalents of tartaric acid. Freeze-drying removes the solvent and produces the product (the ditartrate 'is a white foam. 1H NMR (CD3OD) δ ppm 1.49 (d? J ^ 6.78 Hz? 3 H) 5 1.81 (m? 1H)? 2.13 (m? 2H )? 2.35 (m, 1H), 2.60 (s5 3 H)) 2.64 (s5 3 H) 5 2.76 (S) 3 H) 3 3.36 (m? 4 H)? 3.59 (m5 iH)? 3.74 (m? 2H ) 5 4.47 (s? 4 H) 5 7.77 (d? 1 = 8.48 Hz? 1H), 7.82 (dd, J—8.65, 1.87 Hz, 1H), 7.99 (d, J == 1 7〇 Hz, 1H), 8.10 (d, J 8.82 Hz, 1H), 8.32 (s, 1H), 8.47 (d, J = 8.48 Hz, 1H). MS (DCI-NH3) [m + H] + 388. 6- [2-f (gR) -2-methyl-1 -t. P. Each disease ir ^ Ί -pyrazolium apricot 4 apricotin 4 The title compound is based on the formula of Example 57 and the formula is as follows: J &lt; 10,000 To prepare, but instead use 1- (1H-pyrazol-5-yl) ethan-1-one hydrochloride instead of 丨 (1,3-pethen-2-yl) ethanone, and use 5 drops of saturation Potassium hydroxide in ethanol solution iH NMR (CDC13) δ ppm 1.14 (d, J = 6.1〇Ηζ, 3 Η) ι, 〇, ', 148 (m, 1H), 1.77 (m, 2H), 1.93 (m, 1H), 2.25 (q , J = 8.82 H2 im n2, 1H), 2.40 (m, 2H), 3.01 (m, 2H), 3.14 (m, 1H), 3.30 (m, 1H) 6 m / 6.92 (s, 1H), 7.61 (m, 1H), 7.63 (s, 1H), 7.70 (d, J = 2.03 Hz m, ', iH), 7.81 (d, J = 8.82 Hz, 1H), 8.02 (d, J = 8.48 Hz, 1H), 8 14 m-

； 14 (d，J=8.48 Hz? 1H)。MS (DCI-NH3) [M+H]十 307。; 14 (d, J = 8.48 Hz? 1H). MS (DCI-NH3) [M + H] 307.

Aj^96 89248.doc -194, 200418454 澳-異今{2_:L(2R)二2·甲某-i _吡咯啶某1乙基} -卩奎口林 才7K題化合物係依實例57之方法製備，但其中改用1_(3_溴_ …咢上5基）-乙酉同（參考文獻· μ· j). Amici et al·，J.〇rg. Chem· 1989, 54 ⑴），2646·2650)替代 1-(1,3-魂唑 _2-基）乙酮 。4 NMR(CD3〇D) δ ppm 1.13 (d，J:6.10 Hz，3H)，1.47 (m， 1H)，1.78 (m，2H)，1.95 (m，1H)，2·24 (q，j=8.59 Hz，1H)， 2.40 (m，2H)，3·08 (m，3 H)，3·29 (m，1H)，7 l4 (s，m)，7 67 (dd? 1H)? 7.69 (s5 1H), 7.96 (d5 J-8.48 Hz? 1H), 8.06 (d, J-9·16 Hz，1H)，8.24 (d，J=8.48 Hz，1H)。MS (DCI-NH3) [M+H]+ 386。Aj ^ 96 89248.doc -194, 200418454 Ao-Issue {2_: L (2R)? 2 · A · m-i-pyrrolidine 1-ethyl} -Kuikoukoulincai 7K title compound according to Example 57 It was prepared by the method, but 1_ (3_bromo_… on the 5 group) -acetone was the same (Reference · μ · j). Amici et al ·, J.〇rg. Chem · 1989, 54 ⑴), 2646 2650) instead of 1- (1,3-somatazole_2-yl) ethanone. 4 NMR (CD3OD) δ ppm 1.13 (d, J: 6.10 Hz, 3H), 1.47 (m, 1H), 1.78 (m, 2H), 1.95 (m, 1H), 2.24 (q, j = 8.59 Hz, 1H), 2.40 (m, 2H), 3.08 (m, 3 H), 3.29 (m, 1H), 7 l4 (s, m), 7 67 (dd? 1H)? 7.69 ( s5 1H), 7.96 (d5 J-8.48 Hz? 1H), 8.06 (d, J-9 · 16 Hz, 1H), 8.24 (d, J = 8.48 Hz, 1H). MS (DCI-NH3) [M + H] + 386.

實例9J +吡略读某]乙基κ 口奎琳 標題化合物係依實例57之方法製備，但其中改用叫氣 -3-Ρ比淀基）小乙明替代嘍嗓_2_基）乙酮。！η nmr (CDCl3)5ppmi.14 (d, 1=5.76 HZ,3H), 1.47 (m, 1H), 1.78 (m，2H), L94 (m，1H)，2·25 (q，m 7〇 Hz，ih)，2 4〇 (m，2H)， 3.03 (m, 2H)33.15 (m 1H) 3 30 (m i tt、 、，’， （m，1H)，7.48 (d，J=8.48 Hz， 1H), 7.65 (dd，1H) 7 67 is 1H、 7 〇， J，’ lS，rt)，7·83 (d，J=8.48 Hz，1H)， 8.08 (d，J=8.48 Hz 1ΗΊ 8 21 id τ 〇 ，iH)，(d，J4.48 Hz，1H)，8·51 (dd， J=8.31，2.54 Hz，1ΚΠ 9 11 (dd … -Example 9J + Pyramid] The title compound of ethyl κ and quinine was prepared according to the method of Example 57, but the method was replaced with a gas called 3--3-Pyridyl), which was replaced by cyper-2-yl) ketone. !! η nmr (CDCl3) 5ppmi. 14 (d, 1 = 5.76 HZ, 3H), 1.47 (m, 1H), 1.78 (m, 2H), L94 (m, 1H), 2.25 (q, m 70 Hz) , Ih), 2 40 (m, 2H), 3.03 (m, 2H) 33.15 (m 1H) 3 30 (mitt, ,,,,,, (m, 1H), 7.48 (d, J = 8.48 Hz, 1H ), 7.65 (dd, 1H) 7 67 is 1H, 7 〇, J, 'lS, rt), 7.83 (d, J = 8.48 Hz, 1H), 8.08 (d, J = 8.48 Hz 1ΗΊ 8 21 id τ 〇, iH), (d, J4.48 Hz, 1H), 8.51 (dd, J = 8.31, 2.54 Hz, 1KΠ 9 11 (dd…-

1 ，J〜2.71，0.68 Hz，1H)。MS (DCI-NH3) [M+H]+ 352 〇 實例 89248.doc -195 - 200418454 K3,5-二甲^分-2-基）-6-丄?-丄L2RV2-甲甚-1-吡呔々其] 乙基卜唓4 標題化合物係依實例57之方法製備，但其中改用丨_(3,5_ 二甲基-2-嘍吩基）乙_丨_酮替代噻唑_2_基）乙酮。1h NMR (CDC13) δ ppm 1.14 (d, J=6.1〇 Hz, 3 H), 1.47 (m, 1H), 1.77 (m, 2H), 1.95 (m, lH), 2.25 (m, m), 2.39 (m, 2H), 2.49 (s, 3 H), 2.54 (S, 3 H),3.00 (m, 2H), 3.11 (m, iH), 3.29 (m, 1H), 6.64 (s, 1H), 7.56 (dd, 1H), 7.58 (s, 1H), 7.63 (d, 1=8.821, J ~ 2.71, 0.68 Hz, 1H). MS (DCI-NH3) [M + H] + 352 [It]] The title compound was prepared according to the method of Example 57 except that 丨 _ (3,5_dimethyl-2-fluorenyl) ethyl_ 丨 _one was used instead of thiazole_2_yl. ) Ethyl ketone. 1h NMR (CDC13) δ ppm 1.14 (d, J = 6.1〇Hz, 3 H), 1.47 (m, 1H), 1.77 (m, 2H), 1.95 (m, lH), 2.25 (m, m), 2.39 (m, 2H), 2.49 (s, 3 H), 2.54 (S, 3 H), 3.00 (m, 2H), 3.11 (m, iH), 3.29 (m, 1H), 6.64 (s, 1H), 7.56 (dd, 1H), 7.58 (s, 1H), 7.63 (d, 1 = 8.82

Hz, 1H),,7.99 (d, j=8.14 Hz, 1H), 8.05 (d, J=8.82 Hz, 1H) 〇 MS (DCI-NH3) [M+H]+ 351 0 實例99 u2卜合 _2_其 _中址 標題化合物係依實例57之方法製備，但其中改用2-乙醯 基口塞刀替代1H,塞咬_2_基）乙g同。1h nmr (CDCb) s ppm 1.15 (d, J=6.10 Hz, 3H), 1.49 (m, 1H), 1.77 (m, 2H), 1.96 (m, 1H)，2.26 (q，7〇 Hz, 1H)，2 41 (m, 2h)，3 〇2 ㈤肩， H)&gt; 3.30 (m,lH), 7.15 (dd, J=5.〇9, 3.73 Hz, 1H), 7-45 (dd, J=5.〇9, !.〇2 Hz, 1H), 7.58 (dd, 1H), 7.59 (s, 1H), (，3-?3, 1.02 Hz, 1H), 7.77 (d, J=8.82 Hz, 1H), 8.01 (d,1=8.48 Hz, 1H), 8.08 (d&gt; j=8.82 Hz? ih) 〇 ms (dci_NH3) [M+H] + 323 〇 2_:甲立^咯唉某]乙某“杳啉 W化合物係依實例57之方法製備，但其中改用卜呋η 89248.doc 200418454 -3-基-乙酮（參考文獻· j. M. McNamara et al·，Tetrahedron 1984，40 (22)，4685-4692)替代 噻唑 _2_基）乙酮。4 NMR (CDC13) δ ppm 1.14 (d，J=6.1〇 Hz，3 H)，1.47 (m，1H)， 1.77 (m? 2H)? 1.95 (m, 1H)? 2.25 (q5 J=8.82 Hz? 1H)? 2.40 (m5 2H)，3.01 (m，2H)，3·14 (m，1H)，3.35 (m，lH)，7.10 (dd， J-1.87, 0.85 Hz5 1H), 7.54 (t5 J==i.7〇 Hz? 1H)? 7.57 (d? J=8.48Hz, 1H), 7.99 (d, j = 8.14 Hz, 1H), 8.05 (d, J = 8.82 Hz, 1H) 〇MS (DCI-NH3) [M + H] + 351 0 Example 99 u2 2_Qi_ The title compound in the middle of the site was prepared according to the method of Example 57 except that 2-Hydroxyl mouth-knife was used instead of 1H. 1h nmr (CDCb) s ppm 1.15 (d, J = 6.10 Hz, 3H), 1.49 (m, 1H), 1.77 (m, 2H), 1.96 (m, 1H), 2.26 (q, 70 Hz, 1H) , 2 41 (m, 2h), 3 〇2 shoulders, H) &gt; 3.30 (m, 1H), 7.15 (dd, J = 5.09, 3.73 Hz, 1H), 7-45 (dd, J = 5.09,! .〇2 Hz, 1H), 7.58 (dd, 1H), 7.59 (s, 1H), (, 3-? 3, 1.02 Hz, 1H), 7.77 (d, J = 8.82 Hz , 1H), 8.01 (d, 1 = 8.48 Hz, 1H), 8.08 (d &gt; j = 8.82 Hz? Ih) 〇ms (dci_NH3) [M + H] + 323 〇2_: 甲 立 ^ 咯 唉 某] B A "xanthroline W compound was prepared according to the method of Example 57, but it was replaced by bufur η 89248.doc 200418454-3-yl-ethanone (References · j. M. McNamara et al., Tetrahedron 1984, 40 ( 22), 4685-4692) instead of thiazole_2-yl) ethanone. 4 NMR (CDC13) δ ppm 1.14 (d, J = 6.10 Hz, 3 H), 1.47 (m, 1H), 1.77 (m? 2H )? 1.95 (m, 1H)? 2.25 (q5 J = 8.82 Hz? 1H)? 2.40 (m5 2H), 3.01 (m, 2H), 3.14 (m, 1H), 3.35 (m, lH), 7.10 (dd, J-1.87, 0.85 Hz5 1H), 7.54 (t5 J == i.7〇Hz? 1H)? 7.57 (d? J = 8.48

Hz，lH)，7.58 (dd，1H)，7.60 (s，1H)，8·00 (d，J=8.14 Hz，1H)，Hz, lH), 7.58 (dd, 1H), 7.60 (s, 1H), 8.00 (d, J = 8.14 Hz, 1H),

8.07 (d，7·80 Hz，1H)，8.13 (m，iH)。Ms ⑴ 307 ° $ 才衣通化合物係依實例之女 貝1 J 3 /1万法製備，但其中改用2-乙 基-2_魂哇替代Ml 3-嘧唑2其、/…1 V，）I 主-2-基）乙酮。iHNMR(CDCl3) ppm 1.13 (d, J-6.10 Hz 3 &quot; 3 H)? 1.46 (m, 1H)5 1.76 (m? 2Ϊ8.07 (d, 7.80 Hz, 1H), 8.13 (m, iH). Ms ⑴ 307 ° $ Caiyitong compound was prepared according to the example of female shellfish 1 J 3 / 10,000 method, but in which 2 ethyl-2_ soul wow was used instead of Ml 3-pyrazole 2 its / ... 1 V ,) I main-2-yl) ethyl ketone. iHNMR (CDCl3) ppm 1.13 (d, J-6.10 Hz 3 &quot; 3 H)? 1.46 (m, 1H) 5 1.76 (m? 2Ϊ

1.94 (m，1H)，2.24 (q j=8 59 h7 m、 凡Hz，1H)，2·40 (m，2H)，3.02 (] 2H)，3.13 (m，1H)，3 29 m、α」1.94 (m, 1H), 2.24 (q j = 8 59 h7 m, normal Hz, 1H), 2.40 (m, 2H), 3.02 (] 2H), 3.13 (m, 1H), 3 29 m, α "

.:3.41 (t，j=8 48 HZ，2H)，4. (t，J=8.48 Hz，2H) 7 ^ T im 8 n M T (dd，J=8.48, 2.03 Hz，m)，7.⑴.: 3.41 (t, j = 8 48 HZ, 2H), 4. (t, J = 8.48 Hz, 2H) 7 ^ T im 8 n M T (dd, J = 8.48, 2.03 Hz, m), 7.⑴

)’ 8· 11 (d，J=8.82 Hz 1H) S 1 w [m+h]+ 326。 ，），8.13(S，2HpMS(DCI_NK -乙基丨-44-2-基、-苯 標題化合物係依實例5 7之 万法I備，但其中改用14-二乙 89248.doc -197- 200418454 酉藍苯替代1-(1,3-噻唑-2-基）乙酮。i NMR (CDC13) δ ppm 1.15 (d，J=5.76 Ηζ，3 Η)，1·48 (m，1Η)，1.79 (m，2Η)，1.95 (m， 1H)，2.26 (q，1H)，2.42 (m，2H)，2.67 (s，3 H)，3.04 (m，2H)， 3.15 (m，1H)，3.31 (m，lH)，7.64 (dd，J=8.48, 2.03 Hz，1H)， 7.67 (s，1H)，7.90 (d，J=8.48 Hz，1H)，8·11 (m，3 H)，8_20 (d， J=8.48 Hz，1H)，8.27 (m，2H)。MS (DCI-NH3) [M+H]+359。 實例103 基比咯啶基1乙某卜口奎啉-2_基）_2三氟 专 甲基-吡啶-4_醇 標題化合物係依實例57之方法製備，但其中改用i-(4-輕 基-2-三氟甲基-吡啶_3_基）_乙酮（參考文獻：L. s· Vasil，ev et al·，Russ.Chem.BL 1996，45 (11)，2574-2577)替代 1-(1,3- 魂唆-2-基）乙酮。iHNMR(CD3〇d) δρριη i 43 (d，J=6 44 Hz， 3 H)，1.73 (m，1Η)，2·06 (m，2H)，2.29 (m，1H)，3.10-3.75 (m， 7 H)，6·93 (d，J=5.76 Hz，1H)，7·52 (d，J=8.48 Hz，1H)，7·70 (dd，J=8.65，1.87 Hz，1H)，7·88 (d，J=1.70 Hz，1H)，8.01 (d， J=8.82 Hz, 1H)? 8.23 (d, J=6.10 Hz, 1H)? 8.33 (d, J=8.48 Hz, 1H)。MS (DCI-NH3)[M+H]+ 402。 實例104 κ·3,5-二甲基」比唑_4_基)_6_(2_「i2Rm基小吡咯畦 基1乙基丨-P奋喊 標題化合物係依實例54F之方法製備，但其中改用 二甲基基）·乙酮（參考文獻：E. E Emelinaetal.，) '8 · 11 (d, J = 8.82 Hz 1H) S 1 w [m + h] + 326. ,), 8.13 (S, 2HpMS (DCI_NK -ethyl-44-2-yl, -benzene The title compound was prepared according to the method of Example 57, but 14-diethyl 89248.doc -197- 200418454 Syringene replaces 1- (1,3-thiazol-2-yl) ethanone. I NMR (CDC13) δ ppm 1.15 (d, J = 5.76 Ηζ, 3 Η), 1.48 (m, 1Η), 1.79 (m, 2Η), 1.95 (m, 1H), 2.26 (q, 1H), 2.42 (m, 2H), 2.67 (s, 3 H), 3.04 (m, 2H), 3.15 (m, 1H), 3.31 (m, lH), 7.64 (dd, J = 8.48, 2.03 Hz, 1H), 7.67 (s, 1H), 7.90 (d, J = 8.48 Hz, 1H), 8.11 (m, 3 H), 8_20 (d, J = 8.48 Hz, 1H), 8.27 (m, 2H). MS (DCI-NH3) [M + H] +359. Example 103 Base than pyrrolidinyl 1 ethyl molybdenoline-2_ The title compound was prepared according to the method of Example 57 except that i- (4-lightyl-2-trifluoromethyl-pyridine_3_yl) _ Ethyl ketone (References: L. s · Vasil, ev et al., Russ. Chem. BL 1996, 45 (11), 2574-2577) instead of 1- (1,3- Erythrim-2-yl) ethanone IHNMR (CD3〇d) δρριη i 43 (d, J = 6 44 Hz, 3 H), 1.73 (m, 1Η), 2.06 (m, 2H), 2.29 (m, 1H) , 3.10-3.75 (m, 7 H), 6.93 (d, J = 5.76 Hz, 1H), 7.52 (d, J = 8.48 Hz, 1H), 7.70 (dd, J = 8.65, 1.87 Hz, 1H), 7.88 (d, J = 1.70 Hz, 1H), 8.01 (d, J = 8.82 Hz, 1H)? 8.23 (d, J = 6.10 Hz, 1H)? 8.33 (d, J = 8.48 Hz, 1H). MS (DCI-NH3) [M + H] + 402. Example 104 κ · 3,5-dimethyl "biazole_4_yl) _6_ (2_" i2Rm-based small pyrrolidinyl 1 ethyl The title compound was prepared according to the method of Example 54F, but dimethyl group was used instead. Ethyl ketone (Reference: E. E Emelinaetal.,

Russ· J· 〇rg· Chem. 1994, 30 (1〇)，ι637_1639)替代弘乙醯基 89248.doc -198- 200418454 吡啶。iH NMR(CDC13) δ ppm 1.17 (d，J=5.76 Hz，3 Η)，1·51 (m，1H)，1.80 (m，2H)，1·97 (m, 1H)，2.28 (m，1H)，2.44 (m， 2H)，2.51 (s，3 H)，2.51 (s，3 H)，3.05 (m，2H)，3.15 (m，1H)， 3.32 (m，1H)，7.47 (d，J=8.48 Hz，1H)，7·59 (dd，J=8.48, 2.03 Hz，1H)，7.63 (s，1H)，8.01 (d，J=8.81Hz，1H)，8·10 (d，J=8.81 Hz，1H)。MS(DCI-NH3) [M+H]+ 335。 實例105 6-{2-「（21〇-2-甲基-1-吡咯啶基1乙某丨-2-(11^毗唑-4-基）-崦琳 標題化合物係依實例57之方法製備，但其中改用 p比唆-4-基）-乙酮（參考文獻：G· Heinisch et al·，Monatsh.Russ J. Org. Chem. 1994, 30 (10), ι637_1639) replaces ethanoyl 89248.doc -198-200418454 pyridine. iH NMR (CDC13) δ ppm 1.17 (d, J = 5.76 Hz, 3 Η), 1.51 (m, 1H), 1.80 (m, 2H), 1.97 (m, 1H), 2.28 (m, 1H ), 2.44 (m, 2H), 2.51 (s, 3 H), 2.51 (s, 3 H), 3.05 (m, 2H), 3.15 (m, 1H), 3.32 (m, 1H), 7.47 (d, J = 8.48 Hz, 1H), 7.59 (dd, J = 8.48, 2.03 Hz, 1H), 7.63 (s, 1H), 8.01 (d, J = 8.81Hz, 1H), 8.10 (d, J = 8.81 Hz, 1H). MS (DCI-NH3) [M + H] + 335. Example 105 6- {2-"(21〇-2-Methyl-1-pyrrolidinyl 1 ethyl) -2- (11 ^ pyrazol-4-yl) -zolin The title compound was prepared according to the method of Example 57 Preparation, but in which p than fluoren-4-yl)-ethyl ketone (Reference: G. Heinisch et al., Monatsh.

Chem· 1988，119，253-262)替代 1-(1，3-口塞唑-2-基）乙酮。巾 NMR (CDC13) δ ppm 1·16 (d，J=6.10Hz，3H)，1·48 (m，1H)， 1·76 (m，1H)，1.94 (m，2H)，2.29 (q，J=8.36 Hz，1H)，2.44 (m， 2H)，3·02 (m，2H)，3.22 (m，1H)，3.38 (m，lH)，7.53 (d，J=8.48 Hz，1H)，7.56 (s，1H)，7.57 (dd，1H)，7.97 (d，J=7.46 Hz，1H)， 8.00 (d，J=8.14 Hz，1H)，8.08 (s，2H)，11.14 (br· s，1H)。MS (DCI-NH3) [M+H]+ 307。 實例106 甲基-5-(6-J2-「（2R)-2-甲基-1-吡咯啶某1乙基}-?杏呲Chem. 1988, 119, 253-262) instead of 1- (1,3-orosezol-2-yl) ethanone. NMR (CDC13) δ ppm 1.16 (d, J = 6.10 Hz, 3H), 1.48 (m, 1H), 1.76 (m, 1H), 1.94 (m, 2H), 2.29 (q, J = 8.36 Hz, 1H), 2.44 (m, 2H), 3.02 (m, 2H), 3.22 (m, 1H), 3.38 (m, lH), 7.53 (d, J = 8.48 Hz, 1H), 7.56 (s, 1H), 7.57 (dd, 1H), 7.97 (d, J = 7.46 Hz, 1H), 8.00 (d, J = 8.14 Hz, 1H), 8.08 (s, 2H), 11.14 (br · s , 1H). MS (DCI-NH3) [M + H] + 307. Example 106 Methyl-5- (6-J2-"(2R) -2-methyl-1-pyrrolidine-1ethyl}-?

-2-基）於酿胺 實例106 A 5-乙醯基-2,6-二曱基-1，4-二氪4比啶-3-晴 ' 取含3-胺基巴豆腈（2.0 g，24 mmol)、2,4-戊二酉同（4.9 g， 49 mmol)、多聚甲酸（1.5 g，49 mmol)與六氫p比咬（12滴）之 89248.doc -199- 200418454 乙醇（100 mL)混合物於加熱至回流4小時，冷卻及濃縮至乾 。殘質經乙醚（150 mL)處理。收集固體，以醚洗滌。固體 與二氯甲烷（2 X 100 mL)研磨。合併之二氯甲烷研磨液濃縮 ，產生2·5 g標題化合物。4 NMR (DMSO-d6) δ ppm 1.92 (t， J=1.02 Hz，3 H)，2.09 (s，3H)，2·10 (s，3 H)，3.20 (s，2H)，8.65 (s，1H)。MS (DCI-NH3) [M+H] + 177。2-Alkyl) in amine example 106 A 5-Ethyl-2,6-difluorenyl-1,4-difluorenyl-4bipyridin-3-qing 'Take 3-aminocrotononitrile (2.0 g , 24 mmol), 2,4-pentanepyrazine (4.9 g, 49 mmol), polycarboxylic acid (1.5 g, 49 mmol) and hexahydro p (12 drops) 89284.doc -199- 200418454 ethanol (100 mL) The mixture was heated to reflux for 4 hours, cooled and concentrated to dryness. The residue was treated with ether (150 mL). The solid was collected and washed with ether. The solid was triturated with dichloromethane (2 X 100 mL). The combined dichloromethane triturates were concentrated to give 2.5 g of the title compound. 4 NMR (DMSO-d6) δ ppm 1.92 (t, J = 1.02 Hz, 3 H), 2.09 (s, 3H), 2.10 (s, 3 H), 3.20 (s, 2H), 8.65 (s, 1H). MS (DCI-NH3) [M + H] + 177.

實例106B 一5_-乙醯基-2,6_二甲某菸其鲁 取實例J06A產物（1·〇 g，5.7 mmol)經甲苯（15 mL)處理， 經錳酸鋇（3.0 g，12 mmol)處理，於周溫下攪拌一夜，過滤 。濾液濃縮及層析（依序使用20 : 1與3 : 2己烷··乙酸乙酿） ，產生 0.9 g標題化合物。iH NMR (CDC13) δ ppm 2.60 (s，3 H)， 2.79 (s，3 H)，2·79 (s，3 H)，8·16 (s，1H)。MS (DCI-NH3) [M+H]+ 175。Example 106B 5_-Ethyl-2,6_dimethylamine was extracted from Example J06A (1.0 g, 5.7 mmol) treated with toluene (15 mL) and treated with barium manganate (3.0 g, 12 mmol) ) Treatment, stir overnight at ambient temperature, and filter. The filtrate was concentrated and chromatographed (sequentially using 20: 1 and 3: 2 hexane · ethyl acetate) to yield 0.9 g of the title compound. iH NMR (CDC13) δ ppm 2.60 (s, 3 H), 2.79 (s, 3 H), 2.79 (s, 3 H), 8.16 (s, 1H). MS (DCI-NH3) [M + H] + 175.

實例106C 咯啶某1Λ其卜，杏咻 -2-基g姦脉 標題化合物係依實例57之方法製備，但其中改用5_乙醯 基2’6 —甲基於基氰替代1塞唆-2-基）乙酉同，首先溶離 出實例67產物，其次溶離出標題化合物。1ην廳仰㈤谷 PPm MS ((1,^.43ηζ, 3 H), (m，1Η)，2.2-2.6 (m 3Η) 2 6Wq 7 u、’ - 1，3H)，2·65 (S，3 H)，2.78 (s，3 H)，3.09 (m， 2H), 3.19 (m? 1H) m im c )，3·33 (m，1H)，5·75 (s，1H)，5.90 (s，1H)， 7.52 (d, J=8.48 Hz, IH), 7.66 (dd, J=8.65, 1&lt;8? ^ 1H)? ? ?1 89248.doc -200- 200418454 (s，1H)，7.94 (s，1Η)，8·06 (d，j=8.82 Hz，1H)，8.19 (d，J=8.14Example 106C Pyridine 1 ^ Qi Bu, the title compound of apricotyl-2-yl gmaimai was prepared according to the method of Example 57 except that 5-acetyl 2'6-methyl-methylcyanide was used instead of 1 The same as 2-yl) acetamidine, the product of Example 67 was first isolated, and the title compound was isolated next. 1ην Hall Yang Yangu PPm MS ((1, ^. 43ηζ, 3 H), (m, 1Η), 2.2-2.6 (m 3Η) 2 6Wq 7 u, '-1, 3H), 2.65 (S, 3 H), 2.78 (s, 3 H), 3.09 (m, 2H), 3.19 (m? 1H) m im c), 3.33 (m, 1H), 5.75 (s, 1H), 5.90 ( s, 1H), 7.52 (d, J = 8.48 Hz, IH), 7.66 (dd, J = 8.65, 1 &lt; 8? ^ 1H)??? 1 89248.doc -200- 200418454 (s, 1H), 7.94 (s, 1Η), 8.06 (d, j = 8.82 Hz, 1H), 8.19 (d, J = 8.14

Hz，1H)。MS (DCI-NH3)[M+H]+389 會例107 比哈啶-1-某V乙基6-吡咬-4-某-p套4 標題化合物係依實例5丨之方法製備，但其中改用實例4-叶匕淀基二羥硼酸替代3-吡啶基二羥硼酸。標題化合物經HC1 ’於乙酸乙酯中處理，產生相應之三鹽酸鹽。mp 145_147。〇 (未校正）；MS (ESI) 318 (M+H)+ ; 4 NMR (三鹽酸鹽，CD3〇D， 400 ΜΗζ^) δ 9·12 (1H，m)，9.03 (2H，d)，8.94 (1H，d)，8.65 (2H，d)，8.61 (1H，d)，8.53 (1H，d)，8.12 (1H，d)，4.10 (1H， br)，3.90 (1H，br)，3.80 (1H，br)，3·62 (2H，br*)，3·42 (1H，m)，2.40 (1H，m)，2·3-2·1 (3H，m)，1.82 (1H，br，m)，1.58 (3H，d)。 實例108 K16-甲氧基比咬-3-某V2-「2(R)-（2-甲基叶匕味喊_1·某）一乙 基1-崦啉 標題化合物係依實例5 1之方法製備，但其中改用6-甲氧 基-吡啶-3-基二羥硼酸替代3-吡啶基二羥硼酸。標題化合物 經L-酒石酸，於ΙΡΑ中處理，產生相應之酒石酸鹽。mp 132-134°C (未校正）；MS (ESI) 348 (M+H)+ ;NMR (酒石酸 鹽，DMSO-d6, 400 MHz) δ 8.62 (1Η，d)，8·37 (1Η，d)，8·24 (1H，d)，8·18 (1H，dd)，8.08 (1H，dd)，8·04 (1H，d)，7·52 (1H， d)，6.94 (1H，d)，4.05，3.90 (2H，s)，3·80-3·4 (3H，m)，3.32 (3H，m)，3.04 (ih，q)，2·13 (1H，m)，1.90 (2H，m)，1.60 (1H， m)，1.35，1.03 (3H，d)。 89248.doc -201 - 200418454 f 例 109 风-晚症-3 -基）-2-「2-(2R-甲某-叶匕17各淀-1-基乙基 口奎淋 標題化合物係依實例51之方法製備，但其中改用2,6_二氟 -峨咬-3-基二羥硼酸替代3_吡啶基二羥硼酸。標題化合物經 L-酒石酸，於IPA中處理，產生相應之酒石酸鹽。mp 142-143°C (未校正）；MS (ESI) 354 (M+H)+ ; 4 NMR (酒石酸鹽， DMSO-d6, 400 MHz) δ 8·62 (1H，q)，8.60 (1H，d)，8·21 (1H， s)，8.08 (，1H，d)，7·94 (1H，d)，8.04 (1H，d)，7.59 (1H，d)，7.35 (1H，dd)，4.00 (2H，s)，3.80-3.4 (3H，m)，3·38 (1H，m)，3.25 (2H，m)，2·96 (1H，q)，2.12 (1H，m)，1.89 (2H，m)，1.59 (1H， m)，1.32 (3H，d) 〇 f 例 110 吡啶-3-某V2-f2-(2(Rl二甲基-吡咯啶-1-某V乙基1- 口奎淋 標題化合物係依實例5 1之方法製備，但其中改用2-氣-5-三甲錫烷基-吡啶替代3·吡啶基二羥硼酸。標題化合物經L-酒石酸，於IPA中處理，產生相應之酒石酸鹽。mp 167-1681： (未校正）；MS (ESI) 352 (M+H)+ ; 4 NMR (酒石酸鹽， CD3〇D，400 MHz) δ 8·87 (1H，d)，8·40 (1H，d)，8.05 (1H，d)， 8.02 (1H，dd)，8.13 (1H，d)，8.08 (1H，dd)，7.59 (1H，d)，7.57 (1H，d)，4.40 (2H，s)，4.05 (1H，br，m)，3·78 (1H，br，m)，3.63 (1H，br，m)，3.6-3.4 (3H，m)，3·35 (1H，m)，2.35 (1H，m)，2.14 (2H，m)，1.82 (1H，m)，1.58, 1.15 (3H，d)。 89248.doc -202 200418454 實例111Hz, 1H). MS (DCI-NH3) [M + H] +389 Meeting Example 107 Biharidine-1-A Vethyl 6-pyridine-4-A-P 4 The title compound was prepared according to the method of Example 5 丨, but Wherein, 4-pyridyldihydroxyboric acid was replaced with 4-pyridyldihydroxyboronic acid. The title compound was treated with HC1 'in ethyl acetate to give the corresponding trihydrochloride. mp 145_147. 〇 (uncorrected); MS (ESI) 318 (M + H) +; 4 NMR (trihydrochloride, CD30D, 400 ΜΗζ ^) δ 9 · 12 (1H, m), 9.03 (2H, d) , 8.94 (1H, d), 8.65 (2H, d), 8.61 (1H, d), 8.53 (1H, d), 8.12 (1H, d), 4.10 (1H, br), 3.90 (1H, br), 3.80 (1H, br), 3.62 (2H, br *), 3.42 (1H, m), 2.40 (1H, m), 2.3 · 2 · 1 (3H, m), 1.82 (1H, br, m), 1.58 (3H, d). Example 108 K16-methoxy ratio bite-3-a certain V2- "2 (R)-(2-methyl leaf scent _1 · a certain) monoethyl 1-pyroline The title compound is based on Example 51 It was prepared by the method, but 6-methoxy-pyridin-3-yldihydroxyboronic acid was used instead of 3-pyridyldihydroxyboronic acid. The title compound was treated with L-tartaric acid in IPA to produce the corresponding tartrate salt. Mp 132 -134 ° C (uncorrected); MS (ESI) 348 (M + H) +; NMR (tartrate, DMSO-d6, 400 MHz) δ 8.62 (1Η, d), 8.37 (1Η, d), 8.24 (1H, d), 8.18 (1H, dd), 8.08 (1H, dd), 8.04 (1H, d), 7.52 (1H, d), 6.94 (1H, d), 4.05, 3.90 (2H, s), 3.80-3 · 4 (3H, m), 3.32 (3H, m), 3.04 (ih, q), 2.13 (1H, m), 1.90 (2H, m ), 1.60 (1H, m), 1.35, 1.03 (3H, d). 89248.doc -201-200418454 f Example 109 Wind-late disease-3 -yl) -2- "2- (2R- 甲某-叶) The title compound of 17-yl-1-ylethylkourin was prepared according to the method of Example 51, but 2,6-difluoro-erb-3-yldihydroxyboronic acid was used instead of 3-pyridyldihydroxy Boric acid. The title compound was treated with L-tartaric acid in IPA to produce a phase Tartrate. Mp 142-143 ° C (uncorrected); MS (ESI) 354 (M + H) +; 4 NMR (tartrate, DMSO-d6, 400 MHz) δ 8.62 (1H, q), 8.60 (1H, d), 8.21 (1H, s), 8.08 (, 1H, d), 7.94 (1H, d), 8.04 (1H, d), 7.59 (1H, d), 7.35 (1H , Dd), 4.00 (2H, s), 3.80-3.4 (3H, m), 3.38 (1H, m), 3.25 (2H, m), 2.96 (1H, q), 2.12 (1H, m ), 1.89 (2H, m), 1.59 (1H, m), 1.32 (3H, d) 〇f Example 110 Pyridine-3-some V2-f2- (2 (Rl dimethyl-pyrrolidine-1-some V The title compound of ethyl 1-quinone was prepared according to the method of Example 51, except that 2-gas-5-trimethylstannyl-pyridine was used instead of 3.pyridyldihydroxyboronic acid. The title compound was subjected to L-tartaric acid, Processing in IPA yields the corresponding tartrate. Mp 167-1681: (uncorrected); MS (ESI) 352 (M + H) +; 4 NMR (tartrate, CD3OD, 400 MHz) δ 8.87 (1H, d), 8.40 (1H, d), 8.05 (1H, d), 8.02 (1H, dd), 8.13 (1H, d), 8.08 (1H, dd), 7.59 (1H, d), 7.57 (1H, d), 4.40 (2H, s), 4.05 (1H, br, m), 3.78 (1H, br, m), 3.63 (1H, br, m), 3.6-3.4 (3H, m), 3.35 (1H, m), 2.35 (1H, m), 2.14 (2H, m), 1.82 (1H, m), 1.58, 1.15 (3H, d). 89248.doc -202 200418454 example 111

1 _ p奎琳1 _ p Quilin

標題化合物係依實例5丨之方法製備，但其中改用2 二氯 -吡哫-3-基二羥硼酸替代3_吡啶基二羥硼酸。標題化合物經 HC1，於乙酸乙酯中處理，產生相應之二鹽酸鹽。1〇5_1〇7它 (未校正）；MS (ESI) 386 (Μ+ΗΓ ; iH NMR (二鹽酸鹽， DMSO-d65 400 MHz) δ 8.52 (1H? d)5 8.19 (1H5 s)5 8.15 (1H? d), 8.10 (1H5 d)5 7.94 (1H? dd)5 7.75 (1H5 d)? 7.68 (1H? d)? 3.90 (2H, br, m)，3.66 (1H，br，m)，3.50 (3H，br，m)，3·22 (1H， br, m)52.22(lH? br5 m)?1.96 (2H? br? m)?l.66(1H? br? m)? 1·45 (3H，br，d) 〇 實例112 也哈淀-1-基基卜卜吡哞某—杏4 標題化合物係依實例51之方法製備，但其中改用2_三_第 一 丁基錫k基比畊替代3_ϊτ比咬基二羥酸。Ms 3 (Μ+Η) , Η NMR (CDC135 4Q0 MHz) δ 9.20 (1Η5 d)5 8.70 (1Η5 t)，8.58 (1Η，d)，8·50 (1Η，d)，8.37 (ιη，dd)，8·20 (1Η，d)， 8·19 (1Η，d)，7.43 (1Η，d)，3.4-3.2 (4Η，m)，2.65 (1Η，br，m)， 2.45 (1H，br，m)，2.34 (1H，br，m)，I.95 (1H，br，m)，1·82 (1H， br，m)，1.75 (1H，br，m)，ΐ·5〇 (1H，br，m)，L15 (3H，d)。 實例113 - ~G p各淀-1-基）-乙基 i_6-?密淀-5-某杳口林 柃題化合物係依實例5丨之方法製備，但其中改用5_三-第三 89248.doc -203 - 丁基錫燒基-嘧啶替代3-吡啶基二羥硼酸。標題化合物經HC1The title compound was prepared according to the method of Example 5, except that 2-dichloro-pyridin-3-yldihydroxyboronic acid was used instead of 3-pyridyldihydroxyboronic acid. The title compound was treated with HC1 in ethyl acetate to give the corresponding dihydrochloride. 1〇5_1〇7 it (uncorrected); MS (ESI) 386 (M + (Γ; iH NMR (dihydrochloride, DMSO-d65 400 MHz) δ 8.52 (1H? D) 5 8.19 (1H5 s) 5 8.15 (1H? D), 8.10 (1H5 d) 5 7.94 (1H? Dd) 5 7.75 (1H5 d)? 7.68 (1H? D)? 3.90 (2H, br, m), 3.66 (1H, br, m), 3.50 (3H, br, m), 3.22 (1H, br, m) 52.22 (lH? Br5 m)? 1.96 (2H? Br? M)? 1.66 (1H? Br? M)? 1.45 (3H, br, d) 〇 Example 112 Ye Hadian-1-ylbubpyrazine-apricot 4 The title compound was prepared according to the method of Example 51, but the 2-tri-first butyltin k-group ratio was used instead. Till replace 3_ϊτ than bis-dihydroxy acid. Ms 3 (Μ + Η), Η NMR (CDC135 4Q0 MHz) δ 9.20 (1Η5 d) 5 8.70 (1Η5 t), 8.58 (1Η, d), 8.50 (1Η , D), 8.37 (ιη, dd), 8.20 (1Η, d), 8.19 (1Η, d), 7.43 (1Η, d), 3.4-3.2 (4Η, m), 2.65 (1Η, br , M), 2.45 (1H, br, m), 2.34 (1H, br, m), I.95 (1H, br, m), 1.82 (1H, br, m), 1.75 (1H, br, m), 1.75 (1H, br, m), ΐ · 50 (1H, br, m), L15 (3H, d). Example 113-~ G p each yodo-1-yl) -ethyl i_6-? dense lake -5- some koukoulin The title compound is based on Example 5. The method of preparation, but instead 5_ three - third 89248.doc -203 - butyltin burn-yl - pyrimidine in place of 3-pyridyl glyoxylic acid. Title compound via HC1

’於乙酸乙醋中處理，產生相應之三鹽酸鹽。mp 160-162°C (未校正）；Ms (ESI) 319 (M+H)+ ; 4 NMR (三鹽酸鹽， DMS〇-d6, 400 MHz) δ 9·32 (2H，s)，9.26 (1H，s)，8.70 (1H， d)，8.52 (1H，d)，8·38 (1H，dd)，8.30 (1H，d)，7·82 (1H，d)， 3.92 (1H，m)，3·65 (3H，br，m)，3.50 (2H，br，m)，3.22 (1H，br， m)，2·1〇 (1H，m)，2.00 (2H，br，m)，1.70 (1H，br，m)，1.50 (3H， br，d) o , 實例114 嘧啶-5-某）-2-f2-(2fRV甲其-吡咯啶-1-基） -乙基1 - 口奎?林 標題化合物係依實例51之方法製備，但其中改用2,6-二甲 氧基’啶-5-基二羥硼酸替代3-吡啶基二羥硼酸。MS (ESI) 379 (M+H)+ ; A NMR (CDC13, 400 MHz) δ 8·34 (1H，s)，8·10 (1H，d)，8.07 (1H，d)，7.88 (1H，d)，7·82 (1H，dd)，7·38 (1H， d)，4.06 (3H，s)，4.05 (3H，s)，3.30 (2H，m)，3,22 (2H，m)，2.60 (1H，m)，2·42 (1H，m)，2·30·(1Η，q)，1.95 (1H，^),1.80 (1H， m)，1·72 (1H，m)，1.43 (1H，m)，1·13 (3H，d)。 實例115 士甲基-(4]2」「2-(2(R)-甲基-峨」各咬-1-某)-匕甚杏啉_6-基} -笨基V胺 標題化合物係依實例5 1之方法製備，但其中改用4-二甲墓 胺基苯基二羥硼酸替代3-吡啶基二羥硼酸。標題化合物經L-酒石酸於IPA中處理，產生相應之酒石酸鹽。mp i55-156°c 89248.doc -204- 200418454 (未校正）；MS (ESI) 360 (M+H)+ ; 4 NMR (酒石酸鹽， DMSO-dh 400 MHz) δ 8·30 (1H，d)5 8·ΐ〇 (iH d) 8 02 (1H， dd)，7.95 (1H，d)，7·68 (2H，d)，7.47 (iH，d)，6·83 (2H，d)， 4·00 (2H，s)，3·60 (1H，m)，3.48 (1H，阳)，3 27 (2H m) 3 12 (2H, m)，2·97 (6H，s)，2·82 (1H, m)，2·〇8 (ih，m)，1.83 (2H， m)，1·52 (1H，m)，1.28 (3H，d)。 實例11 6 hiAj_2-『2-(2(R)-甲幕-P比咯淀:丄-基上^基套4 _6_某卜笨 , 某）-乙酮 標題化合物係依實例51之方法製備，但其中改用4_乙醯 基苯基二羥硼酸替代3_吡啶基二羥硼酸。標題化合物經乙_ 酒石酸，於IPA中處理，產生相應之酒石酸鹽。呵瓜丨邮 (未校正）；MS (ESI) 359 (M+H)+; lH nmr (酒石酸鹽， CD3OD, 400 MHz) δ 8.40 (1H, d), 8.24 (1H, s), 8.n (2H, d), 8.09 (2H，m)，7.92 (2H，d)，7.55 (1H，句，4 39 (2H，s)，4 〇i (1H, m), 3.79 (1H, m), 3.63 (1H, m), 3.53 (1H, m),3.50 (2H, m), 3.31(1H, m), 2.64 (3H,. s), 2.38 (lH, m), 2.12(2H, m), 1·82 (1H，m)，1.58 (3H，d)。 實例117 .基）_乙基&quot;l· p奎口林 氯二I 基甲某-毗 ^ 標題化合物係依實例51之方法製備，但其中改用4_氯苯 基二羥硼酸替代3_吡啶基二羥硼酸。標題化合物經Η。，於 乙酸乙酉曰中處理，產生相應之二鹽酸鹽。mp 154-155。(：（未 杈正）；MS (ESI) 351 (M+H)+ ; 4 NMR (二鹽酸鹽，DMSO-d6, B9248.doc - 205 - 200418454 400 MHz) δ 8·70 (1H，d)，8·43 (1H，s)，8·27 (2H，s)，7.90 (2H， d)，7·81 (1H，d)，7.60 (2H，d)，3.90 (1H，br，m)，3·63 (3H，br， m)，3.50 (2H，br，m)，3·23 (1H，br，m)，2.20 (1H，s)，2·00 (2H， m)，1.68 (1H，m)，1.42 (3H，br，d)。 118 -二咬·3_某2_f2」：2(RV甲某-吡咯畦_ ；[-甚v乙 盖口奎琳 標題化合物係依實例51之方法製備，但其中改用2,6_二甲 基-3-(4,气5,5-四甲基_Π，3,2]二氧硼戊環-2_基）_吡啶替代弘 吡哫基二羥硼酸。標題化合物經HC1，於乙酸乙酯中處理 ，產生相應之三鹽酸鹽。mp 176-177°C(未校正）；MS (ESI) 346 (M+H)+ ;巾 nmr (三鹽酸鹽，CD3〇D，4〇〇 μηζ) δ 9·〇8 (1Η，d)，8·46 (2Η，d)，8·42 (1Η，d)，8·18 (1Η，dd)，8·14 (1Η， d)，7.89 (1H，d)，4,〇8 (1H，m)，3.90 (1H，m)，3·82 (2H，m)， 3^65 (2H, br9 m)? 3.42 (1H5 m)5 2.87 (3H5 s)? 2.75 (3H? s)? 2.39 (1H，m)，2.18 (2H，br，m)5 1·83 (1H，br，m)，L58 (3H，d)。 實例119 基}2-[~2-(2(R)二^ 基-吡咯啶-^ v &amp; 基奎口株 桉越化合物係依實例5 1之方法製備，但其中改用弘甲氧 基-5-(4,4,5,5-四甲基二氧硼戊環-2-基）__吡啶替代3_ 吡哫基一羥硼酸。Ms (ESI)348 (m+h)、巾 (CDC13, 40〇 MHz) δ 8.57 (1H，s)，8.34 (1H，d)，8·12 (2H，d)，7.96 (1H，d)， 7.90 (1H5 dd)5 7.48 (1H? dd)? 7.40 (1H5 d)? 3.95 (3H? s)5 3.76, 89248.doc - 206 - 200418454 3.63 (1H, m), 3.4.3 2 (3H, m), 2.64 (1H, m), 2.45 (lH, m), 2.32 (m，q)，i.95 (m，m)，丨 82 (m，的，丨 73 ⑽，叫^ ^ (1H，m)，1.15 (3H，d)。 ’ 實例12^ 一6，（3,5-二曱圣-η 標題化合物係依實例51之方法製備，但其中改用3，％二甲 基-異吟唑-4-基二羥硼酸替代3_吡啶基二羥硼酸。標題化合 物經HC1，，於乙酸乙醋中處理，產生相應之三鹽酸鹽。叫 174-175t：(未校正）；MS (ESI) 336 (M+H)+ ; 4 NMR (三鹽酸 DMSO-d65 400 MHz) δ 8.72 (1H, d)? 8.30 (1H? d)? 8.18 (1H，d)，7·97 (1H，dd)，7·83 (1H，d)，3.90 (1H，br，m)，3·65 (2H，br，m)，3.52 (2H，br，m)，3·23 (1H，br，m)，2.50 (3H，s)， 2·32 (3H，s)，2·20 (2H，br，m)，2.00 (2H，br，m)，1·70 (1H，br， m)，1 ·45 (3H，br，d)。 實例121 -~「2-(2(R) -甲某-p?比p各症-i-基乙某杳啦_6_基}_笨甲酸 甲酉旨 標題化合物係依實例5 1之方法製備，但其中改用‘甲氧羰 基冬基一輕酸替代3-p比淀基二藉硼酸。標題化合物經HC1 ，於乙酸乙酯中處理，產生相應之二鹽酸鹽。mp 172_174。〇 (未校正）；MS (ESI) 375 (M+H)+ ; NMR (二鹽酸鹽_， DMS〇-d6，400 MHz) δ 8.86 (1H，d)，8·60 (1H，s)，8·39 (2H， s)，8.12 (2H，d)，8.04 (2H，d)，7·95 (1H，d)，3.95 (1H，br，m)， 89248.doc -207 - 200418454 3·90 (3H，s)，3.70 (2H，br，m)，3.52 (2H，br，m)，3.24 (1H，br， m)，2.20 (2H，m)，2.00 (2H，br，m)，1·68 (1H，br，m)，1.45 (3H，br，d)。 122'Treated in ethyl acetate to produce the corresponding trihydrochloride. mp 160-162 ° C (uncorrected); Ms (ESI) 319 (M + H) +; 4 NMR (trihydrochloride, DMS〇-d6, 400 MHz) δ 9.32 (2H, s), 9.26 (1H, s), 8.70 (1H, d), 8.52 (1H, d), 8.38 (1H, dd), 8.30 (1H, d), 7.82 (1H, d), 3.92 (1H, m ), 3.65 (3H, br, m), 3.50 (2H, br, m), 3.22 (1H, br, m), 2.10 (1H, m), 2.00 (2H, br, m), 1.70 (1H, br, m), 1.50 (3H, br, d) o, Example 114 Pyrimidine-5-a) -2-f2- (2fRVmethyl-pyrrolidin-1-yl) -ethyl 1- The quinolin title compound was prepared according to the method of Example 51, but 2,6-dimethoxy'pyridin-5-yldihydroxyboronic acid was used instead of 3-pyridyldihydroxyboronic acid. MS (ESI) 379 (M + H) +; A NMR (CDC13, 400 MHz) δ 8.34 (1H, s), 8.10 (1H, d), 8.07 (1H, d), 7.88 (1H, d), 7.82 (1H, dd), 7.38 (1H, d), 4.06 (3H, s), 4.05 (3H, s), 3.30 (2H, m), 3, 22 (2H, m) , 2.60 (1H, m), 2.42 (1H, m), 2.30 · (1Η, q), 1.95 (1H, ^), 1.80 (1H, m), 1.72 (1H, m), 1.43 (1H, m), 1.13 (3H, d). Example 115: S-methyl- (4) 2 "," 2- (2 (R) -methyl-E ", each bite-1-a) -doxetrin-6-yl} -benzyl Vamine title compound system It was prepared according to the method of Example 51, but 4-dimethylpyridylphenyldihydroxyboronic acid was used instead of 3-pyridyldihydroxyboronic acid. The title compound was treated with L-tartaric acid in IPA to generate the corresponding tartrate salt. mp i55-156 ° c 89248.doc -204- 200418454 (uncorrected); MS (ESI) 360 (M + H) +; 4 NMR (tartrate, DMSO-dh 400 MHz) δ 8 · 30 (1H, d ) 5 8 · ΐ〇 (iH d) 8 02 (1H, dd), 7.95 (1H, d), 7.68 (2H, d), 7.47 (iH, d), 6.83 (2H, d), 4 · 00 (2H, s), 3.60 (1H, m), 3.48 (1H, yang), 3 27 (2H m) 3 12 (2H, m), 2.97 (6H, s), 2 · 82 (1H, m), 2.08 (ih, m), 1.83 (2H, m), 1.52 (1H, m), 1.28 (3H, d). Example 11 6 hiAj_2- 『2- (2 (R) -formal-P-pyrrolidone: fluorene-based on base group 4 _6_ certain buben,)-the title compound of ethyl ketone was prepared according to the method of Example 51, but 4_ethyl fluorenyl group was used instead Phenyldihydroxyboric acid replaces 3-pyridyldihydroxyboric acid. The title compound is treated with ethyl tartrate in IPA to produce The corresponding tartrate salt was produced. Posts (uncorrected); MS (ESI) 359 (M + H) +; lH nmr (tartrate, CD3OD, 400 MHz) δ 8.40 (1H, d), 8.24 (1H, s), 8.n (2H, d), 8.09 (2H, m), 7.92 (2H, d), 7.55 (1H, sentence, 4 39 (2H, s), 4 〇i (1H, m), 3.79 (1H, m), 3.63 (1H, m), 3.53 (1H, m), 3.50 (2H, m), 3.31 (1H, m), 2.64 (3H ,. s), 2.38 (lH, m), 2.12 (2H, m), 1.82 (1H, m), 1.58 (3H, d). Example 117. Ethyl) _ethyl &quot; l.p. Kuikoulin chlorodi I methyl a-pyrimidine title compound system Prepared according to the method of Example 51, except that 4-chlorophenyldihydroxyboronic acid was used instead of 3-pyridyldihydroxyboronic acid. The title compound was treated with hydrazone, and treated with ethyl acetate to give the corresponding dihydrochloride. Mp 154-155. (: (Uncorrected); MS (ESI) 351 (M + H) +; 4 NMR (dihydrochloride, DMSO-d6, B9248.doc-205-200418454 400 MHz) δ 8 · 70 (1H, d ), 8.43 (1H, s), 8.27 (2H, s), 7.90 (2H, d), 7.81 (1H, d), 7.60 (2H, d), 3.90 (1H, br, m ), 3.63 (3H, br, m), 3.50 (2H, br, m), 3.23 (1H, br, m), 2.20 (1H, s), 2.00 (2H, m), 1.68 (1H, m), 1.42 (3H, br, d). 118-Two bite 3_some 2_f2 ": 2 (RV A some-pyrrolidine _ ;; [-vv. E. caperium quinine The title compound is based on an example. 51 method, but in which 2,6_dimethyl-3- (4, Ga5,5-tetramethyl_Π, 3,2] dioxoborolan-2-yl) _pyridine was used instead Dipyridyl dihydroxyborate. The title compound was treated with HC1 in ethyl acetate to produce the corresponding trihydrochloride salt. Mp 176-177 ° C (uncorrected); MS (ESI) 346 (M + H) + ; Nmr (trihydrochloride, CD3OD, 400μηζ) δ 9.08 (1Η, d), 8.46 (2Η, d), 8.42 (1Η, d), 8.18 (1Η, dd), 8.14 (1Η, d), 7.89 (1H, d), 4,08 (1H, m), 3.90 (1H, m), 3.82 (2H, m), 3 ^ 65 (2H, br9 m)? 3.42 (1H5 m) 5 2.87 (3H5 s)? 2.75 (3H? s)? 2.39 (1H, m), 2.18 (2H, br, m) 5 1.83 (1H, br, m), L58 (3H, d). Example 119 Group} 2- [~ 2- (2 (R) di ^ -pyrrolidine- ^ v &amp; Jikuikou strain Eucalyptus compound was prepared according to the method of Example 51, but the methoxy group was used instead. -5- (4,4,5,5-tetramethyldioxoborolan-2-yl) __pyridine instead of 3_pyridinyl monohydroxyboronic acid. Ms (ESI) 348 (m + h), towel ( CDC13, 40〇MHz) δ 8.57 (1H, s), 8.34 (1H, d), 8.12 (2H, d), 7.96 (1H, d), 7.90 (1H5 dd) 5 7.48 (1H? Dd)? 7.40 (1H5 d)? 3.95 (3H? S) 5 3.76, 89248.doc-206-200418454 3.63 (1H, m), 3.4.3 2 (3H, m), 2.64 (1H, m), 2.45 (lH, m), 2.32 (m, q), i.95 (m, m), 82 (m, of, 73), called ^ (1H, m), 1.15 (3H, d). '' Example 12 ^ -6, (3,5-Dioxan-η-Title The title compound was prepared according to the method of Example 51, but 3,% dimethyl-isoindazol-4-yldihydroxyboronic acid was used instead of 3 _Pyridyldihydroxyboric acid. The title compound is treated with HC1 in ethyl acetate to produce the corresponding trihydrochloride. Called 174-175t: (uncorrected); MS (ESI) 336 (M + H) +; 4 NMR (DMSO-d65 400 MHz trihydrochloride) δ 8.72 (1H, d)? 8.30 (1H? D)? 8.18 (1H, d), 7.97 (1H, dd), 7.83 (1H, d) , 3.90 (1H, br, m), 3.65 (2H, br, m), 3.52 (2H, br, m), 3.23 (1H, br, m), 2.50 (3H, s), 2 · 32 (3H, s), 2.20 (2H, br, m), 2.00 (2H, br, m), 1.70 (1H, br, m), 1.45 (3H, br, d). Examples 121-~ "2- (2 (R) -methyl-p? Than p-symptoms-i-yl-ethyl-m-do-6-yl} _methaneformate, title compound was prepared according to the method of Example 51 However, instead of using 3-methoxypyridyl mono-light acid instead of 3-p than dianidyl diboronic acid. The title compound was treated with HC1 in ethyl acetate to produce the corresponding dihydrochloride. Mp 172_174. (Uncorrected); MS (ESI) 375 (M + H) +; NM R (dihydrochloride_, DMS0-d6, 400 MHz) δ 8.86 (1H, d), 8.60 (1H, s), 8.39 (2H, s), 8.12 (2H, d), 8.04 (2H, d), 7.95 (1H, d), 3.95 (1H, br, m), 89248.doc -207-200418454 3.90 (3H, s), 3.70 (2H, br, m), 3.52 (2H, br, m), 3.24 (1H, br, m), 2.20 (2H, m), 2.00 (2H, br, m), 1.68 (1H, br, m), 1.45 (3H, br, d). 122

甲基-吡咯畦-1-某V乙基1-6-(4-甲硫烷某-笨基V P奎17林 標題化合物係依實例5 1之方法製備，但其中改用4-甲硫 烷基苯基二羥硼酸替代3-吡啶基二羥硼酸。標題化合物經HC1 ，於乙良乙酯中處理，產生相應之二鹽酸鹽Methyl-pyrrolidin-1-one Vethyl 1-6- (4-methylsulfane, m-benzyl VP, and quinine 17 The title compound was prepared according to the method in Example 51, but 4-methylsulfane was used instead Phenyldihydroxyboronic acid replaces 3-pyridyldihydroxyboronic acid. The title compound is treated with HC1 in ethyl ethyl acetate to produce the corresponding dihydrochloride salt.

0 mp 158 -159〇C (未校正）；MS (ESI) 363 (M+H)+; 4 NMR (二鹽酸鹽， DMSO-d6, 400 MHz) δ 8.79 (1H，d)，8·43 (1H，s)，8.31 (2H， br，s)，7.88 (1H，d)，8.02 (2H，d)，7.43 (2H，d)，3.95 (1H，br， m)，3.67 (2H，br，m)，3·50 (3H，br，m)，3·23 (1H，br，m)，2.53 (3H，s)，2·20 (1H，m)，2.00 (2H，br，m)，1.68 (1H，br，m)，1.45 (3H，bi*，d) 〇 實例123 Θ二基）甲基-吡咯啶-〗_其）-乙基I—奎啉 標題化合物係依實例5丨之方法製備，但其中改用氟 -5-(4,4,5,5-四甲基-[H2]二氧硼戊環_2_基）_吡啶替代3_吡 症基一 1硼酸。標題化合物經hc 1，於乙酸乙酯中處理， 產生相應之三鹽酸鹽。mp 162]63t (未校正）；MS (ESI) 336 (M+H)，HNMR (二鹽酸鹽，DMS〇-d6,4〇〇MHz)S 8 93 (1H， d)，8.77 (1H，d)，8·58 (1H，d)5 8.50 (1H，td)，8·40 (2H，m)， 7·96 (1H，d)，7.40 (1H，dd)，3·95 (1H，br，m)，3·71 (2H，br， 89248.doc -208 - 200418454 m)，3·52 (2H，br，m)，3·24 (1H，br，m)，3.05 (1H，m)，2.20 (1H， m), 2·00 (2H, br, m), 1.68 (1H，br，m)，1.45 (3H，br，d)。 f例12生 5-{2-「2-(2 (RH.基-吡咯喊二乙基-4啉-6-基1-菸某t 標題化合物係依實例5 1之方法製備，但其中改用夂 (4,4,5,5-四甲基-[1，3,2]二氧硼戊環_2_基）_菸基氰替代3_吡 啶基二羥硼酸。標題化合物經L-酒石酸，於IPA中處理，產 生相應之酒石酸鹽。mp 10〇-l〇2t ; MS (ESI) 343 (M+H)+ ; 4 NMR (；酒石酸鹽，DMSO-d6, 400 MHz) δ 9·36 (1H，d)，9.05 (1H，d)，8.81 (1H，dd)，8.49 (1H，d)，8·37 (1H，d)，8·20 (1H， dd)，8.09 (1H，d)，7·59 (1H，d)，4.04 (2H，s)，3.65 (1H，m)， 3.49 (1H，m)，3·36 (2H，m)，3.17 (2H，m)，2·89 (1H，m)，2.09 (1H，m)，1·88 (2H，br，m)，1.56 (1H，br，m)，1.28, 1·05 (3H，d)。 實例125 2,4-二甲氣基- 5- {6-「2-((2R) -甲某-p比哈攻-i-基乙基i_莫_^二0 mp 158 -159 ° C (uncorrected); MS (ESI) 363 (M + H) +; 4 NMR (dihydrochloride, DMSO-d6, 400 MHz) δ 8.79 (1H, d), 8.43 (1H, s), 8.31 (2H, br, s), 7.88 (1H, d), 8.02 (2H, d), 7.43 (2H, d), 3.95 (1H, br, m), 3.67 (2H, br , M), 3.50 (3H, br, m), 3.23 (1H, br, m), 2.53 (3H, s), 2.20 (1H, m), 2.00 (2H, br, m) , 1.68 (1H, br, m), 1.45 (3H, bi *, d). Example 123 Θ diyl) methyl-pyrrolidine-_ its)-ethyl I-quinoline The title compound is according to Example 5 丨It was prepared by the method described above, but it was replaced by fluoro-5- (4,4,5,5-tetramethyl- [H2] dioxoborolan-2-yl) _pyridine instead of 3-pyridyl-1boronic acid. The title compound was treated with hc 1 in ethyl acetate to give the corresponding trihydrochloride. mp 162] 63t (uncorrected); MS (ESI) 336 (M + H), HNMR (dihydrochloride, DMS 0-d6, 400 MHz) S 8 93 (1H, d), 8.77 (1H, d), 8.58 (1H, d) 5 8.50 (1H, td), 8.40 (2H, m), 7.96 (1H, d), 7.40 (1H, dd), 3.95 (1H, br, m), 3.71 (2H, br, 89248.doc -208-200418454 m), 3.52 (2H, br, m), 3.24 (1H, br, m), 3.05 (1H, m ), 2.20 (1H, m), 2.00 (2H, br, m), 1.68 (1H, br, m), 1.45 (3H, br, d). Example 12: 5- {2- "2- (2 (RH.yl-pyrrolidinediethyl-4line-6-yl1-tyanyl) The title compound was prepared according to the method of Example 51, but the modification was Replace 3_pyridyldihydroxyboronic acid with fluorene (4,4,5,5-tetramethyl- [1,3,2] dioxopentyl-2-yl) _nicotinyl cyanide. The title compound is Tartaric acid, treated in IPA to produce the corresponding tartrate. Mp 100-102t; MS (ESI) 343 (M + H) +; 4 NMR (; tartrate, DMSO-d6, 400 MHz) δ 9 · 36 (1H, d), 9.05 (1H, d), 8.81 (1H, dd), 8.49 (1H, d), 8.37 (1H, d), 8.20 (1H, dd), 8.09 (1H, d), 7.59 (1H, d), 4.04 (2H, s), 3.65 (1H, m), 3.49 (1H, m), 3.36 (2H, m), 3.17 (2H, m), 2 89 (1H, m), 2.09 (1H, m), 1.88 (2H, br, m), 1.56 (1H, br, m), 1.28, 1.05 (3H, d). Example 125 2, 4-Dimethylamino- 5- {6- "2-((2R) -methyl-p-bihaden-i-ylethyl i_ 莫 _ ^ 二

基} - p密哈 實例125 A 2-「6-(2,4-二甲氧基-嘧啶-5-某）-塞-2·基-乙醇 取含實例1E產物（.1020 g，0.41 mmol)、2,4-二甲氧基嘧 啶-5-基-二羥硼酸（.0920 g，0.50 mmol)、二氯雙（三苯基膦）_ 鈀（11)(.0096 g，0.014 mmol)與 K3P〇4_H2〇之異丙醇（5 mL)與 水（2 mL)混合物於65°C下攪拌2小時。反應混合物冷卻至室 溫後，減壓濃縮。殘質分溶於鹽水與乙酸乙酯之間。水層 經乙酸乙酯洗滌，合併之有機萃液脫水（硫酸鎂），過濾。滤 89248.doc -209 - 200418454} -P Miha Example 125 A 2- "6- (2,4-dimethoxy-pyrimidine-5-some) -Sep-2 · yl-ethanol Take the product of Example 1E (.1020 g, 0.41 mmol ), 2,4-dimethoxypyrimidin-5-yl-dihydroxyboronic acid (.0920 g, 0.50 mmol), dichlorobis (triphenylphosphine) _palladium (11) (.0096 g, 0.014 mmol) A mixture of isopropanol (5 mL) and water (2 mL) with K3P〇4_H2〇 was stirred at 65 ° C for 2 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. The residue was dissolved in brine and ethyl acetate. Between the esters. The aqueous layer was washed with ethyl acetate, and the combined organic extracts were dehydrated (magnesium sulfate) and filtered. Filtered 89248.doc -209-200418454

液減壓液縮’殘質經管柱層析法純化（7 ·· 3己烷/乙酸乙酯） 。取含產物之溶離份合併，產生（〇〇376 g，收率3〇%)。lH NMR (CDC13, 300 MHz) δ 8·37 (s，1H)，7.95 (s，1Η)，7·86-7.82 (d，J:6 Ηζ，2Η)，7.71 (s，1Η)，7.64-7.59 (d，J=9 Ηζ，1Η)， 7.46-7.6 (s，J=9Hz，1Η)，4.08 (s，3Η)，4·06 (s，3Η)5 3.89-3.84 (t，J二7.5 Ηζ，2Η)，3.30-2.98 (t，J=7.5Hz，2Η)。MS (DCI-NH3) [M+H]+ 311。The residue under reduced pressure and reduced pressure was purified by column chromatography (7 ·· 3 hexane / ethyl acetate). The product-containing fractions were combined and produced (00376 g, yield 30%). lH NMR (CDC13, 300 MHz) δ 8.37 (s, 1H), 7.95 (s, 1Η), 7.86-7.82 (d, J: 6 Ηζ, 2Η), 7.71 (s, 1Η), 7.64- 7.59 (d, J = 9 Ηζ, 1Η), 7.46-7.6 (s, J = 9Hz, 1Η), 4.08 (s, 3Η), 4.06 (s, 3Η) 5 3.89-3.84 (t, J 7.5 Ηζ, 2Η), 3.30-2.98 (t, J = 7.5Hz, 2Η). MS (DCI-NH3) [M + H] + 311.

實例125B ΐ-磺酿甲氧基-嘧啶乙酯 孩化合物係依實例3B之方法製備，但其中改用2_[6_(2,4_ 二甲氧基-嘧啶-5-基）-莕-2-基]乙醇替代丨-p-[心(2-羥乙基) -2-奈基]苯基}乙酮（39mg，收率 84%)。1hnMr(CD3〇d，3〇〇 MHz) δ 8.38 (s，1H)，7.98 (s，1H)，7.9-7.86 (d，J=9 Hz，2H)， 7·7 (s，1H)，7.66-7.61 (d，J=6 Hz，1H)，7.49-7.44 (d，J=6 Hz， 1H)，4·57-4·52 (t，J=7.5 Hz，2H)，4.08 (s，3H)，4.06 (s，3H)， 3.27-3.19 (t，J = 7.5 Hz，2H)。MS (DCI-NH3)[M+H]+ 389。Example 125B The hydrazone-sulfonyl-methoxy-pyrimidine ethyl ester compound was prepared according to the method of Example 3B, but 2_ [6_ (2,4_ dimethoxy-pyrimidin-5-yl)-）-2- was used instead. Propyl] ethanol replaced 丨 -p- [cardi (2-hydroxyethyl) -2-naphthyl] phenyl} ethyl ketone (39 mg, yield 84%). 1hnMr (CD3Od, 300MHz) δ 8.38 (s, 1H), 7.98 (s, 1H), 7.9-7.86 (d, J = 9 Hz, 2H), 7.7 (s, 1H), 7.66 -7.61 (d, J = 6 Hz, 1H), 7.49-7.44 (d, J = 6 Hz, 1H), 4.57-4 · 52 (t, J = 7.5 Hz, 2H), 4.08 (s, 3H ), 4.06 (s, 3H), 3.27-3.19 (t, J = 7.5 Hz, 2H). MS (DCI-NH3) [M + H] + 389.

實例125C n-二甲氧某甲基二吡咯啶小某八λ基m 基} - 口密症 標題化合物係依實例3C之方法製備，但其中改用甲磺酸Example 125C n-Dimethoxymethylenedipyrrolidine, small octa λ group m group}-Oral tightness The title compound was prepared according to the method of Example 3C, but methanesulfonic acid was used instead.

2-[6-(2,4-二甲氧基_嘧啶-5_基）-莕_2_基]_乙酯替代甲磺酸 2-[6-(3-乙醯基苯基）_2-莕基]乙酯（〇 〇〇63 g，收率14%)。rH NMR (CD3OD，300 MHz) δ 8.38 (s，1Η)，7·98 (s，1Η)， 7·9-7·86 (d，J=9 Ηζ，2Η)，7·7 (s，1Η)，7.66-7.61 (d，J=6 Ηζ， 89248.doc -210- 200418454 1H)，7.49-7.44 (d，J=6 Ηζ，1Η)，4·08 (s，3H)，4·〇6 (s，3H)， 3,18-3.11 (m，2H)，3·09-2·96 (m，2H)，2.51-2.4 (m，2H)， 2.39-2.31 (m，1H)，2.10-1.91 (m，1H)，1.89-1.76 (m，2H)， 1.55-1.4 (m，1H)，1.15 (d，J=6 Hz，3H)〇 MS (DCI-NH3)[M+h] + 378 ° 實例126 16-二氟-3-{6-「2-fi2RV2-甲基 比咯啶 _ 1 -基）：1^_^1-莫 _2-基}2- [6- (2,4-dimethoxy_pyrimidin-5_yl) -fluoren-2-yl] _ethyl ester instead of methanesulfonic acid 2- [6- (3-ethylfluorenylphenyl) _2 -Fluorenyl] ethyl ester (0.0003 g, yield 14%). rH NMR (CD3OD, 300 MHz) δ 8.38 (s, 1Η), 7.98 (s, 1Η), 7.9-7 · 86 (d, J = 9 Ηζ, 2Η), 7.7 (s, 1Η ), 7.66-7.61 (d, J = 6 Ηζ, 89248.doc -210- 200418454 1H), 7.49-7.44 (d, J = 6 Ηζ, 1Η), 4.08 (s, 3H), 4.06 (s, 3H), 3,18-3.11 (m, 2H), 3.09-2 · 96 (m, 2H), 2.51-2.4 (m, 2H), 2.39-2.31 (m, 1H), 2.10- 1.91 (m, 1H), 1.89-1.76 (m, 2H), 1.55-1.4 (m, 1H), 1.15 (d, J = 6 Hz, 3H) .MS (DCI-NH3) [M + h] + 378 ° Example 126 16-difluoro-3- {6- "2-fi2RV2-methylpyrrolidin-1-yl): 1 ^ _ ^ 1-mo_2-yl}

膏例126 A 116-(2,6-二氧-毗啶-3-基茶-2-某 1-Λ 醉 該化合物係依實例125Α之方法製備，但其中改用2,6-二 氟吡啶-3-基-二羥硼酸替代2,4-二甲氧基嘧啶-5-基-二羥硼 酸（23 mg，收率 20%)。4 NMR (CD3OD，300 ΜΗζ) δ 8.32-8.25 (m，1Η)，8.04，（s，1Η)，7.91-7.87 (m，2Η)，7.74，（s，1Η)， 7.67-7.62 (d，J=6 Hz，1H)，7.48-7.45 (d，J=6.6 Hz，1H)， 7.15-7.1 (d5 J=5.4 Hz5 1H)9 3.92-3.85 (t5 J=6 Hz, 2H)? 3.06- 2.99 (t，J=6 Hz，2H)。MS (DCI-NH3)[M+H]+ 286。Paste Example 126 A 116- (2,6-dioxo-pyridin-3-yl tea-2-a 1-Λ) This compound was prepared according to the method of Example 125A, but 2,6-difluoropyridine was used instead. -3-yl-dihydroxyboronic acid replaces 2,4-dimethoxypyrimidin-5-yl-dihydroxyboronic acid (23 mg, yield 20%). 4 NMR (CD3OD, 300 ΜΗζ) δ 8.32-8.25 (m , 1Η), 8.04, (s, 1Η), 7.91-7.87 (m, 2Η), 7.74, (s, 1Η), 7.67-7.62 (d, J = 6 Hz, 1H), 7.48-7.45 (d, J = 6.6 Hz, 1H), 7.15-7.1 (d5 J = 5.4 Hz5 1H) 9 3.92-3.85 (t5 J = 6 Hz, 2H)? 3.06- 2.99 (t, J = 6 Hz, 2H). MS (DCI- NH3) [M + H] + 286.

實例126B 二氟-吡啶-3-基）-茬-2-某 酯 該化合物係依實例3Β之方法製備，但其中改用2-[6-(2,6-二氟^比淀+基）-苯-2-基]-乙醇替代1-{3-[6-(2-羥乙基）-2-茶基]苯基}乙酮（24 mg，收率82%)。4 NMR (CD3〇D，300 MHz) δ 8.34,8·25 (m，1H)，8.05 (s，1H)，7·97-7·9 (m，2H)， 7.82 (s5 1H)5 7.72-7.67 (d5 J=6Hz5 1H)? 7.54-7.48 (d5 J=7.8 89248.doc -211 - 200418454Example 126B difluoro-pyridin-3-yl) -stub-2-an ester This compound was prepared according to the method of Example 3B, but in which 2- [6- (2,6-difluoro ^ pyridine + yl) -Benz-2-yl] -ethanol replaced 1- {3- [6- (2-hydroxyethyl) -2-theyl] phenyl} ethyl ketone (24 mg, yield 82%). 4 NMR (CD3OD, 300 MHz) δ 8.34, 8.25 (m, 1H), 8.05 (s, 1H), 7.97-7 · 9 (m, 2H), 7.82 (s5 1H) 5 7.72- 7.67 (d5 J = 6Hz5 1H)? 7.54-7.48 (d5 J = 7.8 89248.doc -211-200418454

Hz, 1H)5 7.17^7. π (d? J=6 Hz5 1H), 4.57-4.52 (t, J^6 Hz5 2H)? 4.15 4·06 (t，J：&quot;6 Hz，2H)，2·94 (s，3H)。MS (DCI-NH3) [M+NH4]+ 381 〇 實例126£ 2，6 氣-3 R) : ? _ f i^ i _ 某）_ 乙某卜萁 _ 2 _ 某} _ 17比咬— 祆過化口物係依實例3C之方法製備，但其中改用甲磺酸 2 [6 (2,6- 一氟·吡啶基）_萘·2_基]_乙酯替代甲磺酸 2-[6-(3-Q 醯基笨基）莕基]乙酯。1h nmr(cD3〇d，3〇〇 MHz) δ 8·34·8·25 (m，1H)，8.05 (s，1Η)，7·97_7·9 (m，2H)， 7.82 (s5 1H)? 7.72-7.67 (d5 J=6 Hz5 1H)) 7.54-7.48 (d5 J-7.8Hz, 1H) 5 7.17 ^ 7. Π (d? J = 6 Hz5 1H), 4.57-4.52 (t, J ^ 6 Hz5 2H)? 4.15 4 · 06 (t, J: &quot; 6 Hz, 2H), 2.94 (s, 3H). MS (DCI-NH3) [M + NH4] + 381 〇 Example 126 £ 2, 6 gas-3 R):? _ Fi ^ i _ Some) _ Yimou Bu _ 2 _ Some} _ 17 than bite — 祆The chemical compound was prepared according to the method of Example 3C, but the methanesulfonic acid 2 [6 (2,6-monofluoro · pyridyl) _naphthalene · 2_yl] _ethyl ester was used instead of the methanesulfonic acid 2- [ 6- (3-Q fluorenylbenzyl) fluorenyl] ethyl ester. 1h nmr (cD3〇d, 300MHz) δ 8.34 · 8 · 25 (m, 1H), 8.05 (s, 1Η), 7.97_7 · 9 (m, 2H), 7.82 (s5 1H)? 7.72-7.67 (d5 J = 6 Hz5 1H)) 7.54-7.48 (d5 J-7.8

Hz，1H)，7.17-7.Π (d，J=6 Hz，1H)，3.18-3.11 (m，2H)， 3.09- 2.96 (m，2H)，2·51-2·4 (m，2H)，2.39-2.31 (m，1H)， 2.10- 1.91 (m，lH)，1.89-1.76 (m，2H)，1.55-1.4 (m，1H)，1.15 (d，J=6 Hz，3H)。MS (DCI-NH3)[M+H]+ 353。 實例127 環..孜基-(3-」6-「2-((21〇2-甲基-吡咯啶-1-某v乙某1-:-2-基}Hz, 1H), 7.17-7.Π (d, J = 6 Hz, 1H), 3.18-3.11 (m, 2H), 3.09- 2.96 (m, 2H), 2.5 · 1-2 · 4 (m, 2H ), 2.39-2.31 (m, 1H), 2.10- 1.91 (m, 1H), 1.89-1.76 (m, 2H), 1.55-1.4 (m, 1H), 1.15 (d, J = 6 Hz, 3H). MS (DCI-NH3) [M + H] + 353. Example 127 Ring: Zinyl- (3-'' 6-``2-((21〇2-methyl-pyrrolidine-1-some v ethyl 1-:-2-yl)

-苯基甲酮 實例127 A (3-溴-笨基環丙基-甲酮 取含 1-(3-溴-苯基）-4-氯-1-氧代-丁烷（1.0 g，3·82 mmol) 與1·〇 Μ雙（三甲矽烷基）胺化鈉（4.21 mL，4.21 mmol，1·1當 量）之甲苯（1〇 mL)混合物於室溫下攪拌3小時。反應混合物減 壓濃縮，殘質分溶於乙酸乙酯與鹽水之間。有機層脫水（硫酸 89248.doc -212- 200418454 鎂），過濾。濾液減壓濃縮，殘質經管柱層析法純化（98 : 2 己垸/乙酸乙酷），產生標題中間物（〇·53 g，收率62%)。4 NMR (CDC13?300 MHz) δ 8.14 (t, J=1.7 Hz, 1H) 7.95-7.92 (m，1H)，7.71-7.67 (m，1H)，7.36 (t，J=7.8 Hz，1Η)，2·66-2·58 (m，1H), 1.29-1.24 (m，2H)，1·11-1·05 (m，2H)。MS (DCI-NH3) [M+H]十 225。-Phenylmethanone Example 127 A (3-Bromo-benzylcyclopropyl-methanone containing 1- (3-bromo-phenyl) -4-chloro-1-oxo-butane (1.0 g, 3 82 mmol) and a toluene (10 mL) mixture of 1.0 M sodium bis (trimethylsilyl) amine (4.21 mL, 4.21 mmol, 1.1 equivalents) was stirred at room temperature for 3 hours. The reaction mixture was decompressed It was concentrated, and the residue was dissolved in ethyl acetate and brine. The organic layer was dehydrated (89248.doc -212- 200418454 magnesium sulfate) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (98: 2垸 / ethyl acetate) to give the title intermediate (0.53 g, yield 62%). 4 NMR (CDC13-300 MHz) δ 8.14 (t, J = 1.7 Hz, 1H) 7.95-7.92 (m, 1H ), 7.71-7.67 (m, 1H), 7.36 (t, J = 7.8 Hz, 1Η), 2.66-2 · 58 (m, 1H), 1.29-1.24 (m, 2H), 1.11--1 05 (m, 2H). MS (DCI-NH3) [M + H] 225.

實例127B 第^ 丁基-二甲基矽烷氧基）-乙某-革基μ苯基} , -環丙基-甲酮 遠化合物係依實例26C之方法製備，但其中改用（3_溴_苯 基）-環丙基··甲g同替代5 -溴口密淀（71 mg，收率61 %)。^ NMR (CDC13? 300 MHz) δ 8.35 (s, 1Η) 8.09-8.02 (m? 2H)? 7.94- 7.87 (m，3H)，7.79-7.71 (m，2H)，7.83-7.58 (t，J=8.1 Hz，1H)， 7.45-7.4 (d，J=7.5 Hz，lH)，4.03-3.96 (q，J=6 Hz，2H)， 3.1-3.04 (t, J=6 Hz, 2H), 2.71-2.69 (m, 1H), 1.35-1.28 (m, 2H), 1.15-1.08 (m? 2H), 0.87 (s, 9H), -.02 (s, 3H) 〇 MS (DCI-NH3) [M+H]+431 〇 實例127Γ 環丙基-{3-[6-(2-羥基-乙基苯基}_甲酮 汶化5物係依貫例26D之方法製備，但其中改用（3-{6-[第 三丁基—二甲基-矽烷氧基]-乙基卜苯-2-基苯基）-環丙基-甲酮㈢代5-[6-(2-{[第二丁基（二甲基）矽烷基]氧丨乙基）_2_ 奈基]嘧哫（71 mg，收率 61%)。iH Nmr (CDC13, 3〇〇 MHz) s 8.35 (s? 1H)5 8.09-8.02 (m5 2H), 7.94^7.87 (m3 3H), 7.79-7.71 89248.doc -213- 200418454 (m，2H)，7.83-7.58 (t，J=8.1 Hz，1H)，7.45-7.4 (d，J=7.5 Hz， 1H)，4.03-3.96 (q，J=6 Hz，2H)，3.1-3.04 (t，J二6 Hz，2H)， 2.71-2.69 (m，1H)，1.35-1.28 (m，2H)，1.15-1.08 (m，2H)。MS (DCI-NH3) [M+H]+ 317。Example 127B The ^ -butyl-dimethylsilyloxy) -ethoxy-derived μphenyl}, -cyclopropyl-methanone remote compound was prepared according to the method of Example 26C, but in which (3-bromo _Phenyl) -cyclopropyl · · g is the same as 5-Bromokouchidian (71 mg, yield 61%). ^ NMR (CDC13? 300 MHz) δ 8.35 (s, 1Η) 8.09-8.02 (m? 2H)? 7.94- 7.87 (m, 3H), 7.79-7.71 (m, 2H), 7.83-7.58 (t, J = 8.1 Hz, 1H), 7.45-7.4 (d, J = 7.5 Hz, 1H), 4.03-3.96 (q, J = 6 Hz, 2H), 3.1-3.04 (t, J = 6 Hz, 2H), 2.71- 2.69 (m, 1H), 1.35-1.28 (m, 2H), 1.15-1.08 (m? 2H), 0.87 (s, 9H), -.02 (s, 3H) 〇MS (DCI-NH3) [M + H] +431 〇 Example 127Γ Cyclopropyl- {3- [6- (2-hydroxy-ethylphenyl} _methanone) 5 was prepared according to the method of Example 26D, but in which (3- {6- [Third-butyl-dimethyl-silyloxy] -ethylphenylbenzene-2-ylphenyl) -cyclopropyl-methanone fluorenated 5- [6- (2-{[ Butyl (dimethyl) silyl] oxy 丨 ethyl) _2_nyl] pyrimidine (71 mg, yield 61%). IH Nmr (CDC13, 300MHz) s 8.35 (s? 1H) 5 8.09 -8.02 (m5 2H), 7.94 ^ 7.87 (m3 3H), 7.79-7.71 89248.doc -213- 200418454 (m, 2H), 7.83-7.58 (t, J = 8.1 Hz, 1H), 7.45-7.4 (d , J = 7.5 Hz, 1H), 4.03-3.96 (q, J = 6 Hz, 2H), 3.1-3.04 (t, J = 6 Hz, 2H), 2.71-2.69 (m, 1H), 1.35-1.28 ( m, 2H), 1.15-1.08 (m, 2H). MS (DCI-NH3) [M + H] + 317

實例127D 甲磺酸2-[6-(3-環丙烷羰基-苯基）-莕-2-基]-乙酯 該化合物係依實例3B之方法製備，但其中改用環丙基 -{3-[6-(2-羥基-乙基莕-2-基]-苯基卜甲酮替代1-{3-[6-(2-羥乙基»莕基]苯基}乙酮（68 mg，收率76%)。if! NMR (CDC135 300 MHz) δ 8.35 (s, 1Η) 8.09-8.02 (m? 2H)? 7.94- 7·87 (m，3H)，7.79-7.71 (m，2Η)，7·83-7·58 (t，Hz，1H)， 7.45-7.4 (d，J=7.5 Hz，1H)，4.1-4.05 (t，J=6 Hz，2H)，3.6 (s， 3H)，3.17-3.02 (t，J=6 Hz，2H)，2.71-2.69 (m，1H)，1.35-1.28 (m，2H)，1·15-1·〇8 (m，2H)。MS (DCI-NH3) [M+NH4]+ 412。 實例127Ε 標題化合物係依實例3C之方法製備，但其中改用甲磺酸 2-[6-(3-環丙烷羰基_苯基）_萘士基]_乙酯替代甲磺酸 2-[6-(3-乙醯基苯基）_2_苯基]乙酯（3 9 mg，收率6%)。巾 NMR (CD3OD， 5 3〇〇 ΜΗζ) δ 8.35 (s? ιΗ) 8.09-8.02 (m5Example 127D 2- [6- (3-Cyclopropanecarbonyl-phenyl) -fluoren-2-yl] -ethyl methanesulfonate This compound was prepared according to the method of Example 3B, but cyclopropyl- {3 was used instead. -[6- (2-hydroxy-ethylfluoren-2-yl] -phenylbenzophenone replaces 1- {3- [6- (2-hydroxyethyl »fluorenyl] phenyl} ethyl ketone (68 mg , Yield 76%). If! NMR (CDC135 300 MHz) δ 8.35 (s, 1Η) 8.09-8.02 (m? 2H)? 7.94- 7.87 (m, 3H), 7.79-7.71 (m, 2Η) , 7.83-7 · 58 (t, Hz, 1H), 7.45-7.4 (d, J = 7.5 Hz, 1H), 4.1-4.05 (t, J = 6 Hz, 2H), 3.6 (s, 3H) , 3.17-3.02 (t, J = 6 Hz, 2H), 2.71-2.69 (m, 1H), 1.35-1.28 (m, 2H), 1.15-1.08 (m, 2H). MS (DCI -NH3) [M + NH4] + 412. Example 127E The title compound was prepared according to the method of Example 3C, except that methanesulfonic acid 2- [6- (3-cyclopropanecarbonyl_phenyl) _naphthyl] was used instead. _Ethyl ester replaces 2- [6- (3-Ethylfluorenylphenyl) -2-phenyl] ethyl methanesulfonate (39 mg, yield 6%). NMR (CD3OD, 5 300MHz) δ 8.35 (s? ιΗ) 8.09-8.02 (m5

89248.doc -214- 200418454 2.58-2.42 (m? ih)? 1.35-1.32 (m? 2H), 1.22-1.12 (m? 6H)? 1.96- 1.83 (m，1H)。MS (DCI-NH3) [M+H]+ 384。 實例128 3-甲氣_羞二6二{6-「2-α2Ι〇2-甲咨啶-1-某V乙基-苯-2-基1 -塔畊89248.doc -214- 200418454 2.58-2.42 (m? Ih)? 1.35-1.32 (m? 2H), 1.22-1.12 (m? 6H)? 1.96- 1.83 (m, 1H). MS (DCI-NH3) [M + H] + 384. EXAMPLE 128

實例128 A 3 - {6-[~2二C第i丁基-二甲基-矽烷氧某V乙某]-苯-2-基卜6-甲 氣基-嗒畊Example 128 A 3-{6- [~ 2 di-C i-butyl-dimethyl-silyloxy V-b] -benzene-2-ylbu 6-methyl

該化合，物係依實例26C之方法製備，但其中改用3-氯-6-甲氧基哈喷替代5-溴。密咬（64 mg，收率76%)。4 NMR (CDC13, 300 MHz) δ 8.43 (s，1H)，8·24-8·2 (d，J=7.5 Hz，1H)， 7.96- 7.81 (m，3H)，7.63 (s，lH)，7·44-7·41 (d，J=6 Hz，1H)， 7.12-7.07 (d，J=9 Hz，1H)，4.96-4.86 (m，2H)，4.22 (s，3H)， 3.03-2.91 (m，2H)，0.87 (s，9H)，-0.02 (s，6H)。MS (DCI-NH3) [M+H]+ 395 〇 實例128$ 氢基-嗒啡某乙醇 垓化a物係依實例26D之方法製備，但其中改用3-[心[2(第 三丁基-二甲基__矽烷氧基&gt; 乙基]_萘_2•基]甲氧基-嗒畊 替代5-[M2-{[第三丁基（二甲基）碎燒基]氧}乙基）1茶基] 嘧啶（6.7 mg，收率 37%)。lH NMR (CDci3, 3〇〇 MHz) s 8 43 (s，1H)，8.24-8.2 (d，J=7.5 Hz，1H)，7·96-7·81 (m，3H)，7.63 (s，1H)，7.44-7.41 (d，1=6 Hz，1H)，7.12-7.07 (d，1=9 Hz，1H)， 4.22 (S? 3H)54.〇3 (q5 J=5.4 Hz, 2H)? 3.09-3.04 (d? J=5.4 Hz5 89248.doc -215 - 200418454 2H)。MS (DCI-NH3) [M+H]+ 281。The compound was prepared according to the method of Example 26C, but 3-chloro-6-methoxyhapent was used instead of 5-bromo. Close bite (64 mg, yield 76%). 4 NMR (CDC13, 300 MHz) δ 8.43 (s, 1H), 8.24-8 · 2 (d, J = 7.5 Hz, 1H), 7.96- 7.81 (m, 3H), 7.63 (s, 1H), 7.44-7.41 (d, J = 6 Hz, 1H), 7.12-7.07 (d, J = 9 Hz, 1H), 4.96-4.86 (m, 2H), 4.22 (s, 3H), 3.03- 2.91 (m, 2H), 0.87 (s, 9H), -0.02 (s, 6H). MS (DCI-NH3) [M + H] + 395 〇 Example 128 $ Hydrogen-Dalphine A ethanolated a system was prepared according to the method of Example 26D, but 3- [心 [2 (三 丁丁-Dimethyl-_silyloxy &gt; ethyl] -naphthalene_2 • yl] methoxy-da-phen replaces 5- [M2-{[third butyl (dimethyl) crushed aryl] oxygen } Ethyl) 1 theophyl] pyrimidine (6.7 mg, yield 37%). 1H NMR (CDci3, 300MHz) s 8 43 (s, 1H), 8.24-8.2 (d, J = 7.5 Hz, 1H), 7.96-7 · 81 (m, 3H), 7.63 (s, 1H), 7.44-7.41 (d, 1 = 6 Hz, 1H), 7.12-7.07 (d, 1 = 9 Hz, 1H), 4.22 (S? 3H) 54.03 (q5 J = 5.4 Hz, 2H) ? 3.09-3.04 (d? J = 5.4 Hz5 89248.doc -215-200418454 2H). MS (DCI-NH3) [M + H] + 281.

實例128C 甲氣基-嗒畊-3-基V茬-2-基1-乙酯 孩化合物係依實例3Β之方法製備，但其中改用2_[6_(6-甲 氧基-塔畊-3-基）-萘-2-基]-乙醇替代1-{3-[6-(2-羥乙基）-2_ 奈基]苯基}乙酮（14 mg，收率 64%)。4 NMR(CDC13，300 MHz) δ 8·43 (s, 1H)，8.24-8.2 (d，J二7·5 Hz，1H)，7.96-7.81 (m，3H)，7.63 (s，1H)，7.44-7.41 (d，J=6 Hz，1H)，7.12-7.07 (d， J=9 Hz，1石），4.57-4.52 (t，J=6 Hz，2H)，4.22 (s，3Η)，4·15-4·06 (t，J=6 Hz，2H) 2·94 (s，3H)。MS (DCI-NH3)[M+NH4]+ 359。Example 128C Methoxy-daken-3-yl V-2--2-1-ethyl ethyl ester was prepared according to the method of Example 3B, but 2_ [6_ (6-methoxy-tac -Yl) -naphthyl-2-yl] -ethanol instead of 1- {3- [6- (2-hydroxyethyl) -2-nylyl] phenyl} ethanone (14 mg, yield 64%). 4 NMR (CDC13, 300 MHz) δ 8.43 (s, 1H), 8.24-8.2 (d, J-27.5 Hz, 1H), 7.96-7.81 (m, 3H), 7.63 (s, 1H), 7.44-7.41 (d, J = 6 Hz, 1H), 7.12-7.07 (d, J = 9 Hz, 1 stone), 4.57-4.52 (t, J = 6 Hz, 2H), 4.22 (s, 3Η), 4 · 15-4 · 06 (t, J = 6 Hz, 2H) 2.94 (s, 3H). MS (DCI-NH3) [M + NH4] + 359.

實例128D 甲基-吡咯啶-l-某 V 乙基-S-2-某 1 口答口井 標題化合物係依實例1H之方法製備，但其中改用甲磺酸 2-[6-(6-甲氧基-嗒畊-3-基）-莕-2-基]乙酯替代4-甲基甲磺 酸2-[6-(4-氰基苯基）_2-萘基]乙酯（3 mg，收率22%)。4 NMR (CD3OD5 300 MHz) (5 8.43 (s? 1H), 8.24-8.2 (d? J=7.5 Hz, 1Η)，7·96-7·81 (m，3H)，7·63 (s，1H)，7.44-7.41 (d，J=6 Hz， 1H)，7.12-7.07 (d，J=9 Hz，lH)，4.17 (s，3H)，3.18-3.11 (m， 2H)，3.09-2.96 (m，2H)，2.51-2.4 (m，2H)，2.39-2.31 (m，1H)， 2.10-1.91 (m5 1H)5 1.89-1.76 (m5 2H), 1.55-1.4 (m? 1H)? 1.15 (d，J=6 Hz，3H)。MS (DCI-NH3) [M+NH4；T 348。 實例129 4二{6-「2-(2-甲基二六氫吡啶-i-基v乙某1_玄_2_基丨_笨基氨 89248.doc -216- 200418454Example 128D Methyl-pyrrolidine-l-V-ethyl-S-2-A 1 well of the title compound was prepared according to the method of Example 1H, but the methanesulfonic acid 2- [6- (6-methyl Oxy-tacken-3-yl) -fluoren-2-yl] ethyl ester instead of 2- [6- (4-cyanophenyl) _2-naphthyl] ethyl 4-methylmethanesulfonate (3 mg , Yield 22%). 4 NMR (CD3OD5 300 MHz) (5 8.43 (s? 1H), 8.24-8.2 (d? J = 7.5 Hz, 1Η), 7.96-7 · 81 (m, 3H), 7.63 (s, 1H ), 7.44-7.41 (d, J = 6 Hz, 1H), 7.12-7.07 (d, J = 9 Hz, 1H), 4.17 (s, 3H), 3.18-3.11 (m, 2H), 3.09-2.96 ( m, 2H), 2.51-2.4 (m, 2H), 2.39-2.31 (m, 1H), 2.10-1.91 (m5 1H) 5 1.89-1.76 (m5 2H), 1.55-1.4 (m? 1H)? 1.15 ( d, J = 6 Hz, 3H). MS (DCI-NH3) [M + NH4; T 348. Example 129 4bis {6- "2- (2-methyldihexahydropyridine-i-yl) 1_ 玄 _2_ 基 丨 _benzyl ammonia 89248.doc -216- 200418454

標題化合物係依實例1H之方法製備，但其中改用2_甲基 六氫吡啶替代（2R)-2-甲基吡咯啶（9 mg，收率8 4%)。lH NMR (CD3〇D，300 MHz) δ 8.17 (s，1H)，7·97-7.9l(m，4H)，7.87-7·75 (m，4Η)，7·45 (d，J二 6 Hz，1H)，urn (m，5H)， 2.55-2.49 (m，2H)，1.81-1.67 (m，4H)，1.46-1.33 (m，2H)，1.08 (d，J二6 Hz，3H)。MS φ(：Ι-ΝΗ3)[Μ+Η]+ 355。 實例130The title compound was prepared according to the method of Example 1H, except that 2-methylhexahydropyridine was used instead of (2R) -2-methylpyrrolidine (9 mg, yield 84%). lH NMR (CD30D, 300 MHz) δ 8.17 (s, 1H), 7.97-7.9l (m, 4H), 7.87-7 · 75 (m, 4Η), 7.45 (d, J 2 6 Hz, 1H), urn (m, 5H), 2.55-2.49 (m, 2H), 1.81-1.67 (m, 4H), 1.46-1.33 (m, 2H), 1.08 (d, J 6 Hz, 3H) . MS φ (: 1-ΝΗ3) [Μ + Η] + 355. Example 130

^基^比咯啶基乙基p茉某氰 標題A合物係依實例m之方法製備，但其中改用（211)-2_ 乙基吡咯啶替代（2R)-2-甲基吡咯啶（13 mg，收率7 5%)。iH NMR (CD3OD，300 MHz) δ 8.17 (s，1H)，7.97-7.91 (m，4H)， 7.87-7.75 (m，4Η)，7.45 (d，J= 6 Ηζ，1Η)，3.29-3.17 (m，2Η)， 3.19-2.95 (m，2H)，2.49-2.42 (m，2H)，2.41-2.31 (m，1H)， 2.14-1.99 (m，1H)，1.89-1.78 (m，2H)，1.63-1.42 (m，2H)， 1·31_1·2 (m，1H)，·99'89 (m，3H)。MS _捕3) [M+H]+355。 實例131 ^·:.··{·6-|&quot;2-((28)^^甲基-吡咯啶-i-基乙某μ茬-2_某卜2H_嗒 畊-3-酮 標題化合物係依實例31H之方法製備，但其中改用（2S)-2-甲基峨嘻淀替代（2R)-2-甲基p比咯啶（42 mg，收率30%)。4 NMR (HC1 鹽，CD3〇D，300 ΜΗζ) δ 812_8 〇6 (m，2H)， 7.97-7.89 (m，2H)，7·82 (s，1Η)，7.68-7.62 (m，1H)，7.55-7.46 (m，2H)，7.15 (dd，J=2，12 Hz，1H)，3.32-3.20 (m，2H)， 3.16-2.99 (m，2H)，3.83-3.51 (m，3H)，2.17-2.02 (m，1H)， -217- 89248.doc 200418454 1·95-1·82 (m，2H)，1.52-1.48 (m，1H)，ι·23 (d，J=2 Hz，3H)。 MS (DCI-NH3) [M+H]+ 334。 實例132 -乙基μ2Η_嗒畊冬酮 標題化合物係依實例3丨Η之方法製備，但其中改用六氫吡 淀替代（2R)-2-甲基ρ比ρ各淀（42 mg，收率5〇〇/〇)。ipj NMR (CD3OD，300 MHz) δ 8.12-8.06 (m，2H)，7.97-7.89 (m，2H)， 7.82 (s，1Η)，7·68-7·62 (m，1H)，7.55-7.46 (m，2H)，7.15 (dd， J=25 12 1H), 3.1-3.0 (m? 2H)?2.84-2.75 (m? 2H)? 2.63- 2.58 (m，4H) L74-L60 (m，4H)，16(M 51 (m，2H)。⑽ (DCI-NH3) [M+H]+ 334。 實例133 U企l~2_(罘二I.基-甲某胺某乙幕上^_2·某i_2H-嗒畊_3_酮 標題化合物係依實例；31H之方法製備，但其中改用甲基(第 三丁基）胺替代（2R)-2-甲基吡咯啶（26 mg，收率31%)。咕 NMR (CD3OD，300 ΜΗζ) δ 8.12-8,06 (m，2H)，7.97-7.89 (m， 2H)，7.82 (s，1H)，7.68-7.62 (m，1H)，7.55-7.46 (m，2H)，7·15 (dd，J=2, 12 Hz，1H)，3·1 (S，3H)，3.0L2.9 (m, 4H)，U3 (s， 9H)。MS (DCI-NH3) [M+H]+ 336。 實例134 胺基-乙基萘^^_2H_嗒〇酮 標題化合物係依實例31Η之方法製備，但其中改用二乙基 月文替代（2R)-2-甲基咐咯啶（η mg，收率14%)。屯nMR (CD3OD5 300 MHz) δ 8.12-8.06 (m, 2H)? 7.97-7.89 (m? 2H), 89248.doc -218- 200418454 7.82 (s, 1H), 7.68-7.62 (m, 1H), 7.55-7.46 (m, 2H), 7.15 (dd, J=2, 12 Hz, 1H), 3.1 (m, 4H), 3.0-2.91 (m? 4H), 1.26-1.19 (m, 6H)。MS (DCI-NH3) [M+H]+ 322。The compound A was prepared according to the method of Example m, but (211) -2-ethylpyrrolidine was used instead of (2R) -2-methylpyrrolidine ( 13 mg, yield 75%). iH NMR (CD3OD, 300 MHz) δ 8.17 (s, 1H), 7.97-7.91 (m, 4H), 7.87-7.75 (m, 4Η), 7.45 (d, J = 6 Ηζ, 1Η), 3.29-3.17 ( m, 2Η), 3.19-2.95 (m, 2H), 2.49-2.42 (m, 2H), 2.41-2.31 (m, 1H), 2.14-1.99 (m, 1H), 1.89-1.78 (m, 2H), 1.63-1.42 (m, 2H), 1.31_1 · 2 (m, 1H), · 99'89 (m, 3H). MS _ trap 3) [M + H] +355. Example 131 ^ :: .. (· 6- | &quot; 2-((28) ^^ methyl-pyrrolidine-i-ylethyl) μ μ-2-some 2H_dagen-3-one The compound was prepared according to the method of Example 31H, but in which (2S) -2-methyl eherine was used instead of (2R) -2-methyl p-pyrrolidine (42 mg, yield 30%). 4 NMR ( HC1 salt, CD3OD, 300 ΜΗζ) δ 812_8 〇6 (m, 2H), 7.97-7.89 (m, 2H), 7.82 (s, 1Η), 7.68-7.62 (m, 1H), 7.55-7.46 (m, 2H), 7.15 (dd, J = 2, 12 Hz, 1H), 3.32-3.20 (m, 2H), 3.16-2.99 (m, 2H), 3.83-3.51 (m, 3H), 2.17-2.02 (m, 1H), -217- 89248.doc 200418454 1.95-1 · 82 (m, 2H), 1.52-1.48 (m, 1H), ι · 23 (d, J = 2 Hz, 3H). MS (DCI-NH3) [M + H] + 334. Example 132 The title compound was prepared according to the method of Example 3, but the hexahydropyridine was used instead of (2R) -2. -Methyl ρ ratio ρ each (42 mg, yield 500 / 〇). Ipj NMR (CD3OD, 300 MHz) δ 8.12-8.06 (m, 2H), 7.97-7.89 (m, 2H), 7.82 ( s, 1Η), 7.68-7 · 62 (m, 1H), 7.55-7.46 (m, 2H), 7.15 (dd, J = 25 12 1H), 3.1-3.0 (m? 2H)? 2.84-2.75 (m? 2H )? 2.63- 2.58 (m, 4H) L74-L60 (m, 4H), 16 (M 51 (m, 2H). ⑽ (DCI-NH3) [M + H] + 334. Example 133 U 企 l ~ 2_ (The hydrazine I-methyl-a certain amine on the second screen ^ _2 · a i_2H-dagen_3_one title compound was prepared according to an example; 31H method, but methyl (third butyl) amine was used instead Replaces (2R) -2-methylpyrrolidine (26 mg, yield 31%). NMR (CD3OD, 300 ΜΗζ) δ 8.12-8,06 (m, 2H), 7.97-7.89 (m, 2H), 7.82 (s, 1H), 7.68-7.62 (m, 1H), 7.55-7.46 (m, 2H), 7.15 (dd, J = 2, 12 Hz, 1H), 3.1 (S, 3H), 3.0L2.9 (m, 4H), U3 (s, 9H). MS (DCI-NH3) [M + H] + 336. Example 134 The title compound of amine-ethylnaphthalene ^ _2H_dahydrone was prepared according to the method of Example 31, but in which diethyl month was used instead of (2R) -2-methylsulfonium (η mg, Yield: 14%). Tun nMR (CD3OD5 300 MHz) δ 8.12-8.06 (m, 2H)? 7.97-7.89 (m? 2H), 89248.doc -218- 200418454 7.82 (s, 1H), 7.68-7.62 (m, 1H), 7.55 -7.46 (m, 2H), 7.15 (dd, J = 2, 12 Hz, 1H), 3.1 (m, 4H), 3.0-2.91 (m? 4H), 1.26-1.19 (m, 6H). MS (DCI-NH3) [M + H] + 322.

實例13S 基鐵乙基）-茶二V2H 一嗒畊一 3_酮 標題化合物係依實例31H之方法製備，但其中改用嗎啉替 代（2R)-2-甲基吡咯啶（27 mg，收率34%)。iH NMR(CD3〇D， 300 MHz) δ 8·12-8·06 (m，2H)，7.97-7.89 (m，2H)，7.82 (s， 1Η)，7·68、7·62 (m，1Η)，7.55-7.46 (m，2Η)，7.15 (dd，J=2，12 Hz，1H)，3.75-3.69 (m，2Η)，3·69-3·62 (m，ih)，3.61- 3·49 (m， 1H)，3.06-2.99 (m，2H)，2·75-2·71 (m，2H)，2.61-2.58 (m，4H) MS (DCI-NH3) [M+H]+ 336 0 實例136 ϋ「2-(乙基-甲基-胺基）-乙基1-篇_2 -苺卜2Η-^·Ρ井·3-酮 標題化合物係依實例3 1Η之方法製備，但其中改用乙基甲Example 13S The title iron compound) -tetra-V2H-dioxan-1_one was prepared according to the method of Example 31H, but morpholine was used instead of (2R) -2-methylpyrrolidine (27 mg, yield). Rate 34%). iH NMR (CD3OD, 300 MHz) δ 8.12-8 · 06 (m, 2H), 7.97-7.89 (m, 2H), 7.82 (s, 1Η), 7.68, 7.62 (m, 1Η), 7.55-7.46 (m, 2Η), 7.15 (dd, J = 2, 12 Hz, 1H), 3.75-3.69 (m, 2Η), 3.69-3 · 62 (m, ih), 3.61- 3.49 (m, 1H), 3.06-2.99 (m, 2H), 2.75-2 · 71 (m, 2H), 2.61-2.58 (m, 4H) MS (DCI-NH3) [M + H] + 336 0 Example 136 "2- (ethyl-methyl-amino) -ethyl 1-2-berry 2 2-^ · P well · 3-one The title compound was prepared according to the method of Example 3 1 Η , But use ethyl a instead

基胺替代（2R)_2-甲基ρ比洛咬（30 mg，收率37%)。4 NMR (CD3〇D,300 MHz) δ 8· 12-8.06 (m, 2H)，7·97-7 89 (m 2H), 7.82 (s? 1H)? 7.68-7.62 (m? 1H)? 7.55-7.46 (m5 2H) 7.15 (dd,Substituted by (2R) _2-methylρbiloxide (30 mg, yield 37%). 4 NMR (CD3OD, 300 MHz) δ 8 · 12-8.06 (m, 2H), 7.97-7 89 (m 2H), 7.82 (s? 1H)? 7.68-7.62 (m? 1H)? 7.55 -7.46 (m5 2H) 7.15 (dd,

J=2，12 Hz，1H)，3.07-2.98 (m，2H)，2.85-2.77 (m，2H)， 2·69,2.6 (m，2H), 2·41 (s，3H)，1.17 (t，J=6 Hz，3H)。MS (DCI-NH3) [M+H]+ 308。 實例137 — 2-{6-「2-((28)-2-氣甲基_口比口各喊_1_基）_ 乙1-基 _2_基}_2H_ 塔？井-3 -酮 -219- 89248.doc 200418454 尸標題化合物係依實例31H之方法製備，但其中改用（s)_2_ 氟甲H各咬替代（2吵2_甲基晚嘻淀（2ι叫，收率24%)。 H NMR (CD3OD? 300 MHz) δ 8.12^8.06 (m? 2Η)? 7.97-7.89 (m，2Η)，7.82 (s，1Η)，7.68-7.62 (m，1Η)，7.55-7.46 (m，2Η)， 7.15 (dd，J—2，12 Hz，1Η)，4·58-4·51 (m，2H)，4.48-4.29 (d， J 36 Hz，1H)，3.33-3.21 (m，2H)，3.06-2.99 (m，2H)，2.8-2.71 (m，1H)，2.54-2.42 (m，1H)，2.G2-1.95 (m，ih)，1.88-1.79 (m， 1H)?1.71-1.59 (m5 1H)? 1.33-1.29 (m? 1H) 〇 MS (DCI-NHs) [M+H]+ ^52。 實例138 基甲基-吡咯處二^)_乙某mn -2 Η - 口答口并-3 - iPl 標題化合物係依實例31H之方法製備，但其中改用（s)_脯J = 2, 12 Hz, 1H), 3.07-2.98 (m, 2H), 2.85-2.77 (m, 2H), 2.69, 2.6 (m, 2H), 2.41 (s, 3H), 1.17 ( t, J = 6 Hz, 3H). MS (DCI-NH3) [M + H] + 308. Example 137 — 2- {6- "2-((28) -2-Gasmethyl_Koubikou __1_yl) _ Ethyl-1-yl_2_yl} _2H_ Tower? Well-3 -one -219- 89248.doc 200418454 The cadaveric title compound was prepared according to the method of Example 31H, but in which (s) _2_fluoromethyl H was replaced with each bite (2 noisy 2_methyl late hexidylate (2 ι bid, yield 24%) ) H NMR (CD3OD? 300 MHz) δ 8.12 ^ 8.06 (m? 2Η)? 7.97-7.89 (m, 2Η), 7.82 (s, 1Η), 7.68-7.62 (m, 1Η), 7.55-7.46 (m , 2Η), 7.15 (dd, J-2, 12 Hz, 1Η), 4.58-4.51 (m, 2H), 4.48-4.29 (d, J 36 Hz, 1H), 3.33-3.21 (m, 2H), 3.06-2.99 (m, 2H), 2.8-2.71 (m, 1H), 2.54-2.42 (m, 1H), 2.G2-1.95 (m, ih), 1.88-1.79 (m, 1H)? 1.71-1.59 (m5 1H)? 1.33-1.29 (m? 1H) 〇MS (DCI-NHs) [M + H] + ^ 52. Example 138 methylmethyl-pyrrole ^) _ ethm mn -2 Η -口 口 口 和 -3-iPl The title compound was prepared according to the method of Example 31H, but (s) _) was used instead.

胺醇替代（2R)-2-甲基p比p各淀（67 mg，收率32%)。if! NMR (CD3OD5 300 MHz) δ 8.12-8.06 (m? 2Η)? 7.97-7.89 (m5 2Η)? 7.82 (S，1Η)，7·68-7·62 (m，1Η)，7·55-7·46 (m，2Η)，7.15 (dd， J=2, 12 Hz，1H)，3.66 (m，2Η)，3·17-3·〇 (m，3H)，2.99-2.93 (m，1H)，2.79-2.73 (m，1H)，2.11-2.02 (m，1H)，1.97-1.82 (m， 3H)，1.8-1.72 (m，1H)。MS (DCI-NH3) [m+H] + 35〇。 實例139 2」,6-「2-(迅)-2二^_基-?比?各淀_1-基）_乙基1_革_2_基卜2士卷口并 -3-酮 - 才々越化合物係依貫例3 1Η之方法製備，但其中改用（2 r) _ 2 _ 乙基p比洛淀替代（2R)-2 -甲基p比洛咬（3.1 mg，收率5 7%)。4 89248.doc -220 - 200418454 NMR (CD3〇D，300 MHz) δ 8.12-8.06 (m，2H)，7.97-7.89 (m， 2Η)，7·82 (s，1H)，7.68-7.62 (m，1H)，7.55-7.46 (m，2H)，7.15 (dd，J=2，12 Hz，1H)，3.29-3.17 (m，2H)，3.19-2.95 (m，2H)， 2.49-2.42 (m，2H)，2.41-2.31 (m，1H)，2.14-1.99 (m，1H)， 1.89-1.78 (m，2H)，1.63-1.42 (m，2H)，1，31-1·2 (m，1H)， • 99'89 (m，3H)。MS (DCI-NH3) [M+H] + 348。 實例140 里-1-基-乙基荃-2-某1-2H-嗒畊-3-酮 標題化^合物係依實例3 1H之方法製備，但其中改用吖咀替 代（2R)-2-甲基吡咯啶（L3 mg，收率2.5%)。iH nmr (CD3OD， 300 MHz) δ 8.12-8,06 (m，2H)，7·97-7·89 (m，2H)，7.82 (s， 1Η)，7.68-7.62 (m，1Η)，7.55-7.46 (m，2Η)，7.15 (dd，J=2, 12 Hz，1H)，3·44-3·2 (m，6Η)，1·36-1·29 (m，2H)，1.18-1.23 (d， J=4.5 Hz，2H)。MS (DCI-NH3) [M+H]+ 306。 實例141 甲基-口丫咀-1-基）-乙某其卜9TT-夺 畊-3-酮 標題化合物係依實例31H之方法製備，但其中改用（2S)_2_ 氟甲基「一曰代（2R)-2 -甲基p比1:7各淀（i.7mg，收率3 4%)。4 NMR (CD3OD5 300 MHz) δ 8.12-8.06 (m, 2Η)? 7.97-7.89 (m52H)5 7.82 (S) ιΗ)? 7.68-7.62 (m? 1H)) 7.55-7.46 (m? 2H)? 7.15 (dd5 J=2? 12 Hz5 lH)?3.24-2.8 (m5 5H), 2.76-2.62 (m5 1H)5 2.09-1.93 (m5 1H)5 1.68-1.53 (m5 1H)5 1.3^1.2 (m, 2H)5 .98-.91 (m，1H)。MS (DCI-NH3) [M+H]+ 337。 89248.doc -221 - 200418454 實例142 羥甲基-口丫咀-1-某V乙某1-革二2_某uh-塔 啡-3-酮 才禾通化合物係依實例3 1Η之方法製備，但其中改用（2 s) - 2 ·* 羥甲基吖咀替代（2R)-2-甲基吡咯啶（2 mg，收率3.7%)。4 NMR (CD3OD，300 MHz) δ 8.12-8.06 (m，2H)，7.97-7.89 (m， 2H)，7.82 (s，1Η)，7·68-7·62 (m，1H)，7.55-7.46 (m，2H)，7·15 (dd，J=2, 12 Hz，1H)，4.08-3.98 (m，1Η)，4·〇-3·73 (m，3H)， 3.55-3.4¾ (m，1H)，3.42-3.34 (m，1H)，3.24-3.14 (m，1H)， 3·09-2·98 (m，2H)，2.33-2.98 (m，2H)，1.34-1.22 (m，1H)。MS (DCI-NH3) [M+H]+ 336。 實例143 2 - {6-「2-((2R，5R)-2,5-二甲基-吡洛啶-1-基 V 乙某 i-革 _2- ϋ -2Η-嗒畊-3-酮 標題化合物係依實例3 1Η之方法製備，但其中改用 (2R，5R)-2,5-二甲基吡咯啶替代（2R)-2_甲基吡咯啶（2 mg，收 率 3.7%)。NMR (CD30D，300 ΜΗζ) δ 8·12-8·06 (m，2H)， 7.97-7.89 (m，2Η)，7·82 (s，1Η)，7·68-7·62 (m，1Η)，7.55-7.46 (m，2H)，7.15 (dd，J=2，12 Hz，1H)，3.51-3.49 (m，1H)， 3.15-3.05 (m，1H)，2·39-2·28 (m，4H)，1.86-1.76 (m，4H)， 1.39-1.46 (d，J=5.1 Hz，6H)。MS (DCI-NH3) [M+H] + 348。 實例144 ' 2-{6-「2-((2R,6S)-2,6-二甲基六氣 p比淀-1-某）一乙某 -篇-2-基} -2H-嗒畊-3-酮 89248.doc -222- 200418454 標題化合物係依實例3 1Η之方法製備，但其中改用 (2R，6S)-2,6-二甲基六氫吡啶替代（2R)_2-甲基吡咯啶（1.2 mg ’ 收率 2.4%)。NMR (CD3〇D，300 ΜΗζ) δ 8.12-8.06 (m， 2Η)，7.97-7.89 (m，2Η)，7.82 (s，1Η)，7.68-7.62 (m，1Η), 7.55-7.46 (m，2H)，7·15 (dd，J=2, 12 Hz，1H)，3.61-3.18 (m， 7H)5 2.1-1.91 (m? 1H)? 1.9-1.84 (m5 1H), 1.74-1.58 (m5 3H) 1.5-1.44 (d，J=3.6 Hz，6H)。MS (DCI-NH3)[M+H]+ 362。 實例145 基-六氫吡啶-l-基）-乙某1-^-2-基丨-2H-嗒 畊-3·•酮 標題化合物係依實例31H之方法製備，但其中改用（3Κ)-3_ #基六氫峨啶替代（211)-2_甲基吡咯啶（1·3 mg，收率2.8%) ° H NMR (CD3〇D，300 ΜΗζ) δ 8.12106 (m，2H)，7.97-7.89 (m，2Η)，7·82 (s，1Η)，7.68-7.62 (m, 1Η)，7·55-7·46 (m，2Η)， 7·15 (dd，J=2, 12 Hz，1Η)，3·78-3·67 (m，1H)，3·1-2·99 (m， 3H)，2.91-2.81 (m，ih)，2.8-2.72 (m，2H)，2,22-2.01 (m，1H)， 1·99-1·89 (m，ih)，1.86-1.78 (m，1H)，1.69-1.54 (m，1H)， 1.36-1.22 (m，1H)。MS (DCI-NH3) [m+H] + 35〇。 實例146 基-六氫吡啶乙基· 畊-3-酮 標題化合物係依實例31H之方法製備，但其中改用（R)-2-甲基六氫吡啶替代（2R)-2-甲基吡咯啶（9 2 mg，收率1.8%) 。4 NMR (CD3〇D，300 MHz) S 8.12{〇6 (m，2Η)，7·97-7·89 89248.doc -223 - 200418454 (m，2Η)，7·82 (s，1H)，7.68-7.62 (m，1Η)，7·55-7·46 (m，2H)， 7.15 (dd，J=2，12 Hz，1Η)，3·14-2·88 (m，5H)，2.66-2.49 (m， 2H)，1.8-1.56 (m，4H)，1.46-1.34 (m，2H)，1.22-1.19 (d，J=4 8The amine alcohol replaced (2R) -2-methyl p to p (67 mg, yield 32%). if! NMR (CD3OD5 300 MHz) δ 8.12-8.06 (m? 2Η)? 7.97-7.89 (m5 2Η)? 7.82 (S, 1Η), 7.68-7 · 62 (m, 1Η), 7.55- 7.46 (m, 2Η), 7.15 (dd, J = 2, 12 Hz, 1H), 3.66 (m, 2Η), 3.17-3 · 〇 (m, 3H), 2.99-2.93 (m, 1H ), 2.79-2.73 (m, 1H), 2.11-2.02 (m, 1H), 1.97-1.82 (m, 3H), 1.8-1.72 (m, 1H). MS (DCI-NH3) [m + H] + 35 °. Example 139 2 ", 6-" 2- (Xun) -2 2-^-yl-?-? Yodo _ 1-yl) _ ethyl 1 _ leather _2 _ jibo 2 ketone ketone -The Caiyue compound was prepared according to the method in Example 3 1Η, but the (2 r) _ 2 _ ethyl p-bilolide was used instead of the (2R) -2 -methyl p-bilolide (3.1 mg, yield) Rate 5 7%). 4 89248.doc -220-200418454 NMR (CD3OD, 300 MHz) δ 8.12-8.06 (m, 2H), 7.97-7.89 (m, 2Η), 7.82 (s, 1H) , 7.68-7.62 (m, 1H), 7.55-7.46 (m, 2H), 7.15 (dd, J = 2, 12 Hz, 1H), 3.29-3.17 (m, 2H), 3.19-2.95 (m, 2H) , 2.49-2.42 (m, 2H), 2.41-2.31 (m, 1H), 2.14-1.99 (m, 1H), 1.89-1.78 (m, 2H), 1.63-1.42 (m, 2H), 1, 31- 1 · 2 (m, 1H), • 99'89 (m, 3H). MS (DCI-NH3) [M + H] + 348. Example 140 Li-1-yl-ethyl quan-2-some 1- The title compound of 2H-dagen-3-one was prepared according to the method of 1H in Example 3, but acryl was used instead of (2R) -2-methylpyrrolidine (L3 mg, yield 2.5%). IH nmr (CD3OD, 300 MHz) δ 8.12-8,06 (m, 2H), 7.97-7 · 89 (m, 2H), 7.82 (s, 1Η), 7.68-7.62 (m, 1Η), 7.55- 7.46 (m, 2Η), 7.15 (dd, J = 2, 12 Hz, 1H), 3.44-3 · 2 (m, 6Η), 1.36-1 · 29 (m, 2H), 1.18-1.23 (d, J = 4.5 Hz, 2H). MS (DCI- NH3) [M + H] + 306. Example 141 Methyl-Mouthyl-1-yl) -Ethylmethyl 9TT-Naphthol-3-one The title compound was prepared according to the method of Example 31H, but it was used instead. (2S) _2_ Fluoromethyl "One generation (2R) -2-methyl p ratio of 1: 7 (i.7mg, yield 3 4%). 4 NMR (CD3OD5 300 MHz) δ 8.12-8.06 ( m, 2Η)? 7.97-7.89 (m52H) 5 7.82 (S) ιΗ)? 7.68-7.62 (m? 1H)) 7.55-7.46 (m? 2H)? 7.15 (dd5 J = 2? 12 Hz5 lH)? 3.24 -2.8 (m5 5H), 2.76-2.62 (m5 1H) 5 2.09-1.93 (m5 1H) 5 1.68-1.53 (m5 1H) 5 1.3 ^ 1.2 (m, 2H) 5 .98-.91 (m, 1H) . MS (DCI-NH3) [M + H] + 337. 89248.doc -221-200418454 Example 142 Hydroxymethyl-Kouyazui-1-Some V B 1-1-2-2-a uh-taffin-3-one compound was prepared according to the method of Example 3 1 , But in which (2 s)-2 · * hydroxymethyl azulide was used instead of (2R) -2-methylpyrrolidine (2 mg, yield 3.7%). 4 NMR (CD3OD, 300 MHz) δ 8.12-8.06 (m, 2H), 7.97-7.89 (m, 2H), 7.82 (s, 1Η), 7.68-7 · 62 (m, 1H), 7.55-7.46 (m, 2H), 7.15 (dd, J = 2, 12 Hz, 1H), 4.08-3.98 (m, 1Η), 4.0 · 3 · 73 (m, 3H), 3.55-3.4¾ (m , 1H), 3.42-3.34 (m, 1H), 3.24-3.14 (m, 1H), 3.09-2 · 98 (m, 2H), 2.33-2.98 (m, 2H), 1.34-1.22 (m, 1H). MS (DCI-NH3) [M + H] + 336. Example 143 2-{6- "2-((2R, 5R) -2,5-Dimethyl-pyrrolidin-1-yl V ethion i-leather_2- ϋ -2 Η- 哒 耕 -3- The ketone title compound was prepared according to the method in Example 3 1Η, but in which (2R, 5R) -2,5-dimethylpyrrolidine was used instead of (2R) -2_methylpyrrolidine (2 mg, yield 3.7%). ). NMR (CD30D, 300 ΜΗζ) δ 8 · 12-8 · 06 (m, 2H), 7.97-7.89 (m, 2Η), 7.82 (s, 1Η), 7.68-7 · 62 (m , 1Η), 7.55-7.46 (m, 2H), 7.15 (dd, J = 2, 12 Hz, 1H), 3.51-3.49 (m, 1H), 3.15-3.05 (m, 1H), 2.39-2 28 (m, 4H), 1.86-1.76 (m, 4H), 1.39-1.46 (d, J = 5.1 Hz, 6H). MS (DCI-NH3) [M + H] + 348. Example 144 '2- {6- "2-((2R, 6S) -2,6-dimethylhexaqi p ratio lake-1-a) -Ethyl-a--2-yl} -2H-dagen-3-one 89248 .doc -222- 200418454 The title compound was prepared according to the method in Example 3 1Η, except that (2R, 6S) -2,6-dimethylhexahydropyridine was used instead of (2R) _2-methylpyrrolidine (1.2 mg 'Yield 2.4%). NMR (CD3OD, 300 ΜΗζ) δ 8.12-8.06 (m, 2Η), 7.97-7.89 (m, 2Η), 7.82 (s, 1Η), 7.68-7.62 (m, 1Η) , 7.55-7.46 (m, 2H), 7 · 15 (dd, J = 2, 12 Hz, 1H), 3.61-3.18 (m, 7H) 5 2.1-1.91 (m? 1H)? 1.9-1.84 (m5 1H), 1.74-1.58 (m5 3H) 1.5- 1.44 (d, J = 3.6 Hz, 6H). MS (DCI-NH3) [M + H] + 362. Example 145 radical-hexahydropyridine-l-yl) -ethyl 1-^-2-yl 丨- The title compound of 2H-dagen-3 ·· one was prepared according to the method of Example 31H, but (3Κ) -3_ # 基 hexahydroeridine was used instead of (211) -2_methylpyrrolidine (1.3 mg , Yield 2.8%) ° H NMR (CD3OD, 300 ΜΗζ) δ 8.12106 (m, 2H), 7.97-7.89 (m, 2Η), 7.82 (s, 1Η), 7.68-7.62 (m, 1Η) ), 7.55-7 · 46 (m, 2Η), 7 · 15 (dd, J = 2, 12 Hz, 1Η), 3.78-3 · 67 (m, 1H), 3.1-2 · 99 (m, 3H), 2.91-2.81 (m, ih), 2.8-2.72 (m, 2H), 2,22-2.01 (m, 1H), 1.99-1.89 (m, ih), 1.86 -1.78 (m, 1H), 1.69-1.54 (m, 1H), 1.36-1.22 (m, 1H). MS (DCI-NH3) [m + H] + 35 °. Example 146 The title compound was prepared according to the method of Example 31H, except that (R) -2-methylhexahydropyridine was used instead of (2R) -2-methylpyrrole. Pyridine (92 mg, yield 1.8%). 4 NMR (CD30D, 300 MHz) S 8.12 {〇6 (m, 2Η), 7.97-7 · 89 89248.doc -223-200418454 (m, 2Η), 7.82 (s, 1H), 7.68-7.62 (m, 1Η), 7.55-7 · 46 (m, 2H), 7.15 (dd, J = 2, 12 Hz, 1Η), 3.14-2 · 88 (m, 5H), 2.66 -2.49 (m, 2H), 1.8-1.56 (m, 4H), 1.46-1.34 (m, 2H), 1.22-1.19 (d, J = 4 8

Hz，3H) 〇 MS (DCI-NH3)[M+H]+ 348。 實例147 基冬{6-「2-((j—R)-2-甲某乙基 _墓^Hz, 3H) MS (DCI-NH3) [M + H] + 348. Example 147 Jidong {6- "2-((j-R) -2-methyl some ethyl _ grave ^

基1 - p比啶 實例147 A 二甲某某 1•乙醇 該化合物係依實例1F之方法製備，但其中改用2,6_二甲基 吡啶基-3-二羥硼酸替代對-氰基苯基二羥硼酸（78mg，收率 35〇/〇) 〇 *H NMR (CD3OD, 300 MHz) δ 8.〇9.8.〇5 (m, 1Η), 7.99-7.87 (m，2H)，7.82_7.79 (m，1Η)，7 66 7 62 (m，ιη)， 7.53-7.44 (m, 2Η), 7.22-7.13 (m, 1Η),4.84-4.51 (t, J=6 Hz, 2H), 3.05-2.98 (t, J=6 Hz, 2H), 2.56 (s, 3H), 2.06 (s, 3H) 〇 MS (DCI-NH3) [M+H]+ 278 〇Example 1147 p-pyridine Example 147 A Dimethyl 1 · ethanol This compound was prepared according to the method of Example 1F, but 2,6-dimethylpyridyl-3-dihydroxyboronic acid was used instead of p-cyano Phenyldihydroxyboric acid (78 mg, yield 35 / 〇) 〇 * H NMR (CD3OD, 300 MHz) δ 8.〇9.8.〇5 (m, 1Η), 7.99-7.87 (m, 2H), 7.82_7 .79 (m, 1Η), 7 66 7 62 (m, ιη), 7.53-7.44 (m, 2Η), 7.22-7.13 (m, 1Η), 4.84-4.51 (t, J = 6 Hz, 2H), 3.05-2.98 (t, J = 6 Hz, 2H), 2.56 (s, 3H), 2.06 (s, 3H) 〇MS (DCI-NH3) [M + H] + 278 〇

±Jli47B 基）冬2•某[乙酿 該化合物係依實例3B之方法製備，但其中改用2-[6-(2,6-一甲基峨呢-3-基）-奈-2-基卜乙醇替代4_[6_(2_經基-乙基）_ ，丁、2 基]苯基氰（9763 g，收率97%)。lH NMR (CD3〇d，3〇〇 MHz) δ 8.09-8.05 (m, 1Η), 7.99-7.87 (m, 2H), 7.82-7.79 (m, 1H), 7.66 7.62 (m,lH), 7.53-7.44 (m} 2H), 7.22-7.13 (m, 1H), 4.57-4.52 (t, J=7.5 Hz, 2H), 4.Ο8 (3,3^^ 3.27-3.19 (t, J=7.5 89248.doc -224- 200418454± Jli47B group) Dong 2 • [The second compound was prepared according to the method of Example 3B, but in which 2- [6- (2,6-monomethylenyl-3-yl) -nai-2- Glycol ethanol replaces 4_ [6_ (2-Cycyl-ethyl) _, butan, 2-yl] phenyl cyanide (9763 g, yield 97%). lH NMR (CD30d, 300MHz) δ 8.09-8.05 (m, 1Η), 7.99-7.87 (m, 2H), 7.82-7.79 (m, 1H), 7.66 7.62 (m, lH), 7.53- 7.44 (m) 2H), 7.22-7.13 (m, 1H), 4.57-4.52 (t, J = 7.5 Hz, 2H), 4.〇8 (3,3 ^^ 3.27-3.19 (t, J = 7.5 89248. doc -224- 200418454

Hz，2H)。MS (DCI-NH3)[M+H]+ 356。Hz, 2H). MS (DCI-NH3) [M + H] + 356.

實例147C 二甲基 甲基-峨略咬 _ 1 -基 V 乙基 1-¾:一2· 基卜吡啶 標題化合物係依實例3C之方法製備，但其中改用甲磺酸 2-[6-(2,6-二甲基-吡啶-3-基）-莕-2-基]-乙酯替代甲磺酸 2-[6-(4-氰基-苯基）-萘-2-基]-乙酯（12 mg，收率12%)。4 NMR (CD3OD，300 ΜΗζ) δ 8.09-8.05 (m，lH)，7.99-7.87 (m， 2H)，7.8^7.79 (m，1H)，7.66-7.62 (m，1H)，7.53-7.44 (m， 2Η)，7·22-7·13 (m，1H)，4.08 (s，3H)，4.06 (s，1H)，3.18-3.11 (m，2H)，3.09-2.96 (m，2H)，2.55 (s，3H)，2.45 (s，3H)， 2·51_2·4 (m，2H)，2·39-2·31 (m，1H)，2·1(Μ·91 (m，1H)， 1.89-1.76 (m，2H)，1.55-1.4 (m，1H)，1.15 (d，J=6 Hz，3H)。 MS (DCI-NH3) [M+H]+ 345。 實例148 5 -{6-「2-((R)-2-甲基-p比哈淀-1-某V乙某荃-2-美~l·遠口坐Example 147C Dimethylmethyl-elenuline_ 1-yl V ethyl 1-¾: -1. 2-pyridine The title compound was prepared according to the method of Example 3C, but the methanesulfonic acid 2- [6- (2,6-dimethyl-pyridin-3-yl) -fluoren-2-yl] -ethyl ester instead of methanesulfonic acid 2- [6- (4-cyano-phenyl) -naphthalene-2-yl] -Ethyl ester (12 mg, yield 12%). 4 NMR (CD3OD, 300 MHz) δ 8.09-8.05 (m, 1H), 7.99-7.87 (m, 2H), 7.8 ^ 7.79 (m, 1H), 7.66-7.62 (m, 1H), 7.53-7.44 (m , 2Η), 7.22-7 · 13 (m, 1H), 4.08 (s, 3H), 4.06 (s, 1H), 3.18-3.11 (m, 2H), 3.09-2.96 (m, 2H), 2.55 (s, 3H), 2.45 (s, 3H), 2.51_2 · 4 (m, 2H), 2.39-2 · 31 (m, 1H), 2.1 (M · 91 (m, 1H), 1.89-1.76 (m, 2H), 1.55-1.4 (m, 1H), 1.15 (d, J = 6 Hz, 3H). MS (DCI-NH3) [M + H] + 345. Example 148 5-{6 -"2-((R) -2-methyl-p

實例148A 2-(6-嘧唑-5-基·苯-2-某_ 取含實例1E產物（206 mg，0.82 mmol)、2-三甲矽烷基-5-三丁基錫-嘧唑（369 mg，0·82 mmol)、二氯雙·（三苯基膦）-姜巴（11)(30 mg ’ 0.43 mmol)與氯化鍾（123 mg，2.9 mmol)之混 合物於l〇〇°C下，於25 mL甲苯中攪拌加熱一夜。反應冷卻 至室溫後，加5 mL KF水溶液稀釋。水層經乙酸乙酯萃取。 有機層脫水（硫酸鎂），過漉排除固體。所得褐色油狀物經管 89248.doc - 225 - 200418454Example 148A 2- (6-Pyrimazol-5-yl · benzene-2-some _) _ Take the product containing Example 1E (206 mg, 0.82 mmol), 2-trimethylsilyl-5-tributyltin-pyrazole (369 mg, 0.82 mmol), a mixture of dichlorobis (triphenylphosphine) -zingerba (11) (30 mg '0.43 mmol) and bell chloride (123 mg, 2.9 mmol) at 100 ° C. It was stirred and heated in 25 mL of toluene overnight. After the reaction was cooled to room temperature, 5 mL of KF aqueous solution was added to dilute. The aqueous layer was extracted with ethyl acetate. The organic layer was dehydrated (magnesium sulfate), and the solid was removed by filtration. 89248.doc-225-200418454

g，收率 39%)。NMR 柱層析法純化l ·· 1己烷/乙酸乙酉旨（〇8工 4.1-3.94 (t，J=5.7 Hz，2H)，3.09 (DCI-NH3) [M+H] + 256。 (CC13D，300 MHz) δ 8.84 (s， 7.89-7.82 (m5 2Η),7.71-7.66g, yield 39%). Purification by NMR column chromatography 1 · 1 hexane / acetic acid acetate (0.8-4.1-3.94 (t, J = 5.7 Hz, 2H), 3.09 (DCI-NH3) [M + H] + 256. , 300 MHz) δ 8.84 (s, 7.89-7.82 (m5 2Η), 7.71-7.66

出)，8·16 (s，1Η)，8.0 (s，1Η)， (m，2H)，7,45-7.4 (m，1H)， -3·〇2 (t，J二5·7Ηζ，2H)。MS(Out), 8.16 (s, 1Η), 8.0 (s, 1Η), (m, 2H), 7,45-7.4 (m, 1H), -3 · 02 (t, J 2 5.7Ηζ, 2H). MS

該化合物係依實例3B之方法製備，但其中改用冰㈣ ，基，〇師乙醇替代卜[6_(2,基·乙基）冬2•基苯基 ^(91 mg ^ ^^86%) 〇 NMR (CC13D? 300 MHz) δ 8.84 (s3 )，6 (S，1Η)，8·〇 (s，1Η)，7.89-7.82 (m，2Η)，7.71-7.66 (，），7·45_7·4 (m，1Η)，4.57-4.52 (t，J=7.5 Ηζ，2Η)，4·08 (’ ),3.27^3.19 (t5 J=7.5 Hz, 2H) 〇 MS (DCI-NH3) [M+H] + 334 〇This compound was prepared according to the method of Example 3B, but it was replaced by glacial, ethyl, and ethyl alcohol instead of [6_ (2, yl.ethyl) dong-2.phenylphenyl ^ (91 mg ^^^ 86%) NMR (CC13D? 300 MHz) δ 8.84 (s3), 6 (S, 1Η), 8. · (s, 1Η), 7.89-7.82 (m, 2Η), 7.71-7.66 (,), 7.45_7 · 4 (m, 1Η), 4.57-4.52 (t, J = 7.5 Ηζ, 2Η), 4.08 ('), 3.27 ^ 3.19 (t5 J = 7.5 Hz, 2H) 〇MS (DCI-NH3) [M + H] + 334 〇

t M 148C ~^^基-咕p备Ur棊乙基H -2-某丨峰 l化$物係依實·例3 C之方法製備，但其中改用甲績酸 2 - (6 - 口裳口伞 c +J. 一、基《•萘-2-基）-乙酯替代曱磺酸2-[6-(4-氰基-苯 丞）-、2-基]，乙酯（53mg，收率 50%hlHNMR(CD3〇D，300 ΜΗΖ) δ 8·84 (s，出），8·16 (s，1H)，8·〇 (s，1H)，7.89-7.82 (m， 2H)，7·71·7·66 (m，2H)，7.45-7.4 (m，1H)，4.08 (s，3H)，4·06 (S，1H)，3.18'3·11 (m，2H)，3.09-2.96 (m，2H)，2.55 (s，3H)， 5 (s’ 3H)，2.51-2.4 (m，2H)，2.39-2.31 (m，1H)，2.10-1.91 (m，1H)，i·89].76 (m，2H)，1.55-1.4 (m，1H)，1.15 (d，J=6 89248.doc -226- 200418454t M 148C ~ ^^-Ur-ethyl ethyl H 2-a certain peak is prepared in accordance with the method of Example 3 C, but in which the formic acid 2-(6-mouth口 口 Umbrella c + J. I. The group "• naphthalene-2-yl) -ethyl ester replaces the sulfonic acid 2- [6- (4-cyano-phenylhydrazone)-, 2-yl], ethyl ester (53mg , Yield 50% hlH NMR (CD3OD, 300 MWZ) δ 8.84 (s, out), 8.16 (s, 1H), 8. (s, 1H), 7.89-7.82 (m, 2H) , 7.71 · 7 · 66 (m, 2H), 7.45-7.4 (m, 1H), 4.08 (s, 3H), 4.06 (S, 1H), 3.18'3 · 11 (m, 2H), 3.09-2.96 (m, 2H), 2.55 (s, 3H), 5 (s' 3H), 2.51-2.4 (m, 2H), 2.39-2.31 (m, 1H), 2.10-1.91 (m, 1H), i · 89] .76 (m, 2H), 1.55-1.4 (m, 1H), 1.15 (d, J = 6 89248.doc -226- 200418454

Hz，3H)。MS (DCI-NH3) [M+H]+ 323。 實例149Hz, 3H). MS (DCI-NH3) [M + H] + 323. Example 149

甲基-吡咯啶-；L_基v乙基μ笨-2-某丨-嘧 實例149 A 基-二甲基-矽烷氧某乙某V萘-2-基μ嘧^ 該化合物係依實例26C之方法製備，但其中改用2_溴嘧啶 替代 5-溴嘧啶（157 mg，收率 60%)，lH NMR (CD3〇D，3〇〇 MHz) δ 8.95 (s5 1Η)5 8.92-8.89 (m? 2Η)? 8.54-8.51 (m? 1Η), 8.07-7.94,（m，3Η)，7·55-7·51 (m，1Η)，7.42-7.38 (m，1Η)， 4.96-4.86 (m，2H)，3·03-2·91 (m，2H)，0.87 (s，9H)，-0.02 (s， 6H)。MS (DCI-NH3) [M+H]+ 365。Methyl-pyrrolidine-; L-yl v ethyl μbenzyl-2-some 丨 -pyrimidine Example 149 A-yl-dimethyl-silyloxymethyl certain naphthyl-2-ylμpyrimidine ^ This compound is based on an example 26C method, but 2-bromopyrimidine instead of 5-bromopyrimidine (157 mg, yield 60%), 1H NMR (CD30D, 300MHz) δ 8.95 (s5 1Η) 5 8.92-8.89 (m? 2Η)? 8.54-8.51 (m? 1Η), 8.07-7.94, (m, 3Η), 7.55-7.51 (m, 1Η), 7.42-7.38 (m, 1Η), 4.96-4.86 (m, 2H), 3.03-2.91 (m, 2H), 0.87 (s, 9H), -0.02 (s, 6H). MS (DCI-NH3) [M + H] + 365.

實例149BExample 149B

[6-。密淀基某）_乙醉 該化合物係依實例26D之方法製備，但其中改用2[6_[(第 二丁基-二甲基-矽烷氧基）乙基]-莕-2-基]-嘧啶替代5_[6_(2-{[第三丁基（二甲基）矽烷基]氧}乙基）_2_萘基嘧啶（56 ，收率72%)。咕 NMR (CD3OD，300 MHz) δ 8·95 (s，1H) 8.92-8.89 (m，2H)，8.54_8·51 (m，ιη)，8·07_7·94 (m，3H)， 7·55,7·51 (m，1H)，7.42-7.38 (m，1H)，413.94 (t，j=5 7 Hz，2h)’， 3.09-3.02 (t，J=5.7 Hz，2H)。MS (DCI-NH3) [M+H]+ 237。[6-. (Michido group) _Ethyl alcohol This compound was prepared according to the method of Example 26D, but 2 [6 _ [(second butyl-dimethyl-silyloxy) ethyl] -fluoren-2-yl] was used instead. -Pyrimidine replaced 5_ [6_ (2-{[third butyl (dimethyl) silyl] oxy} ethyl) _2_naphthylpyrimidine (56, yield 72%). NMR (CD3OD, 300 MHz) δ 8.95 (s, 1H) 8.92-8.89 (m, 2H), 8.54_8 · 51 (m, ιη), 8.07_7 · 94 (m, 3H), 7.55 , 7.51 (m, 1H), 7.42-7.38 (m, 1H), 413.94 (t, j = 57 Hz, 2h) ', 3.09-3.02 (t, J = 5.7 Hz, 2H). MS (DCI-NH3) [M + H] + 237.

實例149C 6 -嘧啶-2 - - 標題化合物係依實例3B之方法製備，但其中改用實例 149B產物替代實例3A產物，產生灰白色固體。 89248.doc -227- 200418454Example 149C 6 -pyrimidine-2--The title compound was prepared according to the method of Example 3B, but the product of Example 149B was used instead of the product of Example 3A to give an off-white solid. 89248.doc -227- 200418454

膏例149D 基 1-萁-2-某卜嘧啶 “越化合物係依實例3C之方法製備，但其中改用實例Paste example 149D group 1- 萁 -2-a certain pyrimidine "The compound was prepared according to the method of Example 3C,

149C產物替代貫例3B產物（56 mg，收率41%)。4 NMR (CD3OD5 300 MHz) δ 8.95 (s? 1H)5 8.92-8.89 (m? 2H)? 8.54- 8·51 (m，1H)，8.07-7.94 (m，3H)，7.55-7.51 (m，1H)，7.42-7.38 (m，1H)，3.24-3.28 (m，1H)，3.12-3.01 (m，1H)，2·75-2·55 (m， 3H)5 2.45-2.34 (m? 2H)? 2.09-1.98 (m5lH)5 1.91-1.78 (m3 2H)? 1H)，1·19 (d，J=6 Hz，3H)。MS (DCI-NH3) [M+H]+ 318。 實例150 甲基-吡咯啶二1-基乙某m-基丨-嗒畊 實例150! 二甲基-碎烷氧1乙基萁-2-某1-6-氯-嗒畊 該化合物係依實例26C之方法製備，但其中改用3,6_二氯 哈喷替代5-溴嘧啶（63 mg，收率32%)。4 NMR (CD3〇D，300 MHz) δ 8.63 (s，1H)，8.37-8.33 (d，J=9 Hz，1H)，8·29-8·24 (d， J-9 Hz，1H)，8.09-8.02 (m，1H)，7.94-7.88 (m，1H)，7.89-7.79 (m，1H)，7.49-7.43 (m，2H)，4.96-4.86 (m，2H)，3.03-2.91 (m， 2H)，0.87 (s，9H)，-0.02 (s，6H)。MS (DCI-NH3) [M+H]+400。 實例1 L6-(6-氯-塔畊-3-其上某i_甲醇 该化合物係依實例26D之方法製備，但其中改用2[6-(第三 丁基-二甲基_矽烷氧基乙基）_莕·2_基]_6_氯_嗒畊替代5_[6_ 89248.doc -228 - 200418454 (2-{[第三丁基（二甲基）矽烷基]氧}乙基）_2_茶基]嘧啶 mg &gt; ^^68〇/〇) 〇 iH NMR (cd3OD, 300 MHz) δ 8.63 (s ιΗ) 8·37-8·33 (d，J=9 Hz，1H)，8.29-8.24 (d，J=9 Hz 1H;’ 8.09-8.02 (m，1H)，7_94_7·88 (m，1H)，7 89_7 79 ，叫， 7.49-7.43 (m，2H)，41_3 94 (t，J=5 7 Hz，2H)，3抓3 的⑴ J二5·7 Hz，2H)。MS (DCI-NH3)[M+H]+271。The 149C product replaced the product of Example 3B (56 mg, yield 41%). 4 NMR (CD3OD5 300 MHz) δ 8.95 (s? 1H) 5 8.92-8.89 (m? 2H)? 8.54- 8.51 (m, 1H), 8.07-7.94 (m, 3H), 7.55-7.51 (m, 1H), 7.42-7.38 (m, 1H), 3.24-3.28 (m, 1H), 3.12-3.01 (m, 1H), 2.75-2 · 55 (m, 3H) 5 2.45-2.34 (m? 2H )? 2.09-1.98 (m5lH) 5 1.91-1.78 (m3 2H)? 1H), 1.19 (d, J = 6 Hz, 3H). MS (DCI-NH3) [M + H] + 318. Example 150 Methyl-pyrrolidinyl 1-ylethyl m-group Example 26C was prepared, but 3,6-dichloroharpent was used instead of 5-bromopyrimidine (63 mg, yield 32%). 4 NMR (CD3OD, 300 MHz) δ 8.63 (s, 1H), 8.37-8.33 (d, J = 9 Hz, 1H), 8.29-8 · 24 (d, J-9 Hz, 1H), 8.09-8.02 (m, 1H), 7.94-7.88 (m, 1H), 7.89-7.79 (m, 1H), 7.49-7.43 (m, 2H), 4.96-4.86 (m, 2H), 3.03-2.91 (m , 2H), 0.87 (s, 9H), -0.02 (s, 6H). MS (DCI-NH3) [M + H] +400. Example 1 L6- (6-Chloro-tagonist-3-an i-methanol above was prepared according to the method of Example 26D, but 2 [6- (third butyl-dimethyl-silyloxy) was used instead. Ethyl) _ 荇 · 2_yl] _6_chloro_dagen replace 5_ [6_ 89248.doc -228-200418454 (2-{[third butyl (dimethyl) silyl] oxy} ethyl) _2_Theanyl] pyrimidine mg &gt; ^^ 68〇 / 〇) 〇iH NMR (cd3OD, 300 MHz) δ 8.63 (s Η) 8.37-8 · 33 (d, J = 9 Hz, 1H), 8.29 -8.24 (d, J = 9 Hz 1H; '8.09-8.02 (m, 1H), 7_94_7 · 88 (m, 1H), 7 89_7 79, called, 7.49-7.43 (m, 2H), 41_3 94 (t, J = 5 7 Hz, 2H), 抓 3 = 3, J = 5 · 7 Hz, 2H). MS (DCI-NH3) [M + H] +271.

實例150C 氯-嗒畊-3-某、二葚-2-基乙酿 標題％合物係依實例3B之方法製備，但其中改用實例 150B產物替代實例3A產物，產生灰白色固體。Example 150C The chloro-dagen-3-, dioxan-2-yl ethyl alcohol was prepared according to the method of Example 3B, but the product of Example 150B was used instead of the product of Example 3A to produce an off-white solid.

實例150DExample 150D

基-吡咯啶-LA)-乙基-2-某b客畊 標題化合物係依實例3C之方法製備，但其中改用實例 15 0C產物替代實例3B產物（3·2 mg，收率16%)。iH NMR (CD3OD，300 MHz) δ 8.63 (s，1H)，8.37-8.33 (d，J=9 Hz，1H)， 8.29-8.24 (d，J=9 Hz，1H)，8.09-8.02 (m，1H)，7.9心7.88 (m， 1H)，7.89-7.79 (m，lH)，7.49-7.43 (m，2H)，3.24-3.28 (m，1H)， 3.12-3.01 (m，1H)，2.75-2.55 (m，3Η)，2·45-2·34 (m，2H)， 2.09-1.98 (m? 1H), 1.91-1.78 (m3 2H)? 1.56-1.41 (m, 1H), 1.19 (d，J=6 Hz，3H)。MS (DCI-NH3) [M+H]+ 352。 實例151 甲某-批咯啶-1-某 某 1-:-2-某^-嘧啶-2二The title compound was prepared according to the method of Example 3C, but the product of Example 15 0C was used instead of the product of Example 3B (3.2 mg, yield 16%). . iH NMR (CD3OD, 300 MHz) δ 8.63 (s, 1H), 8.37-8.33 (d, J = 9 Hz, 1H), 8.29-8.24 (d, J = 9 Hz, 1H), 8.09-8.02 (m, 1H), 7.9 hearts 7.88 (m, 1H), 7.89-7.79 (m, 1H), 7.49-7.43 (m, 2H), 3.24-3.28 (m, 1H), 3.12-3.01 (m, 1H), 2.75- 2.55 (m, 3Η), 2.45-2 · 34 (m, 2H), 2.09-1.98 (m? 1H), 1.91-1.78 (m3 2H)? 1.56-1.41 (m, 1H), 1.19 (d, J = 6 Hz, 3H). MS (DCI-NH3) [M + H] + 352. Example 151 Mem-pyrrolidine-1-somem 1-:-2-some ^ -pyrimidine-2

基胺 實例151A 89248.doc -229- 200418454 奈啶-2-基胺 該化合物係依實例26C之方法製備，但其中改用2_胺基_5_ 琪㈣替代5·漠’咬（85 mg，收率46%)。1h nmr (⑶肌 MHZ) 5 8.79 (S，2H)，8·1 (s，岡，7.98-7.95 (m，2H),7 84 (s, 1H), 7.77-7.74 (d, J=6 Hz, 1H), 7.52-7.47 (d, J=6 Hz, 1H) 4.96-4.86 (m, 2H), 3.03-2.91 (m, 2H), 0.87 (s, 9H), -0.02 (s, 6H)。MS (DCI-NH3) [M+H]+ 380。Example 151A 89248.doc -229- 200418454 Natridin-2-ylamine This compound was prepared according to the method of Example 26C, but 2_amino_5_ qi was used instead of 5. Mo 'bite (85 mg, Yield 46%). 1h nmr (CD muscle MHZ) 5 8.79 (S, 2H), 8.1 (s, Okana, 7.98-7.95 (m, 2H), 7 84 (s, 1H), 7.77-7.74 (d, J = 6 Hz , 1H), 7.52-7.47 (d, J = 6 Hz, 1H) 4.96-4.86 (m, 2H), 3.03-2.91 (m, 2H), 0.87 (s, 9H), -0.02 (s, 6H). MS (DCI-NH3) [M + H] + 380.

實例15 1B ，基-嘧啶-5-某）-茬—2-甚 4化a物係依貫例26D之方法製備，但其中改用第 三丁基-二甲基-矽烷氧基乙基）_茬_2_基]_嘧啶_2_基胺替代 5-[6-(2-·{[第三丁基（二曱基）矽烷基]氧}乙基）_2_萘基]嘧啶 (29 mg，收率 68%)。NMR (CD3〇D, 300 ΜΗζ) δ 8.79 (s, 2Η), 8.1 (s, 1H), 7.98-7.95 (m, 2H), 7.84 (s,lH), 7.77-7.74 (d, J=6 Hz, 1H), 7.52-7.47 (d, J=6 Hz, 1H), 4.1-3.94 (t, J=5.7Example 15 1B, aryl-pyrimidine-5-a) -stubble—2-and 4-a is prepared according to the method of Example 26D, but the third butyl-dimethyl-silyloxyethyl is used instead) _Stub_2_yl] _pyrimidine_2_ylamine instead of 5- [6- (2- · {[third butyl (diamidyl) silyl] oxy} ethyl) _2_naphthyl] pyrimidine ( 29 mg, yield 68%). NMR (CD3〇D, 300 ΜΗζ) δ 8.79 (s, 2Η), 8.1 (s, 1H), 7.98-7.95 (m, 2H), 7.84 (s, lH), 7.77-7.74 (d, J = 6 Hz , 1H), 7.52-7.47 (d, J = 6 Hz, 1H), 4.1-3.94 (t, J = 5.7

Hz,2H), 3.09-3.02 (t, J=5.7 Hz, 2H) ° MS (DCI-NH3) [M+H] + 252 0Hz, 2H), 3.09-3.02 (t, J = 5.7 Hz, 2H) ° MS (DCI-NH3) [M + H] + 252 0

實例151C 胺基-嘧啶巧-某某乙酉旨 標題化合物係依實例3B之方法製備，但其中改用實例 1 5 1B產物替代實例3A產物，產生灰白色固體。 實例151D ' -甲基^^比哈咬—L-基萁-2 -某卜口密咬二 基胺 89248.doc -230- 200418454Example 151C Amine-pyrimidine-a certain acetamidine The title compound was prepared according to the method of Example 3B, but the product of Example 15 1B was used instead of the product of Example 3A to give an off-white solid. Example 151D'-methyl ^^ Biha bite-L-based fluorene-2-a certain bite diamine amine 89248.doc -230- 200418454

標題化合物係依實例3C之方法製備，但其中改用實例 15 1C產物替代貫例3B產物（5.4 mg，收率23%)，4 NMR (CD3〇D，300 ΜΗζ) δ 8.79 (s，2H)，8.1 (s，1H\ 7 98-7.95 (m， 2H)5 7.84 (s5 1H)? 7.77-7.74 (d5 J^6 Hz? 1H)? 7.52-7.47 (d5 卜6 Hz，1H)，3·24-3.28 (m，1H)，3.12-3.(^ (m，1H)，2.75-2.55 (m，3H)，2.45-2.34 (m，2H)，2.09-1.98 1·91-1·78 (m， 2H)，1.56-1.41 (m，1H)，1·19 (d，J=6 Hz，3H)。MS (DCI-NH3) [M+H]+ 333。 , 實例152 k甲基基_吡^^j-基）·乙某基卜 外匕咬 實例15 2 A_ M_6二甲基-矽燒氧幕^^_莫_2_基μ2_甲基比啶 孫化合物係依實例26C之方法製備，但其中改用5_溴_2_ 甲基吡咬替代5-溴嘧啶（61 mg,收率26%)。iHNMRCCDsOD， 300 MHz) δ 9·13 (s，1H)，9.88-9.84 (d，&gt;9, 1H)，8·35 (s，1H)， 8.1-7.98 (m，3H)，7.94-7.89. (m，2H)，7.62-7.57 (d，J:6 Hz， 1H)，4.96-4.86 (m，2H)，3.03-2.91 (m，2H)，2.66 (s，3H)，0.87 (s，9H)，-0.02 (s，6H)。MS (DCI-NH3) [M+H] + 378。 基-吡啶基 1-乙醇 该化合物係依實例26D之方法製備，但其中改用5-[6-(亲 三丁基—二甲基•矽烷氧基乙基）-莕-2-基]-2-甲基-吡啶替代 5-[6-(2-{[第二丁基（二甲基）矽燒基]氧丨乙基）莕基]嘧啶 89248.doc 200418454 (29 mg ’收率 68%)。巾 NMR (CD3〇D，300 MHz) δ 9.13 (s， 1Η)，9.88-9.84 (d，J=9，1Η)，8.35 (s，1Η)，8.1-7.98 (m，3Η)， 7.94-7.89 (m? 2H)? 7.62-7.57 (d? J^6 Hz? 1H)? 4.1-3.94 (t?The title compound was prepared according to the method of Example 3C, but the product of Example 15 was used instead of the product of Example 3B (5.4 mg, yield 23%), 4 NMR (CD30D, 300 ΜΗζ) δ 8.79 (s, 2H) , 8.1 (s, 1H \ 7 98-7.95 (m, 2H) 5 7.84 (s5 1H)? 7.77-7.74 (d5 J ^ 6 Hz? 1H)? 7.52-7.47 (d5 Bu 6 Hz, 1H), 3. · 24-3.28 (m, 1H), 3.12-3. (^ (M, 1H), 2.75-2.55 (m, 3H), 2.45-2.34 (m, 2H), 2.09-1.98 1 · 91-1 · 78 ( m, 2H), 1.56-1.41 (m, 1H), 1.19 (d, J = 6 Hz, 3H). MS (DCI-NH3) [M + H] + 333., Example 152 k methyl group_ Py ^^-)) Example of a certain ketone group 15 2 A_ M_6 dimethyl-silicon oxide curtain ^^ _ Mo_2_yl μ2_ methylpyridine compound according to the method of Example 26C But with 5-bromo_2_methylpyridine instead of 5-bromopyrimidine (61 mg, yield 26%). IHNMRCCDsOD, 300 MHz) δ 9 · 13 (s, 1H), 9.88-9.84 (d , &Gt; 9, 1H), 8.35 (s, 1H), 8.1-7.98 (m, 3H), 7.94-7.89. (M, 2H), 7.62-7.57 (d, J: 6 Hz, 1H), 4.96-4.86 (m, 2H), 3.03-2.91 (m, 2H), 2.66 (s, 3H), 0.87 (s, 9H), -0.02 (s, 6H). MS (DCI-NH3) [M + H] + 378. -Pyridyl 1-ethanol This compound was prepared according to the method of Example 26D, but 5- [6- (tributyl-dimethyl • silyloxyethyl) -fluoren-2-yl]- 2-methyl-pyridine instead of 5- [6- (2-{[second butyl (dimethyl) silyl] oxy] ethyl) fluorenyl] pyrimidine 89248.doc 200418454 (29 mg 'yield 68 %). NMR (CD3OD, 300 MHz) δ 9.13 (s, 1Η), 9.88-9.84 (d, J = 9, 1Η), 8.35 (s, 1Η), 8.1-7.98 (m, 3Η), 7.94-7.89 (m? 2H)? 7.62-7.57 (d? J ^ 6 Hz? 1H)? 4.1-3.94 (t?

J二5·7 Hz，2H)，3.09-3.02 (t，J=5.7 Hz，2H)，2.64 (s，3H)。MS (DCI-NH3) [M + H]+ 250。 實例152C 基-吡啶 標題化合物係依實例3B之方法製備，但其中改用實例 152B產％替代實例3A產物，產生灰白色固體。J 2 5.7 Hz, 2H), 3.09-3.02 (t, J = 5.7 Hz, 2H), 2.64 (s, 3H). MS (DCI-NH3) [M + H] + 250. Example 152C group-pyridine The title compound was prepared according to the method of Example 3B, but the yield of Example 152B was used instead of the product of Example 3A to give an off-white solid.

實例152D ?-甲基-5- {立丄2_((2R)2 -甲基-p比哈电‘ 口比&lt; 標題化合物係依實例3C之方法製備，但其中改用實例 me產物替代實例3B產物（4·δ mg，收率17%卜t (CD3〇D，300 ΜΗζ) δ 9.13 (s，1H)，9.88-9 84 Μ τ η ,δ4 (d5J-9 Ηζ? 1Η) 8·35 (s，1Η)，8.1-7.98 (m，3Η)，7.94-7·89 9m ι ， vm5 2Η)? 7.62-7 57 (d,J=6Hz, 1Η), 3.24-3.28 (m, 1H), 3.12-3.01 (m, 1R) 2 ^ (s，3H)，2·75_2.55 (m，3H)，2.45_2.34 (m，2h)，2 _ % ^ 1H)，1.91-1.78 (m，2H)，1.56-1.41 (m，1H) ， 叫，1.19 (d，J二6 Hz 3H)。MS (DCI-NH3) [M+H]+ 331。 ’ 實例153 lii臭-7-(2-吡咯啶-1-基-乙^ 實例153A 3,7-二溴 89248.doc -232 - 200418454 在含1.3 g (l〇 nnnol)l，5 -茶淀之60 mL CCI4之撥掉落液中 添加4.30 g (23 mmol)溴之6 mL CC14溶液，混合物回流1小 時。以0.5小時時間添加含吡啶（0.79 g，10 mmol)之10 mL CCI4溶液至回流中之混合物中，混合物再加熱12小時，冷 卻’與過濾。深綠色固體經1〇〇 mL 10% NaOH溶液處理1小 時，所得溶液經氯仿萃取。氯仿與CC14反應溶液合併，脫 水（硫酸鈉），過濾與減壓蒸發。殘質使用5%乙酸乙酯之CC14 溶液層析（收率 25%)。M.p. 23 8-23 9°C。4 NMR (CDC13, 300 MHz) δ 8,80 (m，2H)，9.10 (m，2H)。MS (ESI)[M+H]+ 288。Example 152D? -Methyl-5- {Ricoh 2 _ ((2R) 2-Methyl-p-Biharden's mouth ratio "The title compound was prepared according to the method of Example 3C, but the product of Example me was used instead of the example.) 3B product (4 · δ mg, 17% yield (CD3OD, 300 ΜΗζ) δ 9.13 (s, 1H), 9.88-9 84 Μ τ η, δ4 (d5J-9 Ηζ? 1Η) 8.35 (s, 1Η), 8.1-7.98 (m, 3Η), 7.94-7 · 89 9m, vm5 2Η)? 7.62-7 57 (d, J = 6Hz, 1Η), 3.24-3.28 (m, 1H), 3.12-3.01 (m, 1R) 2 ^ (s, 3H), 2.75_2.55 (m, 3H), 2.45_2.34 (m, 2h), 2_% ^ 1H), 1.91-1.78 (m, 2H), 1.56-1.41 (m, 1H), called 1.19 (d, J 2 6 Hz 3H). MS (DCI-NH3) [M + H] + 331. '' Example 153 Lii-7- (2-pyrrolidin-1-yl-ethyl) Example 153A 3,7-Dibromo 89248.doc -232-200418454 at 1.3 g (10nnnol) 1,5-Tetra lake To 60 mL of CCI4, add 4.30 g (23 mmol) of bromine in 6 mL of CC14 solution, and reflux the mixture for 1 hour. Add 0.5 mL of pyridine (0.79 g, 10 mmol) in 10 mL of CCI4 solution to reflux over 0.5 hour In the mixture, the mixture was heated for another 12 hours, cooled and filtered. The dark green solid was treated with 100 mL of 10% NaOH solution for 1 hour, and the resulting solution was extracted with chloroform. The chloroform was combined with the CC14 reaction solution and dehydrated (sodium sulfate) , Filtered and evaporated under reduced pressure. The residue was chromatographed with 5% ethyl acetate in CC14 solution (yield 25%). Mp 23 8-23 9 ° C. 4 NMR (CDC13, 300 MHz) δ 8,80 (m , 2H), 9.10 (m, 2H). MS (ESI) [M + H] + 288.

實例153B s 丁基- (2 -乙氣基-乙婦基）-錫 標題化合物係依 Wollenberg et al J. Am. Chem. Soc. 1977, 99, 7365之方法製備。Example 153B s-Butyl- (2-ethylamino-ethynyl) -tin The title compound was prepared according to the method of Wollenberg et al J. Am. Chem. Soc. 1977, 99, 7365.

實例153C 3 - &gt;臭- 7- (2-乙乳基_乙婦基）_「1,51莫啥 取含 3,7-二漠-i，5-莕淀（〇·5 g，1.74 mmol)、三丁基-2-乙 氧基-乙稀·基錫垸（1·9ΐ mm〇l，〇·69 g)、LiC 1 (8.7 mmol，0.37 g)與0·085 g PdCl2(PPh3)2之50 mL甲苯溶液於95°c下加熱16 小時。冷卻後，添加20 mL 2M KF溶液至混合物中，續撥拌 0.5小時。混合物經1〇〇mLCH2Cl2稀釋，依序經飽和碳酸氫 鈉溶液、鹽水與水洗滌。有機層經硫酸鈉脫水，過遽與減 壓蒸發。殘質使用5% MeOH之Ci^Cl2溶液層析，產生所需 物質’收率55%。hNMMCDChJOOMHzH 1.40(m，3H)， 4·〇5 (m，2H)，5.85 (s，1H)，7.25 (s，1H)，8.15 (m，1H)，8.55 89248.doc - 233 - 200418454 (m，1Η)，8·85 (m，2H)。MS (ESI)[M+H]+ 280。Example 153C 3-&gt; Odor-7- (2-ethyllactyl_ethynyl) _ "1,51 Mohan taken containing 3,7-dimo-i, 5-Yudian (0.5 g, 1.74 mmol), tributyl-2-ethoxy-ethenyl stannol (1.99 mm, 0.019 g), LiC 1 (8.7 mmol, 0.37 g), and 0.085 g PdCl2 (PPh3 ) 50 mL of toluene solution was heated at 95 ° C for 16 hours. After cooling, 20 mL of 2M KF solution was added to the mixture, and stirred for another 0.5 hours. The mixture was diluted with 100 mL of CH2Cl2 and sequentially saturated sodium bicarbonate. The solution, brine and water were washed. The organic layer was dehydrated with sodium sulfate, evaporated and evaporated under reduced pressure. The residue was chromatographed with 5% MeOH in Ci ^ Cl2 to yield the desired substance, with a yield of 55%. HNMMCDChJOOMHzH 1.40 (m, 3H), 4.05 (m, 2H), 5.85 (s, 1H), 7.25 (s, 1H), 8.15 (m, 1H), 8.55 89248.doc-233-200418454 (m, 1Η), 8 · 85 (m, 2H). MS (ESI) [M + H] + 280.

實例153D (7-溴-「1,51苯啶-3-基乙醛 在含實例153C產物（0.25 g，0.89 mmol)之15 mL THF混合 物中添加1.5 mL HC1 (6N)。混合物加熱至回流5小時，冷卻 ，使用Na〇H調整pH至8.0。混合物經75mLCH2Cl2稀釋，依 序經飽和碳酸氫鋼落液、鹽水與水洗務。有機層經硫酸鋼 脫水，過濾與減壓蒸發，產生所需產物，收率95%。iHNMR (CDC13, J00 MHz) δ 3.75 (m，2H)，8·25 (m，1H)，8·60 (m5 1Η)，8·85 (m，1Η)，9·00 (m，1Η)，9·90 (s，1Η)。MS (ESI) [M+H]+ 252。Example 153D (7-bromo- "1,51phenylpyridin-3-ylacetaldehyde) To a 15 mL THF mixture containing the product of Example 153C (0.25 g, 0.89 mmol) was added 1.5 mL HC1 (6N). The mixture was heated to reflux 5 Hours, cool, adjust pH to 8.0 with NaOH. The mixture is diluted with 75mL CH2Cl2, and then washed with saturated bicarbonate steel, brine and water. The organic layer is dehydrated with sulfuric acid steel, filtered and evaporated under reduced pressure to produce the desired product. Yield: 95%. IHNMR (CDC13, J00 MHz) δ 3.75 (m, 2H), 8.25 (m, 1H), 8.60 (m5 1Η), 8.85 (m, 1Η), 9.00 (m, 1Η), 9.90 (s, 1Η). MS (ESI) [M + H] + 252.

實例153E 3-&gt;臭-7-(2-口比口各咬-1-基-乙基）-「1，51篇症 在含實例 153D產物（0.1 g，0.4 mmol)、乙酸（0.4 mmol， 0.025 g)與吡咯啶（〇·44 mmol，0.031 g)之無水 THF (5 ml)攪 拌溶液中添加NaBH(OAc)3 (〇·6 mmol，0.127 g)。於室溫下 12小時後，混合物經50 mL.CH2Cl2稀釋，依序經飽和碳酸 氫鈉溶液、鹽水與水洗滌。有機層經硫酸鈉脫水，過滤與 減壓蒸發，殘質經矽膠使用10% MeOH之CH2C12溶液純化。 得到所需化合物，收率40%。4 NMR (CDC13, 300 ΜΗζ) δ 1.60 (m，4Η)，2·20 (m，4Η)，2.75 (m，4Η)，8.30 (m，1Η)，8.40 (m，1H)，8·90 (m，1H)，9.05 (m，1H)。MS (ESI)[M+H]+ 307、 實例154 izJU-「2-(2R-2_甲某-吡咯啶-1-某V乙基l-M/l革冷 89248.doc - 234 - 200418454 標題化合物係依實例153E之方法製備，但其中改用 (2R)-2-甲基吡咯啶替代吡咯啶。1H NMR (CDC13, 300 MHz) δ 1·20 (d，J=7 Hz，3H)，1.50 (m，4H)，2.20 (m，2H)，2.40 (m， 1H)，2.60 (m，2H)，2.75 (m, 2H)，8.25 (m，1H)，8.45 (m，1H)， 8.85 (m，1H)，9.15 (m，1H)。MS (ESI)[M+H]+ 321。 實例155 - 乳？比淀-1-基-乙某）-「i，51签症 標題化合物係依實例153E之方法製備，但其中改用六氫 淀替代吡咯啶。屯 NMR (CDC13, 300 ΜΗζ) δ 1.45-1.60 (m， 6H)，1.50 (m，4H)，2.30 (m，4H)，8,30 (m，1H)，8.40 (m，1H)， 8.95 (m，1H)，9.10 (m，1H)。MS (ESI)[M+H]+ 321。 實例156 1：.(2,6-二甲基-口比啶-3-基&gt;&gt;-7-「2彳211-2-甲基-外!：咯啶-1-基）- 乙基l-「1，51莫症 取含實例 154產物（50 mg，0.16 mmol)、2,6-二甲基-3-(4,4,5,5-四甲基-[1，3,2]二氧·戊環-2-基）-^ (0.21 mmol ，0.048 g)、Pd(PPh3)2Cl2 (0·007 g，0.008 mmol)與 1M Na2C03 (0.42 mL，0.42 mmol)之異丙醇（5 mL)於無水氮蒙氣下加熱 至90°C 24小時。冷卻後，反應混合物經矽藻土過濾，減壓 濃縮。粗產物經管柱層析法，使用二氯甲烷/甲醇/NH4〇H (90 :10 ·· 1)混合物純化，產生產物（收率53%)。i NMR (DMS〇-d6, 300 MHz) δ 1.25 (d5 J=7 Hz，3H)，1.55 (m，2H)， 1.60 (m，2H)，2.25 (m，2H)，2.35 (m，1H)，2.50 (s，3H)，2.55 (s，3H)，2.60-2.70 (m，4H)，7.20 (m，1H)，7.95 (m，1H)，8.30 - 235 - 89248.doc 200418454 (m，1H)，8·70 (m，iH)，8 9〇 (m，1H)，9.25 (m，1H)。MS (ESI) [M + H]+ 347。 實例157 3-(2,4- =甲罕途-5_基_上二7二甲基-吡咯啶-^基） -乙基 標題化合物係依實例156之方法製備，但其中改用2,4-二 甲氧基嘧哫-5-基二羥硼酸替代2,6_二甲基_3-(4,4,5,5_四甲 基-[1，3,2] 一氧硼戊環基）_ 萘啶。1h nmr (cDCh，3〇〇 MHz) δ 1，20 (d，J=7 Hz，3H)，1.50 (m，2H)，1·65 (m，2H)，2.20 (m，2H)，2.35 (m，ih)，2.65-2.70 (m，4H)，3 85 (s，6H)，8 3〇 (m，1H)，8.70 (m，1H)，8·80 (s，1H)，8 9〇 (叫 m)，9 25 (m， 1H)。MS (ESI) [M+H]+ 380。 —甲基二£^-3-基卜基-乙基苯啶 標題化合物係依實例156之方法製備，但其中改用實例 153E產物替代貫例 154產物。4 NMR (CDCh，300 ΜΗζ) δ 1.55 (m5 4H), 2.35 (m? 4H)? 2.50 (Sj 3H)5 2.55 (s5 3H)? 2.60·2·70 (m，4H)，7.25 (m，1H)，7.90 (m，ih)，8.30 (m，1H)， 8.70 (m，1H)，8.90 (m，lH)，9·25 (m，1H)。MS (ESI) [M+H] + 333 ° 實例1 3.二〔14-二甲氧基-嘌啶基）_7 略啶-^某―乙基） --4-Λ- 、 標題化合物係依實例156之方法製備，但其中改用2,4_二 89248.doc - 236 - 200418454 甲氧基嘧啶-5-基二羥硼酸與153E產物替代2,6-二甲基 -3-(4,4,5,5-四甲基-[1，3,2]二氧硼戊環-2-基）_吡啶與實例 154產物。4 NMR (CDC13, 300 ΜΗζ) δ 1.55 (m，2H)，1.65 (m5 2H)，2.50 (m，4H)，2.60-2.65 (m，4H)，3.80 (s，3H)，3·85 (s， 3H)，8.35 (m，1H)，8.70 (m，1H)，8.85 (s，1H)，8.90 (m，1H)， 9.20 (m，1H) o MS (ESI) [M+H]+ 366。 實例160 3 -（ 2，6-二甲基比淀_3_基）_7 -:氣外卜，淀_i-基一乙甚）雄「1,5~| 標題化合物係依實例15 6之方法製備，但其中改用實例 155產物替代實例 154產物。4 NMR (CDCh，300 ΜΗζ) δ 1.45-160 (m5 6Η)，2.75 (m，4Η)，2·30 (s，3Η)，2·35 (s，3H) 2.55-2.65 (m5 4H)5 7.20 (m，1H)，7.95 (m，1H)，8.20 (m，1H)， 8.65 (m，1H)，8.95 (m，1H)，9·15 (m，1H)。MS (ESI) [M十H] + 347 ° 基氫吡啶 標題化合物係依實例156之方法製備，但其中改用^ _ 曱氧基噹啶基二羥硼酸與實例丨 ，4〜 -卿:四甲基似2]…戊環_2_基= 154產物。H NMR (GDGl3, 3⑻ ΜΗζ) η 4(M 只例 2.45 (m，4Η)，2·65 (m，4H)，3 7G (s，3h)，3 8q (s，阳)’ 6H)， (叫吼 8.75 (m，1H)，請（s，1H)，8 % ㈤，吼 9 % .35 89248.doc -237- 200418454 1H) 〇 MS (ESI) [M+H]十 380 〇 實例161 3.:Ig-_(2(R)- 1 _ 基[吡啶冰某 _異‘株 標題化合物係依實例62G之方法製備，但其中改用4_吡啶 一羥硼酸替代2,6-二氟-3-吡哫二羥硼酸。iH NMR (CDCl3, 400 MHz) δ 9.29 (s5 1H)5 8.71 (dd? 2H)? 8.20 (d? 1H)? 7.93 (dd，lH)，7.88 (d，ϋ Hz，1H)，7·62-7·61 (m，3H)，3.41-3.34 (m，2H)，3.28-3.25 (m，2H)，2·84-2.79 (m，1H)，2.79-2.69 (m， 1H), 2.6J-2.50 (m, 1H)5 2.43-2.37 (m? 1H)? 2.04-1.50 (m3 3H)? 1.22 (m? 3H) 〇 13C NMR (CDC13? 400 MHz) δ 152.1, 150.1，147.0, 136.1，136.0, 128.7, 127.0, 125.6, 121.4, 118.4, 60.8, 53.9, 46.2, 36·9, 32.7, 22.0，18.7，10.4. MS (DCI-NH3) [M+H]+ 318 〇 實例163 啶-3_基）-3-「2-(2 iRV甲某-毗咯啶-1-基V乙 基1 _異4 口林 標題化合物係依實例62G之方法製備，但其中改用2-甲氧 基比啶二羥硼酸替代2,6-二氟-3-吡啶二羥硼酸。1H NMR (CDC13, 400 MHz) δ 9.24 (s，1Η)，9.49 (d，J=3 Ηζ，1Η)，8.04 (s，1H)，7·89 (dd，J=3, 12 Hz，1H)，7.83 (s，2H)，7.55 (s，1H)， 6.87 (dJ-12 Hz, 1H)，4.01 (s，3H)，3.35-3.15 (m，4H)， 2.67-2.58 (m，2H)，2.45-2.28 (m，2H)，2.00-1.46 (m，3 H)， U7 (d，3H)。13c NMR (CDC13，400 MHz) δ 163.4，151.8, 144.9, 137.1，135.7, 135·2, 1291，128.9, 127.2, 126.7, 124.3, 89248.doc - 238 - 200418454 118.1，110.9, 60.3, 54.1，53.8, 46.3, 37.2, 32·9, 22·0，19.2。 MS (DCI-NH3)[M+H]+ 347。 實例164 甲基-p比洛淀-j-基V乙基1-7-嘧淀-5-基-異4 口林 標題化合物係依實例62G之方法製備，但其中改用 5-(4,4,5,5-四甲基_[1，3,2]二氧硼戊環_2_基）_嘧啶替代2,6-二 氟-3-吡啶二羥硼酸。1H NMR (CDC13，400 ΜΗζ) δ 9.29 (s， 1Η)，9·26 (s，1Η)，9·07 (s，2Η)，8·15 (s，1Η)，7·93 (d，J=12 Hz，1Η)，，7·87 (dd，J=3，12 Hz，1H)，7·64 (s，1H)，3.44-3.28 (m，4H)，2.91-2.41 (m，3H)，2.07-1.54 (m，4H)，1.30 (d，J=8 Hz，3H)。13C NMR (CDC13, 400 MHz) δ 157.3，154.6，152.0, 135.9，133.3，132.2，128.5，127·5，127.0，125.6，118·5, 61.1， 53.9, 53.8, 36.7, 32.6, 21.9, 18.5。MS (DCI-NH3)[M+H]+319。 實例165 氟-吡啶-3-基曱某-吡咯啶-1-基V乙基1-異 口奎口林 標題化合物係依實例62G之方法製備，但其中改用2-氟 -5-(4,4,5,5-四甲基-[1，3,2]二氧石朋戊環_2-基）-叶匕淀替代2,6-二氟-3-吡啶二羥硼酸。iHNMR(CDC13, 400MHz) δ 9.26 (s， 1H)，8·53 (m，1H)，8.11-8.06 (m，2H)，7.88 (d，J=8 Hz，1H)， 7.84 (d，J=8 Hz，1H)，7.61 (s，1H)，7.06 (dd，J=4, 12 Hz，1H)， 3.40-3.26 (m，3H)，2.88-2.82 (m，1Η)，2·79-2·72 (m，1H), 2.63-2.58 (m，1H)，2.46-2.39 (m，1H)，2.06-1.52 (m，4H)， 1.27 (d，3H)。13C NMR (CDC13, 400 MHz) δ 164.0，161.6, 89248.doc -239 - 200418454 153.2，151.9，145.7，145.5，139.5，139.4，135.5，134.5，133.7, 133.6, 129.0, 127.0, 127.0, 125.2, 116.3, 109.7, 109.3, 60.9, 53.8, 46.2, 36.7, 32.6, 21.9，18.5。MS(DCI-NH3)[M+H] + 336。 實例166 _5-{3-f2-(2_(R)-甲基4比咯啶-1-基V乙某]-異4啉-7-基菸某氰 標題化合物係依實例62G之方法製備，但其中改用 5-(4,4,5,5-四甲基-[1，3,2]二氧硼戊環基菸基氰替代2,6_ 二氟-3-吡啶二羥硼酸。1H NMR (CDC13, 400 ΜΗζ) δ 9.30 lH)，9.15《d，J=2 Ηζ，1Η)，8·90 (d，J=2 Ηζ，1Η)，8·26 (m，1Η)， 8.16 (d，J=2 Hz，1H)，7.94 (d，J=8 Hz，1H)，7.86 (dd，J=2, 12 Hz，1H)，7·65 (s，1H)，3.44-3.29 (m，3Η)，2·93-2·88 (q，J=8 Hz，1H)，2·82-2·75 (m，1H)，2.66-2.60 (m，1H)，2.49-2.42 (m， 1H)，2.07-1.54 (m，4H)，1.29 (d，J=8 Hz，3H)。13C NMR (CDC13,400 MHz) δ 154.0, 152.0, 151.0, 150.5，136.9, 135.9, 135.7，133.4，128.5，127.5，126.9，125.9,118.2，116.1，110.0, 61.0，53·8，53.7，36.6，32.5，21.9，18·2。MS (DCI-NH3) [M+H]+ 343 〇 實例167 7.-Q二氩比味二甲某比咯啶-卜基乙基μ異 峻淋 標題化合物係依實例62G之方法製備，但其中改用3 -氯-4-吡哫一羥硼酸替代2,6-二氟_3_吡啶二羥硼酸。lH nmr (CDC13, 400 MHz) δ 9.25,（s，1H)，8.72 (s，1Η)，8·57 (d，J二4 HZ，1H)，8·〇5 (s，1H)，7.88 (d，J=8 Hz，1H)，7·78 (dd，J=2, 12, 89248.doc -240- 200418454Example 153E 3- &gt; Odor-7- (2-mouth-to-mouth bite-1-yl-ethyl)-"1,51 cases of the product containing the product of Example 153D (0.1 g, 0.4 mmol), acetic acid (0.4 mmol , 0.025 g) and pyrrolidine (0.44 mmol, 0.031 g) in a stirred solution of anhydrous THF (5 ml) was added with NaBH (OAc) 3 (0.6 mmol, 0.127 g). After 12 hours at room temperature, The mixture was diluted with 50 mL of CH2Cl2 and washed sequentially with saturated sodium bicarbonate solution, brine and water. The organic layer was dehydrated with sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel using 10% MeOH in CH2C12 solution. Required compound, yield 40%. 4 NMR (CDC13, 300 ΜΗζ) δ 1.60 (m, 4Η), 2.20 (m, 4Η), 2.75 (m, 4Η), 8.30 (m, 1Η), 8.40 (m , 1H), 8.90 (m, 1H), 9.05 (m, 1H). MS (ESI) [M + H] + 307, Example 154 izJU- "2- (2R-2_methyl-pyrrolidine- 1-Vethyl 1M / l Geran 89248.doc-234-200418454 The title compound was prepared according to the method of Example 153E, but (2R) -2-methylpyridine was used instead of pyrrolidine. 1H NMR (CDC13 , 300 MHz) δ 1.20 (d, J = 7 Hz, 3H), 1.50 (m, 4H), 2.20 (m, 2H), 2.40 (m, 1H), 2.60 (m, 2H), 2.75 (m, 2H), 8.25 (m, 1H), 8.45 (m, 1H), 8.85 (m, 1H), 9.15 (m, 1H). MS (ESI) [M + H ] + 321. Example 155-Milk? Biyodo-1-yl-B)-"i, 51 The title compound was prepared according to the method of Example 153E, but hexahydro lake was used instead of pyrrolidine. Tun NMR ( CDC13, 300 ΜΗζ) δ 1.45-1.60 (m, 6H), 1.50 (m, 4H), 2.30 (m, 4H), 8,30 (m, 1H), 8.40 (m, 1H), 8.95 (m, 1H ), 9.10 (m, 1H). MS (ESI) [M + H] + 321. Example 156 1:. (2,6-dimethyl-lipidin-3-yl &gt; &gt; -7- " 2 彳 211-2-methyl-exo !: pyridin-1-yl) -ethyl l- "1,51 moz, containing the product of Example 154 (50 mg, 0.16 mmol), 2,6-dimethyl -3- (4,4,5,5-tetramethyl- [1,3,2] dioxopentyl-2-yl)-^ (0.21 mmol, 0.048 g), Pd (PPh3) 2Cl2 (0 • 007 g, 0.008 mmol) and 1M Na2C03 (0.42 mL, 0.42 mmol) in isopropanol (5 mL) were heated to 90 ° C under anhydrous nitrogen for 24 hours. After cooling, the reaction mixture was filtered through celite and concentrated under reduced pressure. The crude product was purified by column chromatography using a dichloromethane / methanol / NH4OH (90: 10 ·· 1) mixture to give the product (yield 53%). i NMR (DMS〇-d6, 300 MHz) δ 1.25 (d5 J = 7 Hz, 3H), 1.55 (m, 2H), 1.60 (m, 2H), 2.25 (m, 2H), 2.35 (m, 1H) , 2.50 (s, 3H), 2.55 (s, 3H), 2.60-2.70 (m, 4H), 7.20 (m, 1H), 7.95 (m, 1H), 8.30-235-89248.doc 200418454 (m, 1H ), 8.70 (m, iH), 89 (m, 1H), 9.25 (m, 1H). MS (ESI) [M + H] + 347. Example 157 3- (2,4- = Methanol-5_yl_ondi-7dimethyl-pyrrolidin- ^ yl) -ethyl The title compound was prepared according to the method of Example 156, but 2,2 was used instead. 4-Dimethoxypyrimidin-5-yldihydroxyboronic acid instead of 2,6_dimethyl_3- (4,4,5,5_tetramethyl- [1,3,2] monooxopentyl Cyclo) _naphthyridine. 1h nmr (cDCh, 300MHz) δ 1,20 (d, J = 7 Hz, 3H), 1.50 (m, 2H), 1.65 (m, 2H), 2.20 (m, 2H), 2.35 ( m, ih), 2.65-2.70 (m, 4H), 3 85 (s, 6H), 8 30 (m, 1H), 8.70 (m, 1H), 8.80 (s, 1H), 8 9 (Called m), 9 25 (m, 1H). MS (ESI) [M + H] + 380. —Methyldi-3-benzyl-ethylphenylidine The title compound was prepared according to the method of Example 156, but the product of Example 153E was used instead of the product of Example 154. 4 NMR (CDCh, 300 ΜΗζ) δ 1.55 (m5 4H), 2.35 (m? 4H)? 2.50 (Sj 3H) 5 2.55 (s5 3H)? 2.60 · 2 · 70 (m, 4H), 7.25 (m, 1H ), 7.90 (m, ih), 8.30 (m, 1H), 8.70 (m, 1H), 8.90 (m, 1H), 9.25 (m, 1H). MS (ESI) [M + H] + 333 ° Example 1 3. Di [14-dimethoxy-puridinyl) _7 L-pyridine- ^ some-ethyl) --4-Λ-, the title compound is based on Example 156 was prepared, but 2,4-di89248.doc-236-200418454 was used instead of 2,6-dimethyl-3- (4, 4,5,5-tetramethyl- [1,3,2] dioxoborolan-2-yl) -pyridine and the product of Example 154. 4 NMR (CDC13, 300 ΜΗζ) δ 1.55 (m, 2H), 1.65 (m5 2H), 2.50 (m, 4H), 2.60-2.65 (m, 4H), 3.80 (s, 3H), 3.85 (s , 3H), 8.35 (m, 1H), 8.70 (m, 1H), 8.85 (s, 1H), 8.90 (m, 1H), 9.20 (m, 1H) o MS (ESI) [M + H] + 366 . Example 160 3-(2,6-Dimethylpyridine_3_yl) _7-: Gas-bubbled, yodo_i-yl-ethyl) androgen "1,5 ~ | The title compound is according to Example 15 6 of It was prepared by the method, but the product of Example 155 was used instead of the product of Example 154. 4 NMR (CDCh, 300 MΗζ) δ 1.45-160 (m5 6Η), 2.75 (m, 4Η), 2.30 (s, 3Η), 2 · 35 (s, 3H) 2.55-2.65 (m5 4H) 5 7.20 (m, 1H), 7.95 (m, 1H), 8.20 (m, 1H), 8.65 (m, 1H), 8.95 (m, 1H), 9 · 15 (m, 1H). MS (ESI) [M 10H] + 347 ° The title compound was prepared according to the method of Example 156, but it was replaced by ^ _ alkoxy when pyridyl dihydroxyborate and the example丨, 4 ~ -Qing: Tetramethyl-like 2] ... Pentacyclo_2_yl = 154 product. H NMR (GDGl3, 3⑻ ΜΗζ) η 4 (M only 2.45 (m, 4Η), 2.65 (m , 4H), 3 7G (s, 3h), 3 8q (s, yang) '6H), (roar 8.75 (m, 1H), please (s, 1H), 8% ㈤, roar 9% .35 89248 .doc -237- 200418454 1H) 〇MS (ESI) [M + H] 10 380 〇 Example 161 3 .: Ig -_ (2 (R)-1 _ group [Pyridyl ice a_iso 'strain title compound is based on Example 62G, but 4-pyridine-hydroxyboron was used instead Replaces 2,6-difluoro-3-pyridine dihydroxyboronic acid. IH NMR (CDCl3, 400 MHz) δ 9.29 (s5 1H) 5 8.71 (dd? 2H)? 8.20 (d? 1H)? 7.93 (dd, lH ), 7.88 (d, ϋ Hz, 1H), 7.62-7 · 61 (m, 3H), 3.41-3.34 (m, 2H), 3.28-3.25 (m, 2H), 2.84-2.79 (m , 1H), 2.79-2.69 (m, 1H), 2.6J-2.50 (m, 1H) 5 2.43-2.37 (m? 1H)? 2.04-1.50 (m3 3H)? 1.22 (m? 3H) 〇13C NMR ( CDC13? 400 MHz) δ 152.1, 150.1, 147.0, 136.1, 136.0, 128.7, 127.0, 125.6, 121.4, 118.4, 60.8, 53.9, 46.2, 36 · 9, 32.7, 22.0, 18.7, 10.4. MS (DCI-NH3) [M + H] + 318 〇 Example 163 pyridin-3-yl) -3- "2- (2 iRV methyl-pyrrolidin-1-yl V ethyl 1 _ iso 4 The title compound is based on Example 62G It was prepared by this method, but 2-methoxypyridine dihydroxyboronic acid was used instead of 2,6-difluoro-3-pyridine dihydroxyboronic acid. 1H NMR (CDC13, 400 MHz) δ 9.24 (s, 1Η), 9.49 (d, J = 3 Ηζ, 1Η), 8.04 (s, 1H), 7.89 (dd, J = 3, 12 Hz, 1H) , 7.83 (s, 2H), 7.55 (s, 1H), 6.87 (dJ-12 Hz, 1H), 4.01 (s, 3H), 3.35-3.15 (m, 4H), 2.67-2.58 (m, 2H), 2.45-2.28 (m, 2H), 2.00-1.46 (m, 3 H), U7 (d, 3H). 13c NMR (CDC13, 400 MHz) δ 163.4, 151.8, 144.9, 137.1, 135.7, 135.2, 1291, 128.9, 127.2, 126.7, 124.3, 89248.doc-238-200418454 118.1, 110.9, 60.3, 54.1, 53.8, 46.3, 37.2, 32.9, 22.0, 19.2. MS (DCI-NH3) [M + H] + 347. Example 164 Methyl-p-bilodine-j-yl-Vethyl 1-7-pyrimido-5-yl-iso- 4-methylline The title compound was prepared according to the method of Example 62G, but 5- (4, 4,5,5-tetramethyl_ [1,3,2] dioxolane-2-yl) _pyrimidine instead of 2,6-difluoro-3-pyridine dihydroxyboronic acid. 1H NMR (CDC13, 400 ΜΗζ) δ 9.29 (s, 1Η), 9.26 (s, 1Η), 9.07 (s, 2Η), 8.15 (s, 1Η), 7.93 (d, J = 12 Hz, 1Η), 7.87 (dd, J = 3, 12 Hz, 1H), 7.64 (s, 1H), 3.44-3.28 (m, 4H), 2.91-2.41 (m, 3H) , 2.07-1.54 (m, 4H), 1.30 (d, J = 8 Hz, 3H). 13C NMR (CDC13, 400 MHz) δ 157.3, 154.6, 152.0, 135.9, 133.3, 132.2, 128.5, 127.5, 127.0, 125.6, 118.5, 61.1, 53.9, 53.8, 36.7, 32.6, 21.9, 18.5. MS (DCI-NH3) [M + H] +319. Example 165 The title compound of fluoro-pyridin-3-ylsulfonium-pyrrolidin-1-yl Vethyl 1-isoquinone was prepared according to the method of Example 62G, but 2-fluoro-5- (4 , 4,5,5-tetramethyl- [1,3,2] dioxopentyl-2-yl) -leafine in place of 2,6-difluoro-3-pyridine dihydroxyboronic acid. iHNMR (CDC13, 400MHz) δ 9.26 (s, 1H), 8.53 (m, 1H), 8.11-8.06 (m, 2H), 7.88 (d, J = 8 Hz, 1H), 7.84 (d, J = 8 Hz, 1H), 7.61 (s, 1H), 7.06 (dd, J = 4, 12 Hz, 1H), 3.40-3.26 (m, 3H), 2.88-2.82 (m, 1Η), 2.79-2 72 (m, 1H), 2.63-2.58 (m, 1H), 2.46-2.39 (m, 1H), 2.06-1.52 (m, 4H), 1.27 (d, 3H). 13C NMR (CDC13, 400 MHz) δ 164.0, 161.6, 89248.doc -239-200418454 153.2, 151.9, 145.7, 145.5, 139.5, 139.4, 135.5, 134.5, 133.7, 133.6, 129.0, 127.0, 127.0, 125.2, 116.3, 109.7, 109.3, 60.9, 53.8, 46.2, 36.7, 32.6, 21.9, 18.5. MS (DCI-NH3) [M + H] + 336. Example 166 The 5- {3-f2- (2_ (R) -methyl 4-pyrrolidin-1-yl V ethyl]]-iso4-line-7-yl cyanide title compound was prepared according to the method of Example 62G, However, 5- (4,4,5,5-tetramethyl- [1,3,2] dioxopentylcyclonicotinyl cyanide was used instead of 2,6-difluoro-3-pyridine dihydroxyboronic acid. 1H NMR (CDC13, 400 ΜΗζ) δ 9.30 lH), 9.15 "d, J = 2 Ηζ, 1Η), 8.90 (d, J = 2 Ηζ, 1Η), 8.26 (m, 1Η), 8.16 (d , J = 2 Hz, 1H), 7.94 (d, J = 8 Hz, 1H), 7.86 (dd, J = 2, 12 Hz, 1H), 7.65 (s, 1H), 3.44-3.29 (m, 3Η), 2.93-2 · 88 (q, J = 8 Hz, 1H), 2.82-2 · 75 (m, 1H), 2.66-2.60 (m, 1H), 2.49-2.42 (m, 1H ), 2.07-1.54 (m, 4H), 1.29 (d, J = 8 Hz, 3H). 13C NMR (CDC13, 400 MHz) δ 154.0, 152.0, 151.0, 150.5, 136.9, 135.9, 135.7, 133.4, 128.5, 127.5, 126.9, 125.9, 118.2, 116.1, 110.0, 61.0, 53.8, 53.7, 36.6, 32.5 , 21.9, 18.2. MS (DCI-NH3) [M + H] + 343 〇 Example 167 7.-Q Diargon specific taste dimethyl a pyrrolidin-b-ethyl ethyl μ isocyanine The title compound was prepared according to the method of Example 62G, but Among them, 3-chloro-4-pyridoxine monohydroxyboronic acid was used instead of 2,6-difluoro-3-pyridine dihydroxyboronic acid. lH nmr (CDC13, 400 MHz) δ 9.25, (s, 1H), 8.72 (s, 1Η), 8.57 (d, J 2 4 HZ, 1H), 8.05 (s, 1H), 7.88 ( d, J = 8 Hz, 1H), 7.78 (dd, J = 2, 12, 89248.doc -240- 200418454

Hz，1H)，7.65 (s，1Η)，7·37 (d，J=4 Hz，1H)，3.47-3.27 (m， 4H)，2.87-2.47 (m，3H)，2.08-1.60 (m，4H)，1.31 (d，J=8 Hz， 3H)。13C NMR (CDC13，400 MHz) δ 153.4，151.9，149.6, 147.5, 146.1，135.7, 134.3, 130.4, 129.7, 127.6, 126.4, 126.0, 124.9， 118.4， 61.1， 53.6， 53.5， 35·3， 35.0， 32.4， 32.3, 21.7, 18·1。MS (DCI-NH3)[M+H]+ 352。 實例168 7-&gt;臭- -甲基-ρ比p各淀-1-基乙基l-p曾琳-4-醇Hz, 1H), 7.65 (s, 1Η), 7.37 (d, J = 4 Hz, 1H), 3.47-3.27 (m, 4H), 2.87-2.47 (m, 3H), 2.08-1.60 (m, 4H), 1.31 (d, J = 8 Hz, 3H). 13C NMR (CDC13, 400 MHz) δ 153.4, 151.9, 149.6, 147.5, 146.1, 135.7, 134.3, 130.4, 129.7, 127.6, 126.4, 126.0, 124.9, 118.4, 61.1, 53.6, 53.5, 35.3, 35.0, 32.4 , 32.3, 21.7, 18 · 1. MS (DCI-NH3) [M + H] + 352. Example 168 7- &gt; Odor --- methyl-ρ ratio p-Ethyl-1-ylethyl l-p-Zinlin-4-ol

, 實例168 A 4-溴-1-碘-2-硝某 慢慢添加 NaNO3(0.83 g，12.00 mmol)至濃 H2S04(9 mL) 中。所得混合物攪拌及加熱至70°C 15分鐘後，冷卻至室溫 (r.t)。然後取4-&gt;臭-2-硝基苯胺（2.4 g，11 ·〇〇 mmol)溶於冰酷 乙酸（22 mL)中，滴加至HSOsNO溶液中，同時保持反應溫 度在40°C以下。添加後，所得混合物於室溫下攪拌3〇分鐘 ’倒至70 C含KI (2.0 g，12.00 mmol)之20 mL水溶液中。保 持溫度下攪拌20分鐘，以150 mL水稀釋，過濾。沉澱經5〇 mL 水洗滌’真2乾燥’產生橙色固體產物，收率86%，未再純 化即用於下一個步驟。1H NMR (CDC13, 300 ΜΗζ) δ 8.00 (d， J二3 Ηζ，1Η)，7·91 (d，J=9 Ηζ，1Η)，7·42 (dd，J二3, 9 Ηζ，1Η) 。MS (DCI_NH3)[M+H]+ 328.8。 實例168B - 5-溴-2-硤-茉某脍 在 15-18°C 之含 SnCl2 (5.20 g，27.44 mmol)之 10mL濃 HC1 89248.doc -241 - 200418454 授拌溶液中快速添加含實例1 68A (1.8 g，5.49 mmol)之乙醇 U 4 mL)溶液。所得混合物加熱至5 5 °C 15分鐘，於冰浴中冷 卻，添加飽和KOH溶液調成鹼性，以250 mL CHC13萃取。 有機相經硫酸鈉脫水，過濾，滤液減壓濃縮。殘質經管柱 層析法純化（100%己烷至50/50己烷/二氯甲烷），產生白色固 體產物，收率 74%。4 NMR (CDC13, 300 ΜΗζ) δ 7.47 (d，J=9 Hz，1H)，6·88 (d，J=3 Hz，1H)，6·62 (dd，J=3, 9 Hz，1H)，4.00 (bs，1H)。MS (DCI-NH3)[M]+ 297。Example 168 A 4-Bromo-1-iodo-2-nitrate was slowly added NaNO3 (0.83 g, 12.00 mmol) to concentrated H2S04 (9 mL). The resulting mixture was stirred and heated to 70 ° C for 15 minutes, and then cooled to room temperature (r.t.). Then 4- &gt; odor-2-nitroaniline (2.4 g, 11.0 mmol) was dissolved in ice-cooled acetic acid (22 mL) and added dropwise to the HSOsNO solution while keeping the reaction temperature below 40 ° C . After the addition, the resulting mixture was stirred at room temperature for 30 minutes' and poured into 70 C of 20 mL of an aqueous solution containing KI (2.0 g, 12.00 mmol). Stir for 20 minutes while maintaining temperature, dilute with 150 mL of water, and filter. The precipitate was washed 'true 2 dry' with 50 mL of water to give an orange solid product with a yield of 86%, which was used in the next step without further purification. 1H NMR (CDC13, 300 ΜΗζ) δ 8.00 (d, J 2 3 Ηζ, 1Η), 7.91 (d, J = 9 Ηζ, 1Η), 7.42 (dd, J 2 3, 9 Ηζ, 1Η) . MS (DCI_NH3) [M + H] + 328.8. Example 168B-5-bromo-2-hydrazone-jasmine tincture at 15-18 ° C in 10 mL concentrated HC1 containing SnCl2 (5.20 g, 27.44 mmol) 89248.doc -241-200418454 68A (1.8 g, 5.49 mmol) in ethanol U 4 mL). The resulting mixture was heated to 5 5 ° C for 15 minutes, cooled in an ice bath, saturated with KOH solution to make it alkaline, and extracted with 250 mL of CHC13. The organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100% hexane to 50/50 hexane / methylene chloride) to give a white solid product in a yield of 74%. 4 NMR (CDC13, 300 ΜΗζ) δ 7.47 (d, J = 9 Hz, 1H), 6.88 (d, J = 3 Hz, 1H), 6.62 (dd, J = 3, 9 Hz, 1H) , 4.00 (bs, 1H). MS (DCI-NH3) [M] + 297.

, 言例168C L溴-2-「4-((2R)-2-甲基-吡咯啶-1-基丁-1-炔基μ茉某脖 取含實例 168Β (0·2 g，0.67 mmol)、1-丁 _3_ 块基-(2R)-2-甲基-p比咯淀（7.4 mL之0· 1 Μ乙腈溶液，0.74 mmol)與三乙胺 (10 mL，72.0 mmol)之溶液經氮氣脫氣10分鐘，同時於室溫 下攪拌。然後，添加 Pd(PPh3)2Cl2 (0.010 g，0.013 mmol)與 Cul (〇·〇〇3 g，0.013 mmol)，所得混合物再脫氣1〇分鐘，密 封，於室溫下攪拌1 8小時。其内容物減壓濃縮，殘質溶於 100 mL二氯甲烷中，以各50· mL飽和NaHC〇3、50 mL水與50 mL鹽水洗滌2次，經硫酸鈉脫水，減壓濃縮。粗產物經管 柱層析法純化（100%二氯甲烷至95: 5二氯甲烷/甲醇），產生 產物，收率30%，為淺黃色油狀物。1H NMR (CDC13，300 MHz) δ 7.03 (d，卜9 Hz，1H)，6.88 (d，J=3 Ηζ，1Η)，6.68 (dd， J=3,9Hz，lH)，3.41-3.20(m，2H)，2.79-2.52 (m，5H)，2.12-2·04 (m，lH)，1.92-1.82 (m，2H)，1.56-1.47 (m，1H)，1.25 (d， J=6 Hz，3H)。MS (ESI)[M+H]+ 308。 89248.doc -242 - 200418454Example 168C L bromo-2- "4-((2R) -2-methyl-pyrrolidin-1-ylbut-1-alkynyl μ Moss, a sample containing 168B (0.2 g, 0.67 mmol ), 1-but_3_ block- (2R) -2-methyl-p-pyrrole (7.4 mL of a 0.1 M acetonitrile solution, 0.74 mmol) and triethylamine (10 mL, 72.0 mmol) Degassed with nitrogen for 10 minutes while stirring at room temperature. Then, Pd (PPh3) 2Cl2 (0.010 g, 0.013 mmol) and Cul (0.03 g, 0.013 mmol) were added, and the resulting mixture was degassed for another 1.0. It was sealed for 15 minutes and stirred at room temperature for 18 hours. Its contents were concentrated under reduced pressure, and the residue was dissolved in 100 mL of dichloromethane, washed with 50 mL of saturated NaHC03, 50 mL of water and 50 mL of brine 2 It was then dehydrated with sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (100% dichloromethane to 95: 5 dichloromethane / methanol) to give the product in a 30% yield as a pale yellow oil. 1H NMR (CDC13, 300 MHz) δ 7.03 (d, Bu 9 Hz, 1H), 6.88 (d, J = 3 Ηζ, 1Η), 6.68 (dd, J = 3, 9Hz, 1H), 3.41-3.20 ( m, 2H), 2.79-2.52 (m, 5H), 2.12-2 · 04 (m, 1H), 1.92-1.82 (m, 2H), 1.56-1.47 (m, 1H), 1.25 (d, J = 6 Hz, 3H). MS (ESI) [M + H] + 308. 89248.doc -242-200418454

4j^JL68D 二甲基jA咯啶-1-基 V 乙某 在含實例168C (0.10 g，〇·325 mmol)之2 mL水混合物中添 加1·5 mL 6 M HC1。所得溶液冷卻至〇°c，滴加NaN〇2 (〇 〇34 g ’ 0.488 mmol)之1 mL水〉谷液。所得混合物於〇°c下授掉％ 为叙’然後加熱至9 0 C 1小時。冷卻後，過濾、内容物，沉嚴 物經10 mL水洗滌，減壓乾燥，產生褐色固體之鹽酸鹽型產 物’收率47%，未再純化即使用。1η NMR (CD3OD，300 MHz) δ 8.10 (d，J二9 Hz，1H)，7.82 (d，J=3 Hz，1H)，7·60 (dd，J=3, 9 Hz，1H)，3.89-3.76 (m，2H)，3.58-3.53 (m，1H) 3.42-3.23 (m， 4H)，2.38-2.30 (m，1H)，2.16-2.06 (m，2H)，1.83-1.75 (m， 1H)，1.51 (d，J=6 Hz, 3H)。MS (ESI) [M]十336。 實例1694j ^ JL68D Dimethyl jA pyridin-1-yl V ethoxylate To a 2 mL water mixture containing Example 168C (0.10 g, 0.325 mmol) was added 1.5 mL 6 M HC1. The resulting solution was cooled to 0 ° C, and 1 mL of water> cereal solution of NaNO2 (0034 g '0.488 mmol) was added dropwise. The resulting mixture was allowed to lose %% at 0 ° C and then heated to 90 ° C for 1 hour. After cooling, the contents were filtered and the precipitate was washed with 10 mL of water and dried under reduced pressure to give a brown solid hydrochloride type product with a yield of 47%, which was used without further purification. 1η NMR (CD3OD, 300 MHz) δ 8.10 (d, J = 9 Hz, 1H), 7.82 (d, J = 3 Hz, 1H), 7.60 (dd, J = 3, 9 Hz, 1H), 3.89 -3.76 (m, 2H), 3.58-3.53 (m, 1H) 3.42-3.23 (m, 4H), 2.38-2.30 (m, 1H), 2.16-2.06 (m, 2H), 1.83-1.75 (m, 1H) ), 1.51 (d, J = 6 Hz, 3H). MS (ESI) [M] 336. Example 169

二37基-峨咯啶-l-某vr」其1-噌啉_7-某^_茉某教 實例169 ATwo 37-based-errolidine-l-some vr "its 1-pyridin-7_some ^ _ Mo Mou Example 169 A

1-(2-胺某-4-溴-笨基丁 - 3·块-1-酶 標題化合物係依實例168C之方法製備，但其中改用3-丁 炔-1-醇替代丁 -3—決基_(2R)-2-甲基-吡咯啶。1h NMR (CD3〇D，300 MHz) δ 7.03 (d，J=9 Hz，1H)，6.88 (d，J=3 Hz， 1H)，6.68 (dd，J=3, 9 Hz，1H)，3.73 (t，j=6 Hz，2H)，2·65 (t， &gt;6 Hz，2H)。MS (DCI-NH3) [M]+24〇 [M+NH3]+ 257。 實例169B · 臭- 3- (2 -無基-乙基木·4_醇 標題化合物係依實例168D之方法製備，但其中改用實例 89248.doc -243 - 200418454 169八產物替代實例168(：：產物。1]9[^乂11(€03〇0,3 00 ?^1^)3 8.07 (d，J=：9 Hz，1H)，7·77 (d，J=3 Ηζ，1Η)，7·54 (dd，J=3, 9 Hz，1H)，3.92 (t，J=6 Hz，2H)，3.02 (t，J=6 Hz, 2H)。MS (DCI-NH3)[M]+ 269。1- (2-Amine-4-bromo-benzylbutan-3 · block-1-enzyme The title compound was prepared according to the method of Example 168C, but 3-butyne-1-ol was used instead of but-3- Decanyl_ (2R) -2-methyl-pyrrolidine. 1h NMR (CD30D, 300 MHz) δ 7.03 (d, J = 9 Hz, 1H), 6.88 (d, J = 3 Hz, 1H), 6.68 (dd, J = 3, 9 Hz, 1H), 3.73 (t, j = 6 Hz, 2H), 2.65 (t, &gt; 6 Hz, 2H). MS (DCI-NH3) [M] + 24〇 [M + NH3] + 257. Example 169B · Stinky 3- 3- (2- unradical-ethyl wood · 4-ol The title compound was prepared according to the method of Example 168D, but Example 89248.doc -243 was used instead. -200418454 169 Eight product substitution examples 168 (:: product.1) 9 [^ 乂 11 (€ 03〇0,3 00? ^ 1 ^) 3 8.07 (d, J =: 9 Hz, 1H), 7.77 (d, J = 3 Ηζ, 1Η), 7.54 (dd, J = 3, 9 Hz, 1H), 3.92 (t, J = 6 Hz, 2H), 3.02 (t, J = 6 Hz, 2H) .MS (DCI-NH3) [M] + 269.

實例169CExample 169C

ZzA-4-氯-3-(2-氣-乙基）-噌啉 在含貫例169B產物（〇·20 g，〇·744 mmol)之氯苯（5 mL)攪 拌混合物中添加p〇Cl3 (0.10 mL，1.11 mmol)與無水吡啶 (0·018 ml，〇·223 mmol)。所得混合物加熱至l〇〇°C 1小時， 冷卻至室溫，然後減壓濃縮。殘質經1〇 mL飽和K2C03溶液 中和，以25 mL二氯甲燒萃取2次，濃縮。粗產物經管柱層 析法純化（50 : 50己烷/二氯甲烷至1〇〇〇/。二氯甲烷），產生收 率 42%之褐色固體產物。1H NMR (CDC13, 300 ΜΗζ) δ 8.14 (d，J=9 Ηζ，1Η)，7.54 (d，J=3 Ηζ，1Η)，7.49 (dd，J=3, 9 Ηζ， 1H)，3.95 (t，J=6 Hz，2H)，3.28 (t，J=6 Hz，2H)。MS (DCI-NH3) [M+H]+ 307。ZzA-4-chloro-3- (2-gas-ethyl) -xanthroline was added to a stirred mixture of chlorobenzene (5 mL) containing the product of Example 169B (0.20 g, 0.744 mmol), and pCl3 was added. (0.10 mL, 1.11 mmol) and anhydrous pyridine (0.018 ml, 0.223 mmol). The resulting mixture was heated to 100 ° C for 1 hour, cooled to room temperature, and then concentrated under reduced pressure. The residue was neutralized with 10 mL of a saturated K2C03 solution, extracted twice with 25 mL of dichloromethane, and concentrated. The crude product was purified by column chromatography (50:50 hexane / dichloromethane to 1000 /. Dichloromethane) to give a brown solid product in a yield of 42%. 1H NMR (CDC13, 300 ΜΗζ) δ 8.14 (d, J = 9 Ηζ, 1Η), 7.54 (d, J = 3 Ηζ, 1Η), 7.49 (dd, J = 3, 9 Ηζ, 1H), 3.95 (t , J = 6 Hz, 2H), 3.28 (t, J = 6 Hz, 2H). MS (DCI-NH3) [M + H] + 307.

實例169D 4-「3-(2-氣-乙基V噌啉-7-某V苽某I 取含實例169C產物（0.095 g，0.312 mmol)、4-氰基苯基二 罗I 硼酸（0.046 g，0.343 mmol)、Pd(PPh3)2Cl2 (0.011 g，0.016 mmol)與 1 M Na2C〇3 (0.778 mL，0·778 mmol)之脫氣異丙醇/ 甲苯（5 mL，1 : 1)混合物於無水氮蒙氣下加熱至9〇°C 24小日寺 。冷卻後，反應混合物經20 mL水稀釋，以25 mL二氣甲燒 萃取2次，減壓濃縮。粗產物經管柱層析法純化（100%二氯 89248.doc -244- 200418454 甲烷至99 : 1二氯甲烷/甲醇），產生收率50%之橙褐色固體 產物。4 NMR (CDCI3，300 ΜΗζ) δ 8.76 (d，J=3 Hz，1H)，8·〇2 (dd，J=3，9 Hz，1H)，7.96 (d，J=9 Hz，1H)，7.87 (q，J=9 Hz， 4H)，7.80 (s，1H)，4·14 (t，J=6 Hz，2H)，3.69 (t，J=6 Hz，2H) 。MS (DCI-NH3) [M-C1]+ 258，[M+H]+ 294。Example 169D 4- "3- (2-Gas-Ethyl Vyridin-7-A-V-A-I) A product containing the product of Example 169C (0.095 g, 0.312 mmol), 4-cyanophenyldi-ro-I boronic acid (0.046 g, 0.343 mmol), a mixture of Pd (PPh3) 2Cl2 (0.011 g, 0.016 mmol) and 1 M Na2CO3 (0.778 mL, 0.7778 mmol) in degassed isopropanol / toluene (5 mL, 1: 1) It was heated to 90 ° C 24 Xiaori Temple under anhydrous nitrogen. After cooling, the reaction mixture was diluted with 20 mL of water, extracted twice with 25 mL of dichloromethane, and concentrated under reduced pressure. The crude product was subjected to column chromatography. Purification (100% dichloro 89248.doc -244- 200418454 methane to 99: 1 dichloromethane / methanol) yielded an orange-brown solid product in 50% yield. 4 NMR (CDCI3, 300 ΜΗζ) δ 8.76 (d, J = 3 Hz, 1H), 8.02 (dd, J = 3, 9 Hz, 1H), 7.96 (d, J = 9 Hz, 1H), 7.87 (q, J = 9 Hz, 4H), 7.80 ( s, 1H), 4 · 14 (t, J = 6 Hz, 2H), 3.69 (t, J = 6 Hz, 2H). MS (DCI-NH3) [M-C1] + 258, [M + H] + 294.

實例169E 1二{3-「2-((消旋^逢」-2_甲基-?比哈淀-1-基）-乙某1_嗜|?林-7_某卜 苯基氣 添加消，旋性2_甲基p比洛淀（〇·5 mL，無溶劑）至實例169D 產物（0.01 g，0.034 mmol)中，於密封試管中加熱至65。〇 18 小時。冷卻後，反應混合物減壓濃縮，經管柱層析法純化 (100%二氯甲烷至95: 5二氯甲烷/甲醇），產生收率43%之 黃褐色半固體產物。4 NMR (CD3〇D，300 ΜΗζ) δ 8.72 (m， 1H)，8.20 (dd，J=3, 9 Hz，1Η)，8·16 (s，1H)，8.11 (d，J=9 Hz， 1H)，8.06 (d，J=9 Hz，2H)，7.91 (d，J=9 Hz，2Η)，3·58-3·46 (m， 4H)? 2.85-2.65 (m, 2H)? 2.57-2.51 (m5 iH)? 2.03-1.90 (m5 1H)，1.89-1.83 (m，2H)，1.56-1.50 (m，1H)，121 (d，卜6 Hz， 3H)。MS (ESI) [M+H]十 343。 實例170 Z-i臭-4-氯甲基—:吡务乙某％噌啉 標題化合物係依實例169C之方法製備，但其中改用實例 168D產物替代實例 169B產物。iH NMr (CD3〇D，3⑻ MHz) -s 8·69 (d，J=3 Hz，1H)，8.21 (d，J=9 Ηζ，1Η)，8·07 (dd，J=3，9 Hz，1H)，3.63-3.58 (m，2H)，3.46-3.30 (m，2H)，2.73-2.64 (m， 89248.doc -245 - 200418454 1H)，2.55-2.42 (m，2H)，2.06-1.95 (m，1H)，1.84-1.77 (m， 2H)，1.48-1.41 (m，1H)，1.14 (d，J=6 Hz, 3H)。MS (ESI) [M] + 354。 實例171 4-{4二|^-3-「2-((21〇-2-甲某 ^比咯啶-1-基乙某 1-噌 4 基卜笨基氰 取含實例168D產物（0.30 g，0.805 mmol)、4-氰基苯基二 羥硼酸（0.15 g，1.05 mmol)、Pd(PPh3)2Cl2 (0.03 g，0.04 mmol)、與 1 M Na2C03 (2·01 mL，2·01 mmol)之異丙醇（15 mL)混合物於無水氮蒙氣下加熱至9〇°C下2天。冷卻後，反 應混合物經寅氏鹽過濾，減壓濃縮。粗產物經管柱層析法 純化（100%二氯甲烷至90: 10二氣甲烷/甲醇），產生收率33% 之淺褐色固體產物。h NMR (CD3OD，300 ΜΗζ) δ 8.29 (d， J=9 Ηζ，1Η)，7·95 (q，&gt;9 Ηζ，4Η)，7·83 (d，J=3 Ηζ，1Η)，7·75 (dd，J=3, 9 Hz，1H)，3.49-3.42 (m，2H)，3.17-3.12 (m，2H)， 2.78- 2.73 (m, 2H)5 2.62-2.59 (m, 1H), 2.12-2.09 (m? 1H)5 1.92-1.84 (m，2Η)，1·61-1·53 (m，1H)，1.25 (d，J=6 Hz，3H)。 MS (ESI) [M+H]+ 359。 實例172 基^啶小某乙某卜噌4 _7_基卜笨基氧 標題化合物係依實例171之方法製備，但其中改用實例 170產物替代實例 168D產物。iH NMR (CD3〇d，3〇〇 MHz) s 8.69 (d, J=3 Hz, 1H), 8.32 (d, J=9 Hz, lH), 8.19 (dd,J=3, 9 89248.doc -246 - 200418454Example 169E 1 bis {3- "2-((racemic ^ Feng" -2_methyl-? Bihadien-1-yl) -B 1-1 || Lin-7_ certain phenyl gas addition In the case of acetone, 2-methyl-p-biletone (0.5 mL, solvent-free) to the product of Example 169D (0.01 g, 0.034 mmol) was heated in a sealed test tube to 65.18 hours. After cooling, the reaction The mixture was concentrated under reduced pressure and purified by column chromatography (100% dichloromethane to 95: 5 dichloromethane / methanol) to yield a yellow-brown semi-solid product in 43% yield. 4 NMR (CD3OD, 300 ΜΗζ) δ 8.72 (m, 1H), 8.20 (dd, J = 3, 9 Hz, 1Η), 8.16 (s, 1H), 8.11 (d, J = 9 Hz, 1H), 8.06 (d, J = 9 Hz, 2H), 7.91 (d, J = 9 Hz, 2Η), 3.58-3 · 46 (m, 4H)? 2.85-2.65 (m, 2H)? 2.57-2.51 (m5 iH)? 2.03-1.90 (m5 1H), 1.89-1.83 (m, 2H), 1.56-1.50 (m, 1H), 121 (d, Bu 6 Hz, 3H). MS (ESI) [M + H] ten 343. Example 170 Zi odor -4-Chloromethyl—: Pyridoxine, a certain% phosphonium title compound was prepared according to the method of Example 169C, but the product of Example 168D was used instead of the product of Example 169B. IH NMr (CD3OD, 3⑻ MHz) -s 8 · 69 (d, J = 3 Hz, 1H), 8.21 (d J = 9 Ηζ, 1Η), 8.07 (dd, J = 3, 9 Hz, 1H), 3.63-3.58 (m, 2H), 3.46-3.30 (m, 2H), 2.73-2.64 (m, 89248. doc -245-200418454 1H), 2.55-2.42 (m, 2H), 2.06-1.95 (m, 1H), 1.84-1.77 (m, 2H), 1.48-1.41 (m, 1H), 1.14 (d, J = 6 Hz, 3H). MS (ESI) [M] + 354. Example 171 4- {4 二 | ^ -3- "2-((21〇-2-methyl ^ than pyrrolidin-1-ylethyl) 1- 噌 4 phenylbenzyl cyanide contains the product of Example 168D (0.30 g, 0.805 mmol), 4-cyanophenyldihydroxyboric acid (0.15 g, 1.05 mmol), Pd (PPh3) 2Cl2 (0.03 g, 0.04 mmol ), And a mixture of 1 M Na2C03 (2.01 mL, 2.01 mmol) in isopropanol (15 mL) was heated to 90 ° C for 2 days under an anhydrous nitrogen blanket. After cooling, the reaction mixture was filtered through Yin's salt and concentrated under reduced pressure. The crude product was purified by column chromatography (100% dichloromethane to 90:10 two gas methane / methanol) to give a light brown solid product in 33% yield. h NMR (CD3OD, 300 ΜΗζ) δ 8.29 (d, J = 9 Ηζ, 1Η), 7.95 (q, &gt; 9 Ηζ, 4Η), 7.83 (d, J = 3 Ηζ, 1Η), 7 · 75 (dd, J = 3, 9 Hz, 1H), 3.49-3.42 (m, 2H), 3.17-3.12 (m, 2H), 2.78- 2.73 (m, 2H) 5 2.62-2.59 (m, 1H) , 2.12-2.09 (m? 1H) 5 1.92-1.84 (m, 2Η), 1.61-1-153 (m, 1H), 1.25 (d, J = 6 Hz, 3H). MS (ESI) [M + H] + 359. Example 172 Aminopyridine, Bambu, Bambu 4-7_Bibmyloxy The title compound was prepared according to the method of Example 171, but the product of Example 170 was used instead of the product of Example 168D. iH NMR (CD3Od, 300MHz) s 8.69 (d, J = 3 Hz, 1H), 8.32 (d, J = 9 Hz, lH), 8.19 (dd, J = 3, 9 89248.doc- 246-200418454

Hz，1H)，8.06 (d，J=9 Hz，2H)，7.92，（d，J=9 Hz，2H)， 4.88-4.77 (m，1Η)，3·71-3·49 (m，4H)，3.06-2.91 (m5 2H)， 2.81-2.73 (m，1H)，2.19-2.10 (m，1H)，1.97-1.90 (m，2H)， 1.61-1.53 (m，1H)，1.48 (d，J=6 Hz，6H)，1.25 (d, J二6 Hz，3H) 。MS (ESI)[M+H]+ 401 〇 173 甲基二^^^-基v乙某-噌啉-7_基1_笨基氰 標題化合物係依實例丨69E之方法製備，但其中改用i_ 甲基六氧峨呼替代2_甲基吡咯啶。iH NMR (CD3〇D，300 MHz) δ 8.70 (m，1H)，8·19 (dd，J=3, 9 Hz，1H)，8.13 (s，1H)， 8.11-8.01 (m，3Η)，7·91 (d，J=9 Hz，2H)，3.44 (t，J:6 Hz，2H)， 2.95 (t，J=6 Hz，2H)，2.75-2.45 (m，8Η)，2·28 (s，3H)。MS (ESI)[M+H]+ 358。 實例174 土六氤吡啶-1-基_乙某y噂丄林·7_基1·笨基氰 標題化合物係依實例169E之方法製備，但其中改用六氫 口比呢替代2-甲基吡咯啶。ϋΜΙΙ (CD3〇D，3 00 ΜΗζ) δ 8.70 (m，1Η)，8·19 (dd，J=3, 9 Ηζ，1Η)，8·13 (s，1Η)，8.12-8.04 (m， 3H)，7.91 (d，J=9 Hz，2H)，3.44 (t，Hz，2H)，2.91 (t，J=6 Hz，2H)，2.61 (m，4H)，1.65 (m，4H)，1·5ΐ (m，2H)。MS (ESI) [M+H]+ 343 〇 實例175 - 4-[3-(2-p比洛淀-1-基-乙基）-嗜琳基]-苯基氰 標題化合物係依實例169E之方法製備，但其中改用说哈 89248.doc -247- 200418454 啶替代2-甲基吡咯啶。h NMR (CD3OD，300 MHz) δ 8·71 (m， 1Η)，8.20 (dd，J二3, 9 Ηζ，1Η)，8·15 (s，1Η)，8·11 (d，J=9 Ηζ， 1H)，8.06 (d，J=9 Hz，2H)，7·92 (d，J=9 Hz，2H)，3.50 (t，J二9 Hz, 2H)，3.21 (t，J=9 Hz，2H)，2.85 (m，4H)，1·90 (m，4H)。 MS (ESI) [M + H] + 329。 實例176 4zl3-「2-((2R)-2-甲某-吡咯啶-1-某V乙某1-噌啉-7-某丨-笨基氰Hz, 1H), 8.06 (d, J = 9 Hz, 2H), 7.92, (d, J = 9 Hz, 2H), 4.88-4.77 (m, 1Η), 3.71-3 · 49 (m, 4H ), 3.06-2.91 (m5 2H), 2.81-2.73 (m, 1H), 2.19-2.10 (m, 1H), 1.97-1.90 (m, 2H), 1.61-1.53 (m, 1H), 1.48 (d, J = 6 Hz, 6H), 1.25 (d, J = 6 Hz, 3H). MS (ESI) [M + H] + 401 〇173 Methyldi ^^^-yl v Ethyl-pyridin-7-yl 1-benzyl cyanide Replace 2-methylpyrrolidine with i-methylhexaoxane. iH NMR (CD3OD, 300 MHz) δ 8.70 (m, 1H), 8.19 (dd, J = 3, 9 Hz, 1H), 8.13 (s, 1H), 8.11-8.01 (m, 3Η), 7.91 (d, J = 9 Hz, 2H), 3.44 (t, J: 6 Hz, 2H), 2.95 (t, J = 6 Hz, 2H), 2.75-2.45 (m, 8Η), 2.28 (s, 3H). MS (ESI) [M + H] + 358. Example 174 Geohexapyridin-1-yl_Ethylpyridin · 7_yl1 · Benzylcyanocyanide The title compound was prepared according to the method in Example 169E, but hexahydropyridine was used instead of 2-methyl Pyrrolidine. ϋΜΙΙ (CD3OD, 3 00 ΜΗζ) δ 8.70 (m, 1Η), 8.19 (dd, J = 3, 9 Ηζ, 1Η), 8.13 (s, 1Η), 8.12-8.04 (m, 3H ), 7.91 (d, J = 9 Hz, 2H), 3.44 (t, Hz, 2H), 2.91 (t, J = 6 Hz, 2H), 2.61 (m, 4H), 1.65 (m, 4H), 1 5ΐ (m, 2H). MS (ESI) [M + H] + 343 〇 Example 175-4- [3- (2-pBilodoline-1-yl-ethyl) -linophilyl] -phenylcyanine The title compound is according to Example 169E It was prepared by the method described above, but it was replaced by said pyrene 89248.doc -247- 200418454 pyridine instead of 2-methylpyrrolidine. h NMR (CD3OD, 300 MHz) δ 8.71 (m, 1Η), 8.20 (dd, J 2 3, 9 Ηζ, 1Η), 8.15 (s, 1Η), 8.11 (d, J = 9 Ηζ, 1H), 8.06 (d, J = 9 Hz, 2H), 7.92 (d, J = 9 Hz, 2H), 3.50 (t, J = 9 Hz, 2H), 3.21 (t, J = 9 Hz, 2H), 2.85 (m, 4H), 1.90 (m, 4H). MS (ESI) [M + H] +329. Example 176 4zl3-``2-((2R) -2-methyl-pyrrolidine-1-some V ethyl 1-pyridin-7-some 丨 -benzyl cyanide

取（2R)-2-甲基吡咯啶（L)-酒石酸鹽（1〇〇 g，0.425 mmol) 分溶於甲，苯（〇·5 mL)與5 M NaOH/鹽水（1 : 1，共1 mL)之間 。取有機相加至實例169D產物（0.01 g，0.034 mmol)中，於 密封試管中加熱至85°C 48小時。冷卻後，反應混合物減壓 濃縮’經管柱層析法純化（丨00%二氯甲烷至95: 5二氯甲烷 /甲醇）’產生收率27%之黃色固體產物。1η NMR (CD3〇D，(2R) -2-methylpyrrolidine (L) -tartrate (100 g, 0.425 mmol) was separated and dissolved in formazan, benzene (0.5 mL) and 5 M NaOH / brine (1: 1). 1 mL). The organic phase was added to the product of Example 169D (0.01 g, 0.034 mmol) and heated in a sealed test tube to 85 ° C for 48 hours. After cooling, the reaction mixture was concentrated under reduced pressure 'and purified by column chromatography (00% dichloromethane to 95: 5 dichloromethane / methanol)' to give a yellow solid product in a yield of 27%. 1η NMR (CD3〇D,

300 MHz) δ 8.73 (m，1H)，8.21 (dd，J=3, 9 Hz，1H)，8·14 (s， 1H), 8.12 (d，J=9 Hz，1H)，8.06 (d，J=9 Hz，2H)，7.92 (d，J=9 Hz，2H)，3.72-3.48 (m，4H)，3.15-2.90 (m，2H)，2.86-2.75 (m， 1H)? 2.21-2.10 (m? 1H)5 1.98-1.91 (m? 2H)5 1.67-1.60 (m? 1H), 1·31 (d，J=6 Hz，3H)。MS (ESI) [M+H]+ 343。 實例177 甲基-峨咯基乙基1-噌4 _7-某 苯基氰 ，標題化合物係依實例酬之方法製備，但其中改用⑽ 唉-(2R)·2·基·曱醇替代 2m各唉。4 NMR (CD3〇D，30 MHz) δ 8.71 (m, 1H), 8.19 (dd, J=3, 9 Hz, 1H), 8.15 (s, 1H) 89248.doc -248 - 200418454 8.10 (d，J=9 Ηζ，1Η)，8·06 (d，J=9 Hz，2H)，7.91 (d，J=9 Hz， 2H)，3.58-3.43 (m，4H)，2·92 (m，1H)，2.73 (m，1H)，2.48 (m， 1H)，2.01-1.92 (m，2H)，1.85-1.67 (m，4H)。MS (ESI) [M + H] + 359 ° 實例178 嗎4-4-某-乙基）-噌啉-7-基1-笨基氰 標題化合物係依實例169E之方法製備，但其中改用嗎啉 替代 2-甲基吡咯啶。4 NMR (CD3OD，300 ΜΗζ) δ 8.70 (m， 1H)，8.19“dd，J=3, 9 Hz，1H)，8.14 (s，1H)，8.10 (d，J=9 Hz， 1H)，8.05 (d，J=9 Hz，2H)，7.91 (d，J=9 Hz，2H)，3.70 (t，J=4.5 Hz，4H)，3.44 (t，J=9 Hz，2H)，2.94 (t，J=9 Hz，2H)，2.61 (t， J=4.5 Hz，4H) 〇 MS (ESI) [M+H]+ 345。 實例179 iii..3-「2-(4-甲基-六氤吡啶-i-基乙基μ噌4 某卜笨基氰 標題化合物係依實例169E之方法製備，但其中改用4-甲 基六氫吡啶替代2-甲基吡咯啶。b NMR (CD3OD，300 MHz) δ 8.71 (m，1H)，8.19 (dd，J=3，9 Hz，1H)，8.13 (s，1H)，8·10 (d，J=9 Ηζ，1Η)，8·Ό5 (d，J=9 Hz，2H)，7·91 (d，Hz，2H)， 3.47 (t，J=6 Hz，2H)，3.14 (m，2H)，3·00,（m，2H)，2.26 (m， 2H)，1.73，（m，2H)，1·48_1·44 (m，1H)，1.32-1.28 (ni，2H)， 〇·96 (d，J=6 Hz，3H)。MS (ESI) [M+H]+ 357。 180 (乙基-甲基-胺4)_乙基[噌啉_7_某卜笔盖直^ 標題化合物係依實例169E之方法製備，但其中改用乙基- 89248.doc •249- 200418454 甲基-胺替代2-甲基吡咯啶。士 NMR (CD3OD，300 MHz) δ 8.70 (m，1Η)，8·19 (dd，J二3, 9 Ηζ，1Η)，8.13 (s，1Η)，8.10 (d， J=9 Hz，1H)，8.06 (d，J=9 Hz，2H)，7.91 (d，J=9 Hz，2H)，3·43 (t，J=6 Hz，2H)，2.99 (t，J=6Hz，2H)，2.61 (q，J=9 Hz，2H)， 2.40 (s，3H)，1.12 (t，J-9 Hz, 3H)。MS (ESI) [M+H] + 317。 實例181 7-(2,6-二甲基-吡啶基）-3-「2-((2R)-2-甲某：比咯啶-1-基 乙基1-噌啉 取含實，例 169C產物（0.100 g，0.328 mmol)、2,6·二甲基 -3-(4,4,5,5-四甲基-[1，3,2]二氧硼戊環-2-基）-吡啶（0.077 g， 0.328 mmol)、Pd(PPli3)2Cl2 (0.012 g ’ 0.017 mmol)與 1 Μ300 MHz) δ 8.73 (m, 1H), 8.21 (dd, J = 3, 9 Hz, 1H), 8.14 (s, 1H), 8.12 (d, J = 9 Hz, 1H), 8.06 (d, J = 9 Hz, 2H), 7.92 (d, J = 9 Hz, 2H), 3.72-3.48 (m, 4H), 3.15-2.90 (m, 2H), 2.86-2.75 (m, 1H)? 2.21-2.10 (m? 1H) 5 1.98-1.91 (m? 2H) 5 1.67-1.60 (m? 1H), 1.31 (d, J = 6 Hz, 3H). MS (ESI) [M + H] + 343. Example 177 Methyl-errolylethyl 1-fluorene 4- 7-phenylphenyl cyanide, the title compound was prepared according to the method of the example, but ⑽ 唉-(2R) · 2 · yl · fluorenol was used instead of 2m Each one. 4 NMR (CD3OD, 30 MHz) δ 8.71 (m, 1H), 8.19 (dd, J = 3, 9 Hz, 1H), 8.15 (s, 1H) 89248.doc -248-200418454 8.10 (d, J = 9 Ηζ, 1Η), 8.06 (d, J = 9 Hz, 2H), 7.91 (d, J = 9 Hz, 2H), 3.58-3.43 (m, 4H), 2.92 (m, 1H) , 2.73 (m, 1H), 2.48 (m, 1H), 2.01-1.92 (m, 2H), 1.85-1.67 (m, 4H). MS (ESI) [M + H] + 359 ° Example 178? 4-4-a-ethyl) -pyridin-7-yl 1-benzylcyanocyanide The title compound was prepared according to the method in Example 169E, but the following was used instead Morpholine replaces 2-methylpyrrolidine. 4 NMR (CD3OD, 300 MHz) δ 8.70 (m, 1H), 8.19 "dd, J = 3, 9 Hz, 1H), 8.14 (s, 1H), 8.10 (d, J = 9 Hz, 1H), 8.05 (d, J = 9 Hz, 2H), 7.91 (d, J = 9 Hz, 2H), 3.70 (t, J = 4.5 Hz, 4H), 3.44 (t, J = 9 Hz, 2H), 2.94 (t , J = 9 Hz, 2H), 2.61 (t, J = 4.5 Hz, 4H) 〇MS (ESI) [M + H] + 345. Example 179 iii .. 3- "2- (4-methyl-hexa氤 pyridine-i-ylethyl μ 噌 4 The title compound was prepared according to the method of Example 169E, but 4-methylhexahydropyridine was used instead of 2-methylpyrrolidine. B NMR (CD3OD, 300 MHz) δ 8.71 (m, 1H), 8.19 (dd, J = 3, 9 Hz, 1H), 8.13 (s, 1H), 8.10 (d, J = 9 Ηζ, 1Η), 8 · Ό5 ( d, J = 9 Hz, 2H), 7.91 (d, Hz, 2H), 3.47 (t, J = 6 Hz, 2H), 3.14 (m, 2H), 3.00, (m, 2H), 2.26 (m, 2H), 1.73, (m, 2H), 1.48_1.44 (m, 1H), 1.32-1.28 (ni, 2H), 0.96 (d, J = 6 Hz, 3H). MS (ESI) [M + H] + 357. 180 (Ethyl-methyl-amine 4) _ethyl [xantholin_7_b] Cover the title compound ^ The title compound was prepared according to the method of Example 169E, but the modification was With ethyl-89248.doc • 249-2 00418454 Methyl-amine replaces 2-methylpyrrolidine. NMR (CD3OD, 300 MHz) δ 8.70 (m, 1Η), 8.19 (dd, J 2 3, 9 Ηζ, 1Η), 8.13 (s, 1Η) ), 8.10 (d, J = 9 Hz, 1H), 8.06 (d, J = 9 Hz, 2H), 7.91 (d, J = 9 Hz, 2H), 3.43 (t, J = 6 Hz, 2H ), 2.99 (t, J = 6Hz, 2H), 2.61 (q, J = 9 Hz, 2H), 2.40 (s, 3H), 1.12 (t, J-9 Hz, 3H). MS (ESI) [M + H] + 317. Example 181 7- (2,6-dimethyl-pyridyl) -3- "2-((2R) -2-methyl: than pyrrolidin-1-ylethyl 1-fluorene The porphyrin contains the product of Example 169C (0.100 g, 0.328 mmol), 2,6 · dimethyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxopentyl Cyclo-2-yl) -pyridine (0.077 g, 0.328 mmol), Pd (PPli3) 2Cl2 (0.012 g '0.017 mmol) and 1 μM

Na2C〇3 (〇·820 mL，0.820 mmol)之脫氣異丙醇 / 甲苯（5 mL， 1 : 1)混合物於無水於氮蒙氣下加熱至9 0 °C 2 4小時。冷卻後 ’反應混合物過滤’以20 mL水稀釋’以25 mL二氯甲燒萃 取2次’減壓丨辰縮。然後取（2 R) - 2 -甲基。比p各淀（l ) _酒石酸鹽 (.100 g，〇·425 mmol)分溶於甲苯（0.5 mL)與 5 M NaOH/鹽水 (1 : 1，共1 mL)之間。甲苯相（0.5 mL)隨後加至含上述粗產 物之乙腈（3 mL)溶液中，所得混合物於密封試管中加熱至 8 5 °C 4 8小時。冷卻時，混合物減壓濃縮，經管柱層析法純 化（100%二氯曱烷至95: 5二氯甲燒/甲醇），產生標題化合物 。4 NMR (CD3OD，300 ΜΗζ) δ 8.38 (m，1H)，8.19 (s，ih), 8.06 (d，J=9 Hz，1H)，7·84 (dd，J=3, 9 Hz，1H)，7·76 (d，J=9 Hz，1H)，7.27 (d，J=9 Hz，1H)，3.52_3·28 (m，4H)，2.78-2.62 (m，2H)，2·59 (s，3H)，2.52 (s，3H)，2.46&gt;2.39 (m，1H)，2 〇8_ 89248.doc -250- 200418454 1.98 (m5 1H)? 1.86-1.78 (m? 2H)? 1.56-1.42 (m5 1H)5 1.18 (d? 卜6 Hz，3H)。Ms (ESI) [M+H] + 347。 實例182 甲基-吡咯啶-1-基)-乙基1-噌基卜笨基氰 標題化合物係依實例1 8 1之方法製備，但其中改用3-氰基 苯基二羥硼酸替代2,6-二甲基-3-(4,4,5,5-四甲基-[1，3,2]二 氧硼戊環 _2_ 基）-吡啶。iH NMr (CD3〇D，3〇〇 ΜΗζ) δ 8.73 (m，1Η)，8.28-8.13 (m，5Η)，7.83 (dd，J=3, 9 Ηζ，1Η)，7.76 (d， Hz，ih)，3.82-3.60 (m，4H)，3·41-3·28 (m，2H)，3.18-3.06 (m，1H)，2.36-2.21 (m，1H)，2·13-2·〇2 (m，2Η)，1·78-1·71 (m， 1]«)，1·41 (d，J=6 Hz，3H)。MS (ESI) [M+H]+ 343。 , 實例185 基-吡咯啶小幕上^乙基l-噌u—某菸篡氧 標題化合物係依實例181之方法製備，但其中改用 5-(4,4,5,5-四甲基-[1，3,2]二氧硼戊環_2-基）_菸基氰替代2,6_ 二甲基-3-(4,4,5,5-四甲基-[1，3,2]二氧硼戊環_2-基）_吡啶。 !H NMR (CD3〇D5 300 MHz) δ 9.36 (m5 1Η)? 9.03 (m? 1Η)5 8.84 (s，1Η)，8·78 (m，1Η)，8.28-8.24 (m，2Η)，8.19 (d，J=9A mixture of Na2C03 (0 · 820 mL, 0.820 mmol) in degassed isopropanol / toluene (5 mL, 1: 1) was heated to 90 ° C for 2 hours under anhydrous nitrogen. After cooling, the reaction mixture was filtered, diluted with 20 mL of water, and extracted with 25 mL of dichloromethane. The pressure was reduced and reduced. Then take (2 R)-2 -methyl. Each of the precipitates (l) _tartrate (.100 g, 0.425 mmol) was separately dissolved in toluene (0.5 mL) and 5 M NaOH / brine (1: 1, a total of 1 mL). The toluene phase (0.5 mL) was then added to a solution of the above crude product in acetonitrile (3 mL), and the resulting mixture was heated in a sealed tube to 8 5 ° C for 4 8 hours. When cooling, the mixture was concentrated under reduced pressure and purified by column chromatography (100% dichloromethane to 95: 5 dichloromethane / methanol) to give the title compound. 4 NMR (CD3OD, 300 MHz) δ 8.38 (m, 1H), 8.19 (s, ih), 8.06 (d, J = 9 Hz, 1H), 7.84 (dd, J = 3, 9 Hz, 1H) , 7.76 (d, J = 9 Hz, 1H), 7.27 (d, J = 9 Hz, 1H), 3.52_3 · 28 (m, 4H), 2.78-2.62 (m, 2H), 2.59 ( s, 3H), 2.52 (s, 3H), 2.46 &gt; 2.39 (m, 1H), 2 0_89248.doc -250- 200418454 1.98 (m5 1H)? 1.86-1.78 (m? 2H)? 1.56-1.42 (m5 1H) 5 1.18 (d? Bu 6 Hz, 3H). Ms (ESI) [M + H] + 347. Example 182 Methyl-pyrrolidin-1-yl) -ethyl 1-fluorenylbenzyl cyanocyanide The title compound was prepared according to the method in Example 181, but 3-cyanophenyldihydroxyboronic acid was used instead of 2 , 6-Dimethyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxolane-2-yl) -pyridine. iH NMr (CD3OD, 300MΗζ) δ 8.73 (m, 1Η), 8.28-8.13 (m, 5Η), 7.83 (dd, J = 3, 9 Ηζ, 1Η), 7.76 (d, Hz, ih ), 3.82-3.60 (m, 4H), 3.41-3 · 28 (m, 2H), 3.18-3.06 (m, 1H), 2.36-2.21 (m, 1H), 2.13-2 · 〇2 (m, 2Η), 1.78-1 · 71 (m, 1] «), 1.41 (d, J = 6 Hz, 3H). MS (ESI) [M + H] + 343. Example 185 Ethyl-pyrrolidine on the small screen ^ ethyl l- 噌 u—The title compound was prepared according to the method of Example 181, but 5- (4,4,5,5-tetramethyl -[1,3,2] Dioxolane_2-yl) _nicotinyl cyanide instead of 2,6_dimethyl-3- (4,4,5,5-tetramethyl- [1,3, 2] Dioxolan-2-yl) -pyridine. ! H NMR (CD3OD5 300 MHz) δ 9.36 (m5 1Η)? 9.03 (m? 1Η) 5 8.84 (s, 1Η), 8.78 (m, 1Η), 8.28-8.24 (m, 2Η), 8.19 (d, J = 9

Hz? 1H)? 4.16-3.97 (m5 1H)? 3.82-3.57 (m5 5H)? 3.38-3.26 (m5 1H)? 2.41-2.32 (m? IH), 2.29-2.17 (m? 2H)? 1.84^1.78 (m! 1H), 1.43 (d，J=6 Hz，3H)。MS (ESI) [M+H]+ 344。 實例186 氟-苯基- 3 -「2 - ((2 R_) - 2 -甲基-也曾啉 標題化合物係依實例181之方法製備，但其中改用心氣苯 基二羥硼酸替代2,6-二甲基-3-(4,4,5,5-四甲基-Π，3,2]二氧 硼戊環-2_基）-吡啶。1H NMR (CD3〇D，3〇〇 MHz) s 8·62 加 1Η)，8·21-8·07 (m，3Η)，7.92-7.87 (m，2Η)，7 33-7 25 ㈤，2印 89248.doc - 252 - 200418454 4.03- 3.95 (m，1H)，3.83-3.53 (m，5H)，3.07-2.99 (m，1H)， 2.41-2.30 (m? lH)5 2.18-2.10 (m? 2H)? 1.82-1.77 (m? 1H)? 1.43 (d，J=6 Hz，3H)。MS (ESI) [M+H] + 336。 實例187 {3-「2-比咯啶小基八乙某卜噌啉某卜吡咯 -1-羧酸第三丁 標題化合物係依實例181之方法製備，但其中改用1-(第三 丁氧羰基）晚鳴_2-二羥硼酸替代2,6-二甲基-3-(4,4,5,5-四甲 基 _[1，3,2J 一氧硼戊環基）吡啶。1]H nmr (CD3OD，300 ΜΗΖ) δ 8·36 (m，1Ή)，8.19 (s，1H)，7.96 (d，&gt;9 Hz，1H)，7·87 ⑽，J—3, 9 Hz，1Ή)，7·47 (m，1H)，6.47 (m，1H)，6.37 (m，1H)， 4.03- 3.95 (m5 iH)5 3.82-3.5 1 (m5 5H)?3.27-3.23 (m? 1H), 2.38-2.27 (m5 iH)? 2.18-2.06 (m? 2H)? 1.82-1.77 (m, 1H)? 1.42 (d, 1=6 〇tt、 Ηζ，3H)，1.38 (s，9H)。MS (ESI) [M+H]+ 407。 實例188 ^ ^ ^ 基-P比洛淀-1 -基）-乙基1 -嗜淋-7 -基卜苯 基.V甲醇 標題化合物你^ 乃係依貫例18 1之方法製備，但其中改用3-(羥基 -甲基）苯基-^ 1 一沒硼酸替代2,6-二甲基_3_(4,4,5,5_四甲基 [，3,2]一氧硼戊環-2-基）-吡啶。1H NMR (CD3OD，300 MHz) δ 8.62 (m 1 Η、 〇 ’ ），8.19-8.03(m，3H)，7.83-7.76 (m，2H)，7.57- 7.43 (m, 2H) 4 Ίέ：, - 八 4·76 (s，2Η)，3·58-3·38 (m，4H)，2.84-2.45 (m， 3H), 2.12-2 〇2 r (m5 1H)，1.92-1.82 (m，2H)，1·57-1·46 (m， 1H), 1.21 (d 、，J 6 Hz，3H)。MS (ESI) [M+H]+ 348。 89248.doc 200418454 7 實例189 甲基-吡咯啶-1-某V乙基1-噌啉 標題化八％ 广 &quot;切係依實例181之方法製備，但其中改用3,5-二 氟笨基二声_ # 一 ^ 工別馱替代2,6-二甲基_3-(4,4,5,5-四甲基-[1，3,2] '一氧石朋戊環-9甘 △基）、吡啶。4 NMR (CD3〇D，300 ΜΗζ) δ 8.60 (m5 1H)? 8 22 r • z (s，1H)，8.10-8.03 (m，2H)，7.81-7.75 (m，1H)， 7.23-7 17 vm，2Η)，4·05-3·96 (m，1H)，3.82-3.51 (m，5H)， 3.27-3 23 rm • Vm，阳)，2.38-2.27 (m，1H)，2.18-2.06 (m，2H)， 82 l’7;(m，iH)，ι·42 (d，J二ό Hz，3H)。MS (ESI) [M+H] + 354 〇 膏例190 ^ ^比鳴-症-1-基V乙某]-7 -違吩-3 -基·p曾淋 t通化a物係依實例181之方法製備，但其中改用3-p塞吩 一羥硼酸替代2,6·二甲基-3-(4,4,5,5-四甲基m2]二氧硼 戊環-2-基）-吡啶。lH NMR (CD3OD，300 ΜΗζ) δ 8.63 (m， 1Η)，8·28 (dd，J=3, 9 Ηζ，㈤，8.18 (s，1Η)，8.05 (m，2Η)， 7.76 (m，1H)，7.63 (m，1H)，4.05-3.96 (m，1H)，3.83-3.52 (m， 5H)，3.27-3.23 (m，ih)，2.41-2.30 (m，1H)，2 l8-2 〇6 (m， 2H)，1.83-1.77 (m，1H)，1.43 (d，J=6 Hz，3H)。MS (ESI) [M+H]+ 324。 f 例 191 7-(4-氣,-苯基 標題化合物係依實例181之方法製備，但其中改用4_氣 苯基二羥硼酸替代2,6-二甲基-3-(4,4,5,5-四甲基-[H2]二 89248.doc -254- 200418454 氧爛戊if 〇 # 衣基）-吡啶。1Η NMR (CD3〇D，300 MHz) δ 8·64 (m，iH) r 〇1。 ，121-8.06 (m，3H)，7.88-7.82 (m，2H)，7.60-7.54 (m， 2H)5 4 . ，3·96 (m，1H)，3.83-3.53 (m，5H)，3.07-2.99 (m， 2·41、2·30 (m，ih)，2.18-2.09 (m，2H)，1.82-1.76 (m， 1 Η) I44/1 (d，J=6 Hz，3H)。MS (ESI) [M+H]+ 352。 實例192 甲某-吡咯啶-i-基 v 乙基 μ 嗜？林 ^Α合物係依實例181之方法製備，但其中改用4-乙氧 基苯基一羥硼酸替代2,6-二甲基-3-(4,4,5,5-四甲基-[1，3,2] 一氧爛戊環 _2-基）_吡啶。4 NMR (CD3OD，300 ΜΗζ) δ 8.59 (m，出），8.21 (dd，J=3, 9 Ηζ，1Η)，8.18 (s，1Η)，8.06 (d，J=9 Hz，1H)，7.82-7.78 (m，2H)，7.10-7.06 (m，2H)，4.14 (q，J=6 Hz，2H)，4·〇5-3·97 (m，1H)，3.83-3.55 (m，5Η)，3·07-2·98 (m， 1H)，2.41-2.30 (m，1H)，2.19-2.07 (m，2H)，1.82-1.76 (m， 1H)，1.44 (t，J=6 Hz，3H), 1·41 (d，J=6 Hz，3H)。MS (ESI) [M+H]+ 362 〇 實例193 1zIML2R)-2-甲某-吡咯啶-1-基V乙基1-7-ΠΗ-吡咯 在含貫例187產物（0.007 g’ 0.017 mmol)之四氫咬喃（2 mL) 落液中添加NaOMe (0.03 mL，25%甲醇溶液），於室溫下擅; 拌3小時。反應混合物減壓濃縮，再溶於水（2 mL)中，以乙 酸乙酯（2 mL)萃取，經硫酸鈉脫水與濃縮，產生收率76%之 黃色固體產物。1H NMR (CD3OD，300 ΜΗζ) δ 8.31 (m，1H) 89248.doc -255 - 200418454 8.02 (dd，J=3, 9 Ηζ，1Η)，7·90 (s，1H)，7.79 (d，J=9 Hz，1H)， 6.89 (m，1H)，6·71 (m，1H)，6.18 (m，1Η)，3·33-3·19 (m，4H)， 2.53-2.22 (m5 3H)5 1.96-1.87 (m, 1H)5 1.77- 1.64 (m5 2H)5 1.43-1.37 (m，1H)，1.06 (d，J=6 Hz，3H)。MS (ESI) [M+H] + 307 ° 實例194 基）-6-{2-「i2RV2-甲甚-1-岫呔政 基1乙基} - 口套啦 標題化，合物係依實例57之方法製備，但其中改用ι_(1，5-一甲基·1Η-峨唾基）_乙酮（參考文獻ρ· Schen_ et al，jHz? 1H)? 4.16-3.97 (m5 1H)? 3.82-3.57 (m5 5H)? 3.38-3.26 (m5 1H)? 2.41-2.32 (m? IH), 2.29-2.17 (m? 2H)? 1.84 ^ 1.78 (m! 1H), 1.43 (d, J = 6 Hz, 3H). MS (ESI) [M + H] + 344. Example 186 Fluoro-phenyl-3-"2-((2 R_)-2 -methyl-yanthroline" The title compound was prepared according to the method of Example 181, but instead of 2,6 phenyl dihydroxyboronic acid -Dimethyl-3- (4,4,5,5-tetramethyl-Π, 3,2] dioxolane-2-yl) -pyridine. 1H NMR (CD3OD, 300MHz ) s 8.62 plus 1Η), 8.21-8 · 07 (m, 3Η), 7.92-7.87 (m, 2Η), 7 33-7 25 ㈤, 2 seals 89248.doc-252-200418454 4.03- 3.95 (m, 1H), 3.83-3.53 (m, 5H), 3.07-2.99 (m, 1H), 2.41-2.30 (m? lH) 5 2.18-2.10 (m? 2H)? 1.82-1.77 (m? 1H) 1.43 (d, J = 6 Hz, 3H). MS (ESI) [M + H] + 336. Example 187 {3-``2-Pyrrolidine small group octamethoxine oxoporphyrin oxpyrrole-1- The title compound of carboxylic acid tert-butyl was prepared according to the method of Example 181, but 1- (tertiary butoxycarbonyl) wanming_2-dihydroxyboronic acid was used instead of 2,6-dimethyl-3- (4, 4,5,5-tetramethyl_ [1,3,2J monooxolanyl] pyridine. 1] H nmr (CD3OD, 300 ΜΗZ) δ 8.36 (m, 1Ή), 8.19 (s, 1H ), 7.96 (d, &gt; 9 Hz, 1H), 7.87 ⑽, J-3, 9 Hz, 1Ή), 7.47 (m, 1H), 6.47 (m, 1H), 6.37 (m, 1H ) 4.03- 3.95 (m5 iH) 5 3.82-3.5 1 (m5 5H)? 3.27-3.23 (m? 1H), 2.38-2.27 (m5 iH)? 2.18-2.06 (m? 2H)? 1.82-1.77 (m, 1H )? 1.42 (d, 1 = 6 〇tt, Ηζ, 3H), 1.38 (s, 9H). MS (ESI) [M + H] + 407. Example 188 ^ ^ ^ Billodiline -1- ) -Ethyl 1-Lymphophil-7-yl phenyl. V The title compound of methanol was prepared in accordance with the method of Example 18 1 except that 3- (hydroxy-methyl) phenyl- ^ was used instead. 1 Monoboric acid replaces 2,6-dimethyl-3 ((4,4,5,5_tetramethyl [, 3,2] monooxolan-2-yl) -pyridine. 1H NMR (CD3OD, 300 MHz) δ 8.62 (m 1 Η, 〇 ′), 8.19-8.03 (m, 3H), 7.83-7.76 (m, 2H), 7.57- 7.43 (m, 2H) 4 Ί:--8 4.76 ( s, 2Η), 3.58-3 · 38 (m, 4H), 2.84-2.45 (m, 3H), 2.12-2 〇2 r (m5 1H), 1.92-1.82 (m, 2H), 1.57 -1 · 46 (m, 1H), 1.21 (d, J 6 Hz, 3H). MS (ESI) [M + H] + 348. 89248.doc 200418454 7 Example 189 Methyl-pyrrolidin-1-one Vethyl 1-pyridinium titled eight% Cantonese "was prepared according to the method of Example 181, but 3,5-difluorobenzine was used instead.基 二 声 _ # 一 ^ Gongbeiyi instead of 2,6-dimethyl_3- (4,4,5,5-tetramethyl- [1,3,2] 'Monoxide Glycyl), pyridine. 4 NMR (CD3OD, 300 MHz) δ 8.60 (m5 1H)? 8 22 r • z (s, 1H), 8.10-8.03 (m, 2H), 7.81-7.75 (m, 1H), 7.23-7 17 vm, 2Η), 4.05-3.96 (m, 1H), 3.2-3.51 (m, 5H), 3.27-3 23 rm • Vm, male), 2.38-2.27 (m, 1H), 2.18-2.06 (m, 2H), 82 l'7; (m, iH), ι · 42 (d, J Er Hz, 3H). MS (ESI) [M + H] + 354 〇 Paste Example 190 ^ ^ Biming-Zheng-1-yl V Yimou] -7-phenphen-3-yl-p-Zenglintongtonga System according to Example 181 Prepared by the method, but in which 3-p-thiophene monohydroxyboronic acid was used instead of 2,6 · dimethyl-3- (4,4,5,5-tetramethylm2] dioxolane-2-yl ) -Pyridine. lH NMR (CD3OD, 300 ΜΗζ) δ 8.63 (m, 1Η), 8.28 (dd, J = 3, 9 Ηζ, ㈤, 8.18 (s, 1Η), 8.05 (m, 2Η), 7.76 (m, 1H ), 7.63 (m, 1H), 4.05-3.96 (m, 1H), 3.83-3.52 (m, 5H), 3.27-3.23 (m, ih), 2.41-2.30 (m, 1H), 2 l8-2. 6 (m, 2H), 1.83-1.77 (m, 1H), 1.43 (d, J = 6 Hz, 3H). MS (ESI) [M + H] + 324. f Example 191 7- (4-Gas, -The phenyl title compound was prepared according to the method of Example 181, but 4- 4-phenylphenylboronic acid was used instead of 2,6-dimethyl-3- (4,4,5,5-tetramethyl- [ H2] di 89248.doc -254- 200418454 oxolamine 〇 # 衣 基 -pyridine. 1。 NMR (CD3OD, 300 MHz) δ 8.64 (m, iH) r 〇1, 121-8.06 ( m, 3H), 7.88-7.82 (m, 2H), 7.60-7.54 (m, 2H) 5 4., 3.96 (m, 1H), 3.83-3.53 (m, 5H), 3.07-2.99 (m, 2.41, 2.30 (m, ih), 2.18-2.09 (m, 2H), 1.82-1.76 (m, 1 Η) I44 / 1 (d, J = 6 Hz, 3H). MS (ESI) [ M + H] + 352. Example 192 A certain-pyrrolidine-i-yl v ethyl μ phosphonium ^ A compound was prepared according to the method of Example 181, but 4-ethoxyphenyl monohydroxy was used instead. Boric acid replacement 2 , 6-dimethyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxolan-2-yl) _pyridine. 4 NMR (CD3OD, 300 ΜΗζ) δ 8.59 (m, out), 8.21 (dd, J = 3, 9 Ηζ, 1Η), 8.18 (s, 1Η), 8.06 (d, J = 9 Hz, 1H), 7.82-7.78 (m, 2H), 7.10-7.06 (m, 2H), 4.14 (q, J = 6 Hz, 2H), 4.05-3 · 97 (m, 1H), 3.83-3.55 (m, 5Η), 3.07-2 · 98 (m, 1H), 2.41-2.30 (m, 1H), 2.19-2.07 (m, 2H), 1.82-1.76 (m, 1H), 1.44 (t, J = 6 Hz, 3H), 1.41 ( d, J = 6 Hz, 3H). MS (ESI) [M + H] + 362 〇 Example 193 1zIML2R) -2-methyl-pyrrolidin-1-yl V ethyl 1-7-ΠΗ-pyrrole containing the product of Example 187 (0.007 g '0.017 mmol Add NaOMe (0.03 mL, 25% methanol solution) to the falling solution of tetrahydrobitan (2 mL), and stir at room temperature; stir for 3 hours. The reaction mixture was concentrated under reduced pressure, redissolved in water (2 mL), extracted with ethyl acetate (2 mL), dehydrated and concentrated with sodium sulfate, to give a yellow solid product with a yield of 76%. 1H NMR (CD3OD, 300 ΜΗζ) δ 8.31 (m, 1H) 89248.doc -255-200418454 8.02 (dd, J = 3, 9 Ηζ, 1Η), 7.90 (s, 1H), 7.79 (d, J = 9 Hz, 1H), 6.89 (m, 1H), 6.71 (m, 1H), 6.18 (m, 1Η), 3.33-3 · 19 (m, 4H), 2.53-2.22 (m5 3H) 5 1.96-1.87 (m, 1H) 5 1.77- 1.64 (m5 2H) 5 1.43-1.37 (m, 1H), 1.06 (d, J = 6 Hz, 3H). MS (ESI) [M + H] + 307 ° Example 194 group) -6- {2- "i2RV2-methyl even-1-fluorenyl 1ethyl}-Mouthpiece titled, compound system according to Example 57 Method, but in which ι_ (1,5-monomethyl · 1Η-esialyl) _ethyl ketone was used instead (Reference ρ · Schen_ et al, j

Heterocycl. Chem· 19，1982，1355-1361)替代 l-(l，3-口塞唑-2- 基）-乙酉同。1H NMR (300 MHz，CD30D) S 1·20 (d，J=6 Hz，3 H)，1.5 (m，1H)，1.84 (m，2H)，2.07 (m，1H)，2.60 (m，3 H)， 2.72 (s，3 H)，3·〇5 (m，2H)，3.23 (m，1H)，3.35 (m，1H)，3·1 (s，3 H)，7·64 (dd，J=9 Hz，J=3 Hz，1H)，7.69 (d，J=9 Hz，1H)， 7·73 (d，J=1.70 Hz，1H)，7·94 (d，J=9 Hz，1H)，7.96 (d，J=1.70 Hz，1H)，8·22 (d，J=9 Hz，1H); (DCI/NH3) m/z 335 (M+H)+。 實例195 生物活性測定法 為測定本發明代表性化合物作為組織胺_3受體配位體（h3 受體配位體）之有效性，依據過去噌說明之方法進行下列試 驗（European Journal of Pharmacology, 188:219-227 (1990); Journal of Pharmacology and Experimental Therapeutics, 275: 598-604 (1995); Journal of Pharmacology and Experimental 89248.doc - 256 - 200418454Heterocycl. Chem. 19, 1982, 1355-1361) replaces l- (l, 3-orosezol-2-yl) -acetamidine. 1H NMR (300 MHz, CD30D) S 1.20 (d, J = 6 Hz, 3 H), 1.5 (m, 1H), 1.84 (m, 2H), 2.07 (m, 1H), 2.60 (m, 3 H), 2.72 (s, 3 H), 3.05 (m, 2H), 3.23 (m, 1H), 3.35 (m, 1H), 3.1 (s, 3 H), 7.64 (dd , J = 9 Hz, J = 3 Hz, 1H), 7.69 (d, J = 9 Hz, 1H), 7.73 (d, J = 1.70 Hz, 1H), 7.94 (d, J = 9 Hz , 1H), 7.96 (d, J = 1.70 Hz, 1H), 8.22 (d, J = 9 Hz, 1H); (DCI / NH3) m / z 335 (M + H) +. Example 195 Biological activity assay To determine the effectiveness of a representative compound of the present invention as a histamine_3 receptor ligand (h3 receptor ligand), the following test was performed according to the method described in the past (European Journal of Pharmacology, 188: 219-227 (1990); Journal of Pharmacology and Experimental Therapeutics, 275: 598-604 (1995); Journal of Pharmacology and Experimental 89248.doc-256-200418454

Therapeutics，276:1009-1015 (1996);與Biochemical Pharmacology， 22:3099-3108 (1973)) ° 簡言之，取雄性Sprague-Dawley大老鼠之腦皮質（1 g組織 /1 0 mL緩衝液）於50 mM Tris-HCl/5 mM EDTA (含蛋白酶抑 制劑混合液（Calbiochem藥廠）），使用均質器（polytron)設定 在20,500 rpm下均質化。均質液於40,000 X g下離心20分鐘 。傾析上澄液，離心塊稱重。離心塊於均質器中再懸浮於 40 mL 50 mM Tris-HCl/5 mM EDTA (含蛋白酶抑制劑）中均 質化，於,40,000 X g下離心20分鐘。取膜之離心塊再懸浮於 6.25倍體積（每克離心塊濕重）之50 mM Tris-HCl/5 mM EDTA (含蛋白酶抑制劑）中，分小份於液態氮中急速冷凍， 保存在-70°C下直到用於分析為止。大老鼠腦皮質膜（12 mg 濕重/支試管）與（3Η)-Ν-α-甲基組織胺（約0.6 nM)，在含或不 含H3受體揭抗劑下培養，總培養體積為0.5 mL 50mM Tris-HCl/5 mM EDTA (pH 7·7)。取試驗化合物溶於DMSO 中 ，產生20 mM溶液，經一系列稀釋後，加至培養混合物中 ，然後添加膜，開始進行培養分析法。使用硫普醯胺 (Thioperamide)(3 μΜ)來測定非專一結合性。於25°C下進行 結合性培養30分鐘後，添加2 mL冰冷50 mM Tris-HCl (pH 7.7)中止反應，經浸泡過0.3%聚乙二亞胺之Unifilter過濾板 (Packard)過濾。此等濾器再經各2 mL冰冷50 mM Tris-HCl 洗滌4次，乾燥1小時。採用液體閃爍計數器測定放射活性 。其結果採用Hill轉換法分析，使用Cheng-Prusoff公式決定 89248.doc -257- 200418454 一般而言，本發明代表性化合物已在上述分析法中證實 其結合親和性為約8 10 ιιΜ至約0 · 12 nM。本發明較佳化合物 與組織胺-3受體結合之親和性為約1〇〇 nM至約0·12 nM。本 發明更佳化合物與組織胺-3受體結合之親和性為約2〇 nM 至約 0.12 nM。 本發明化合物為藉由改變受體之活性而調節組織胺受 體功能之組織胺-3受體配位體。此等化合物可為抑制受體 基礎活性之反促效劑，或其可為完全阻斷活化受體之促效 劑作用之^擷抗劑。此等化合物亦可為部份阻斷或部份活化 _ 組織胺-3受體之部份促效劑，或其可為活化受體之促效劑。 咸了解，上述詳細說明與實例僅供說明，並未限制本發 明之範圍，本發明之範圍僅受附錄之申請專利範圍及其同 等物之限制。習此相關技藝之人士咸了解所揭示具體實施 例·^多種變化與修飾。此等變化與修飾（包括本發明彼等相 關（化學結構式、取代基、衍生物、中間物、合成法、調 配物與/或使用方法）均可在不偏離其精神與範圍下進行。 89248.doc -258-Therapeutics, 276: 1009-1015 (1996); and Biochemical Pharmacology, 22: 3099-3108 (1973)) ° In brief, the cerebral cortex of male Sprague-Dawley rats (1 g tissue / 1 0 mL buffer) Homogenize at 50 mM Tris-HCl / 5 mM EDTA (protease inhibitor-containing mixture (Calbiochem)) using a polytron setting at 20,500 rpm. The homogenate was centrifuged at 40,000 X g for 20 minutes. Decant the clear solution and weigh the centrifuge block. The centrifuge block was resuspended in a homogenizer in 40 mL of 50 mM Tris-HCl / 5 mM EDTA (with protease inhibitor) and homogenized, and centrifuged at 40,000 X g for 20 minutes. The centrifuged block of the membrane was resuspended in 50 mM Tris-HCl / 5 mM EDTA (containing protease inhibitor) at 6.25 times the volume (wet weight per gram of centrifuged block), frozen in small portions in liquid nitrogen, and stored frozen in- At 70 ° C until used for analysis. Rat cerebral cortex (12 mg wet weight per test tube) and (3Η) -N-α-methylhistamine (about 0.6 nM), cultured with or without H3 receptor antagonist, total culture volume 0.5 mL of 50 mM Tris-HCl / 5 mM EDTA (pH 7 · 7). The test compound was dissolved in DMSO to produce a 20 mM solution. After a series of dilutions, it was added to the culture mixture, and then the membrane was added to start the culture analysis method. Thioperamide (3 μM) was used to determine non-specific binding. After performing incubation at 25 ° C for 30 minutes, the reaction was stopped by adding 2 mL of ice-cold 50 mM Tris-HCl (pH 7.7), and filtered through a Unifilter filter plate (Packard) soaked with 0.3% polyethyleneimine. These filters were washed 4 times with 2 mL of ice-cold 50 mM Tris-HCl and dried for 1 hour. Radioactivity was measured using a liquid scintillation counter. The results were analyzed using the Hill conversion method, and Cheng-Prusoff formula was used to determine 89248.doc -257- 200418454. In general, the representative compounds of the present invention have been confirmed in the above analysis to have a binding affinity of about 8 10 μM to about 0 · 12 nM. The affinity of the preferred compounds of the present invention for binding to the histamine-3 receptor is from about 100 nM to about 0.12 nM. A better compound of the present invention has an affinity for binding to the histamine-3 receptor from about 20 nM to about 0.12 nM. The compounds of the present invention are histamine-3 receptor ligands that modulate the function of the histamine receptor by altering the activity of the receptor. These compounds may be anti-agonists that inhibit the basic activity of the receptor, or they may be anti-agonists that completely block the effect of the agonist that activates the receptor. These compounds can also be partial agonists that partially block or partially activate the histamine-3 receptor, or they can be agonists that activate the receptor. It is understood that the above detailed description and examples are for illustration only, and do not limit the scope of the present invention, and the scope of the present invention is limited only by the scope of the appended patent applications and their equivalents. Those skilled in the art will understand the specific embodiments disclosed ^ various changes and modifications. These changes and modifications (including their related to the present invention (chemical structural formula, substituents, derivatives, intermediates, synthetic methods, formulations and / or methods of use) can be made without departing from its spirit and scope. 89248 .doc -258-

Claims (1)

200418454 拾、申請專利範固： •—種式⑴化合物：200418454 Patent application and application: • —Species ⑴ compounds: 或其醫藥上可接受之鹽類、酯類、醯胺類或前藥，其中： ¥與¥分別獨立選自下列組成之群中：CH、CF與N ; X、X、2與2’分別獨立為C或N ; Rl 與 R*2 中之一&gt; 係選自下列組成之群中：鹵素、氰基、 與 L2R6 ; Ri與R2中另-個係選自下列組成之群中：氫、燒基、 、氧土芳基、環烷基、鹵素、氰基與硫烷氧基，但其 限制條件為當Z，為N時則r2不存在； 田X為N時則&amp;不存在，或I係選自下列組成之群中 •氬烷基、烷氧基、卣素、氰基與硫烷氧基； 當Z為N時則Rsa不存在，或係選自下列組成之群中 •氫、甲基、烷氧基、画素與氰基； s X為N時則Rsb不存在，或係選自下列組成之群中 •氫、烷基、烷氧基、由素、羥基、氰基與硫烷氧基 IU與R5分別獨立選自下列組成之群中··烷基、鹵烷基 、羥烷基、烷氧烷基、環烷基、環烷基烷基及（NRaRb) 89248.doc 200418454 氮原子共同形成如下武之 ^基’或I與r5與其所附接之 非芳香環：Or a pharmaceutically acceptable salt, ester, amidine or prodrug thereof, wherein: ¥ and ¥ are independently selected from the group consisting of: CH, CF and N; X, X, 2 and 2 'respectively Independently C or N; one of Rl and R * 2> is selected from the group consisting of halogen, cyano, and L2R6; the other of Ri and R2 is selected from the group consisting of: hydrogen , Alkynyl, oxoaryl, cycloalkyl, halogen, cyano, and thioalkoxy, but the restriction is that when Z is N, r2 does not exist; when X is N, &amp; does not exist , Or I is selected from the group consisting of: argon alkyl, alkoxy, halogen, cyano, and thioalkoxy; when Z is N, Rsa does not exist, or is selected from the group consisting of • Hydrogen, methyl, alkoxy, pixel and cyano; when s X is N, Rsb does not exist, or is selected from the group consisting of: • hydrogen, alkyl, alkoxy, sulfone, hydroxyl, cyanide And thioalkoxy IU and R5 are independently selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, and (NRaRb) 89248 .doc 200418454 nitrogen atom Together, they form the following bases or I and r5 and the non-aromatic ring to which they are attached: R6傷選自下列組成之群中烷基；R6 is selected from alkyl groups in the group consisting of: ⑼ &gt;芳基、雜芳基、雜環與環 R r R 8、R 9與R丨。每次出現時分別獨立選自下列組成之 群中：m基、氟燒基與燒基；或—對R_R8或一 對R9與R10共同形成C3_C6環，其中〇、⑽個選自〇、N 或S之雜原子置換環中碳原子； Ru、Ru、R13與R〗4分別獨立選自下列組成之群中：氫 、羥基、羥烷基、烷基與氟； Q係選自下列組成之群中：一鍵結、〇、s與nr15 ; L為-[C(Rl6)(Rl7)]n-或-[C(R16)(R17)]p〇-; L2係選自下列組成之群中：一键結、-〇-、-C( = 〇)-、 -S-、-[C(R18)(Ri9)]q-、·〇-[(：(Κ18)(Ι119)ν、-NH-與-N(烷 基）-; R!5係選自下列組成之群中··氫、烷基、酿基、酿胺墓 、與甲醯基； Ru與R17每次出現時分別獨立選自下列組成足群中： 89248.doc 200418454 氫、烷基、烷氧基與氟； 尺18與1^9每次出現時分別獨立選自下列組成之群中： 虱、經基、烷基、烷氧基與氟； I與Ry每次出現時分關立選自下列組成之群中：氮 、、踁基、烷基、烷氧基、烷胺基、二烷胺基與氟，或Rx 或Ry中 &lt; 一與相鄰碳原子上Rx或Ry共同代表一共價鍵， 因此使相鄰碳原子之間形成雙鍵； m為1至5之整數； η為，1至6之整數； ρ為2至6之整數；及 q為1至4之整數； 其中X、X’、Y、γ’、2與2，中〇、者可為氮；但其 限制條件為當X，4N時則I不存在；當Z*N時則不存 在，當Z’為N時則I不存在；及當χ為N時則R3b不存在。 2.根據申請專利範圍第丨項之化合物，其中&amp;為溴、氰基、 或 l2r6。 3·根據申請專利範圍第i項之化合物，其中R^L也，L2籲 為-CH(OH)-、-C卜〇)-或一鍵結，且r6為芳基、雜芳基、 雜環或環燒基。 4·根據申請專利範圍第1項之化合物，其中1為L2R6，l2 為鍵結’且R6為芳基’其中芳基為經〇、1或2個選自下 列組成之群中之取代基取代之苯基··氰基、鹵素、-NRaL 、規氧基、羥烷基、烷羰基、烷氧羰基、環烷羰基、烷 磺醯基、函烷基與硫烷氧基。 89248.doc 200418454 5. 根據申請專利範圍第i項之化合物，其中心為^!^，L2 為一鍵結，且R6為選自下列組成之群中：P夫喃基、咪口坐 基、異P塞吐基、異4峻基、$二咬基、P号峻基、P比畊基 、吡唑基、嗒啡基、嗒畊酮基、吡啶酮基、吡啶基、嘧 咬基、咯基、四唑基、嘧二唑基、噻唑基、嘧吩基、 二P井基與三吐基，其係經0、1、2或3個選自下列組成之 群中之取代基取代：-NRARB、齒素、烷基、氰基、烷氧 亞胺基、烷氧羰基、（NRARB)羰基、烷羰基、鹵烷基、 與烷氰基。 6. 根據申請專利範圍第1項之化合物，其中Ri為L2r6，L2 為一鍵結，且R6為選自下列組成之群中：吖畔基、吖粗 基、吖呒基、吖4烷基、二氫嘍唑基、嗎啉基' 六氫吡 井基、六氫被咬基、p比哈淀基、p比洛p林基、硫嗎π林基、 四氫吡啶基、四氫呋喃基與四氫吡喃基。 7 .根據申請專利範圍第1項之化合物，其中與分別獨立 選自甲基、乙基與丙基。 8 ·根據申請專利範圍第1項之化合物，其中&amp;4與與其所附 接之氮原子共同形成如式（a)代表之4-至8 -員非芳香環。 9·根據申請專利範圍第8項之化合物，其中4_至8_員非芳香 環係選自下列組成之群中：吖哩基、吖咩基、4呼基、 &lt; p各咬基、p比嘻p林基、六氫？比淀基、六氫？比p井與四氫峨 啶基，其係經0、1或2個選自下列組成之群中之取代基耳又 代：烷基、羥烷基、氟烷基與-NRARB-。 1〇·根據申請專利範圍第8項之化合物，其中h、尺8、^與 89248.doc 200418454 1 〇所代表之至少一個取代基為選自下列組成之群中：燒 基、鹵素、氟烷基與羥烷基，或Rx或心所代表之至少一 個取代基為選自下列組成之群中：氫、羥基、與氟。 11. 12. 13. 14. 15. 16. 17. 18. 19. 根據申凊專利範圍第8項之化合物，其中該4至8員非芳香 裱係選自下列組成之群中··甲基吡咯啶基、乙基吡咯啶 基一甲基胺基咐P各淀基、異丙基说嘻咱:基、異丁基p比 p各呢基、羥甲基吡咯啶基與氟甲基吡咯啶基。 根據申請專利範圍第i項之化合物，其中以4與1與其所附 接之氧原子共同形成嗎啉基或硫嗎啉基。 · 根據申請專利範圍第i項之化合物，其中R7、R8、1與 所代表之至少一個取代基為羥烷基、氟烷基或烷基。 根據申請專利範圍第！項之化合物，其中R7、h、^與 Rio所代表之至少一個取代基為甲基、乙基、氟甲基、或 羥甲基。 根據申請專利範圍第i項之化合物，其中R7、R8、心與 Rio所代表之至少一個取代基為烷基，其他三個取代基為 氫。 根據申請專利範圍第丨項之化合物，其中R11、R12、R13 與R14分別為氫。 根據申Μ專利範圍第1項之化合物，其中R&quot;與Rl2分別為 氫，且Rl 3與R〗4分別獨立選自氫與烷基。 根據申請專利範圍第}項之化合物，其中係選自下刿 組成之群中··氫、烷基、醯胺基與甲醯基。 根據申Μ專利範圍第1項之化合物，其中R! 6與R17為氫。 89248.doc 200418454 20. 根據申請專利範圍第1項之化合物，其中R18與R19為 21. 根據申請專利範圍第1項之化合物，其中m為2或3。 22. 根據申請專利範圍第1項之化合物，其中η為2或3。 23. 根據申請專利範圍第1項之化合物，其中ρ為2。 24. 根據申請專利範圍第1項之化合物，其中q為1。 25. 根據申請專利範圍第1項之化合物，其中 Y與丫’為CH ; X、X，、Z與 Z，為 C ;且 R&quot;2、，R3、R3a與 R3b為氫。 26. 根據申請專利範圍第1項之化合物，其中 Y與Y’為CH ; X、X’與 Z為 C ; R3、R3a與 R3b為氫； Z义N ;且 R2不存在。 27. 根據申請專利範圍第1項之化合物，其中 Y與丫’為CH ; X’、Z，與 Z為 C ; R2、R3與R3a為氫； X為N ;且 R3b不存在。 28. 根據申請專利範圍第1項之化合物，其中 Y與丫’為CH ; X、X，與 Z’為 C ; 89248.doc -6- 200418454 R2、R3與R3b為氮； Z為N ;且 R3a不存在。 29. 根據申請專利範圍第1項之化合物，其中 Y為 CH ; X、X’、Z與 Z，為 C ; R2、R3、與 R3b為氮；且 Y，為 N。 30. 根據电請專利範圍第1項之化合物，其中 Y與Yf為CH ; X與π為C ; R2與R3b為氫； X丨為N ; Z為N ;且 R3與R3不存在。 3 1.根據申請專利範圍第1項之化合物，其中 X、Xf、Z與 Z’為 C ; R2、R3、R3a與 R3b為氫； Y為N ;且 Yf 為 N。 32.根據申請專利範圍第1項之化合物，其中 Y，為 CH ; X、X’與 Z為 C ; R3、R3a與 R3b為氫； 89248.doc 200418454 Y為N ; Z%N ;且 R2不存在。 33. 根據申請專利範圍第1項之化合物，其中 Y，為 CH ; X、Z與 Z’為 C ; R2、R3a與 R3b為氫； Y為N ; X，$N ;且 R3不存在。 34. 根據申請專利範圍第1項之化合物，其中 Yf 為 CH ; X、X’與 Z1為 C ; R2、R3與R3b為氣； Y為N ; Z為N ;且 R3a不存在。 3 5.根據申請專利範圍第1項之化合物，其中 Y為 CH ; X、乂’與乙為C ; Κ·3、R3a 與 R3b 為氫； Y，為 N ; Zf為N :且 R2不存在。 89248.doc 200418454 36. 根據申請專利範圍第1項之化合物，其中 Y與Y’為CH ; Zf與Z為C ; R2與R3a為氫； X丨為N ; X為N ;且 R3與R3b不存在。 37. 根據申請專利範圍第1項之化合物，其中 Y^CH ； X、X’、Z與 Zf 為0; R2、R3、R3a與 R3b為氮；且 Y為N。 3 8.根據申請專利範圍第1項之化合物，其中 Y與Yf為CH ; X’與 ζ’Λ c ; R2與R3為氫； X為N ; Z為N ;且 與R3b不存在。 39.根據申請專利範圍第1項之化合物，其中 Y為 CH ; X、Zf 與 Z為 C ; R2、R3a與 R3b為氮； Y’為 N ; 89248.doc 200418454 X’為N ;且 I不存在。 40. 41. 42. 根據申請專利範圍第1項之化合物，其中·· R4L2R6’其中L4-鍵結，R64雜芳基或雜環； R2、R3、R3a與 R3b為氫； L為-[C(R16)(R17)]n-; η為2 ; Rl6與Rl7每次出現時為氫； 汉4离R5共同形成式（a)甲基吡咯啶基環，其中R7、、 1與尺1()中之一為甲基，其餘三個取代基為氫； Y與Y’為CH ;且 X、X，、Z與 Z，為 c。 根據申請專利範圍第40項之化合物，其中Ri為選自2H_ 嗒畊-3-酮-2-基之雜芳基。 根據申請專利範圍第1項之化合物，其係選自下列組成之 群中： 4-(6-{2-[(2R)-2-甲基+峨咯唉基]乙基}_2_審基）苯基 氰； (2R)-l-[2-(6-溴-2-莕基）乙基]-2-甲基吡咯啶； l_[3-(6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜孓苯基）苯 基]乙酮； 2-[3-(6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜孓莕基）苯 基]-2-丙醇； 6- {2-[(2R)-2 -甲基-Ι-t：比哈淀基]乙基卜2-審基氨； 89248.doc -10- 200418454 4-(6- {[(2R)-2 -甲基- l-p比咯啶基]甲基卜2-莕基）苯基氰； 3- (6-{2-[(2R)-2 -甲基-1-吨洛淀基]乙基卜2-蕃基）苯基 氰； 4- (6-{2-[(211)-2-甲基-14比咯啶基]乙基卜2_萘基）峨啶； 3- (6- {2-[(2R)-2-曱基-1-吡咯啶基]乙基卜2-莕基）p比啶； (3 -氟苯基）（6 - {2-[(2R)-2 -甲基- Ι-p比咯淀基]乙基卜2-蕃 基)甲醇； 3,5 -二甲基-4-(6-{2-[(2R)-2-甲基_1_峨哈咬基]乙基} _2-莕基）異吟唑； 4- （6-{2-[(2S)-2-(輕甲基）-1-吡咯啶基]乙基卜莕基） 苯基氰； 4-(6-{2-[(3R)-3-輕基小p比嘻淀基]乙基卜2_審基）苯基 氰； 4-{6-[2-(2-異丁基-1-吡咯啶基）乙基]_2_莕基}苯基氰； 4-{6-[2-(2-異丙基-1-吡咯啶基）乙基]_2_莕基}苯基氰； 4-(6-{2-[(3R)-3-(二甲基胺基）-1-p比洛淀基]乙基}_2_審 基)苯基氰； 4-{6-[2-(二乙基胺基）乙基]-2-莕基}苯基氰； 4-{6-[2-(二甲基胺基）乙基；μ2-莕基}苯基氰； 4-(6-{2-[乙基（異丙基）胺基]乙基卜2-莕基）苯基氰； 4-(6-{2-[第三丁基（甲基）胺基]乙基卜2-萘基）苯基氰； 4-(6-{2-[(2S)-2-甲基-1-吡咯啶基]乙基卜2-蒸基）苯基 氰； 4-(6-{2-[(2R)-2 -甲基-1-六氫吡啶基]乙基卜2-蕃基）苯 89248.doc -11 - 200418454 基孩i ; 4- {6-[2-(2,5-二氫-1H-吡咯-1-基）乙基]-2-萘基}苯基氰; 4-(6-{2-[甲基（丙基）胺基]乙基卜2-莕基）苯基氰； 4- (6-{2-[(2-#至乙基）（甲基）胺基]乙基}-2-茶基）苯基氰； 5- (6-{2-[(2R)-2 -甲基- Ι- p比洛淀基]乙基]»-2 -茶基）p密淀； 4-(6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基}·2-莕基）嗎啉； 2-(6-{2-[(2R)-2-甲基- Ι- p比洛淀基]乙基卜2 -茶基）_1，3_ 嘧唑； 4-(&amp;{2-[(2S)-2-(氟曱基）-1-吡咯啶基]乙基卜2-莕基） 苯基氰； (3-氟苯基）（6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基}_2_莕 基）甲酮； 2- (6-{2 -[(2R)-2-甲基-Ι-p比嘻淀-1-基]-乙基]·- 2-審-2-基) -2H-嗒畊-3-酮； 2 -甲乳_5-(6-{2-[(2 R) - 2-甲基- 各淀基]乙基}-2 -蕃 基）p比淀； 4-(6-{2-[(2R)-2-(羥甲基）-1-吡咯啶基]乙基卜2-莕基） 苯基氰； 4-{6-[2-(2 -甲基-Ι-p比17各淀基）乙基]-2 -奈基}苯基氣； 4-{6-[2_(1-吡咯啶基）乙基]-2-莕基}苯基氰； 4-(6- {2-[(2R)_2-甲基-1-外[:咯啶基]乙基卜2_莕基）硫嗎 琳； 1-{2-[(6-溴-2-茬基）氧]乙基}吡洛啶； 3- {6-[2-(1-吡咯啶基）乙氧基]-2-莕基}苯基氰； 89248.doc -12- 200418454 3-{6-[2-(l -口比洛症基）乙氧基]-2 -荅基}p比咬； 3-(6-{2-[(2R)-2 -曱基- Ι-p比略淀基]乙氧基卜2-茶基）苯 基氰； 3- (6-{2-[(2R)-2-甲基-1-吡咯啶基]乙氧基}_2-萘基）吡 啶； 4- (2-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜6-喳啉基）苯 基氰； 6-(4-氟苯基）-2-{2-[(2幻-2-甲基-1-?比嘻症基]乙基}??奎 琳，^ 3-(2-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜6_喳啉基）苯 基氰； 1- [3-(2-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜6-喹啉基） 苯基]乙酮； 6-(4-甲氧苯基）-2-{2_[(2R)-2_甲基小吡咯啶基]乙基} 口奎琳； 2- {2-[(2R)-2-甲基-1-吡咯啶基]乙基}-6-[4-(三氟甲基） 苯基]峻淋； 2-{2-[(211)-2-甲基-14比咯啶基]乙基}-6-[4-(甲磺醯基） 苯基]喹啉； 6-(3,5-二氟苯基）-2-{2-[(2R)-2-甲基-1-吡咯啶基]乙基} 口奎琳； (3-氟苯基）（2-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜6-喹 啉基）甲酮； 2-{2-[(2R)-2-甲基-1^比咯啶基]乙基}-6-(3-咕啶基）喳 89248.doc -13 - 200418454 淋； 4-(3-{2-[(2R)-2-甲基-1-吡咯啶基]乙基}-7-異喳啉基） 苯基氰； 3- (3-{2-[(2R)-2-甲基-1-吡咯啶基]乙基}-7-異喹啉基） 苯基氣， 6-{2-[(2R)-2-甲基-Ι-p比p各淀基]乙基}-2-(3-p比淀基）口查 口林， 6-{2-[(2R)-2-甲基- Ι- p比洛淀基]乙基}-2-(4-p比淀基）口奎 琳；， 6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基}-2-(2-吡啶基）喳 口林， 6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基}-2-(1，3-嘍唑-2-基）喹啉； 2-(2,4-二甲基-i，3-嘧唑-5-基）-6-{2-[(211)-2-甲基-1-口比 p各淀基]乙基} p奎淋； 6- {2-[(2R)-2-甲基-1-吡咯啶基]乙基}-2-(2-吡畊基）喹 琳； l-[6-(6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜2-喳啉基） -2 -17比淀基]乙酉同； 4 (2 {2-[(2 R) - 2-甲基-1_ρ比洛淀基]乙基}-6 - 口奎α号琳基） 苯基氰； 4- (3_{2-[(2R)-2-甲基-1-外[:咯啶基]乙基卜6_喳啰啉基-) 苯基氰； 7- (2,6-二氟_3_吡啶基）-3_{2吖甲基-1β吡咯啶基] 89248.doc -14- 200418454 乙基}異峻琳； 3 - {2 - [ (2 R) - 2-甲基-l-p比洛淀基]乙基}-7-(3-ρ比淀基）異 口奎口林； 3- (苯甲氧基）-2-甲基-6-{2-[(2R)-2-甲基-1-毗咯啶基] 乙基}峻淋； 2-環丙基-6-{2-[(2R)-2_甲基-1-吡咯啶基]乙基}喳啉； 4- (6-{2-[(2R)-2 -甲基- Ι- p比p各淀基]乙基}-2-p奎峻基）冬 基氰； 2,6-，二甲基-5-(6-{2-[(2R)-2-甲基-1-说咯啶基]乙基} -2 -邊ρ林基）於基氰； 2-(3-甲基-2_峨呼基）_6-{2-[(2R)-2-甲基-1-吡咯啶基] 乙基}峻p林； 5- (6-{2-[(2R)-2 -甲基-1-峨洛淀基]乙基}-2-ρ奎淋基）-3- 異呤唑羧酸乙酯； 5-(6-{2-[(2R)-2 -甲基- Ι- p比p各淀基]乙基}-2-峻琳基）-2- 嘧吩腈； 5-(6-{2-[(2R)-2 -甲基- Ι-p比洛淀基]乙基}-2_ 口奎淋基）-2· 噻吩羧基亞胺酸乙酯； 2-(2,4-二甲基-1，3-噚唑-5-基）-6-{2-[(211)-2-甲基-1-吡 咯啶基]乙基}喹啉； 3 -甲基- 5- (6-{2-[(2R)-2-甲基- Ι- p比p各咬基]乙基卜2 -峻 淋基）-4-異4峻竣酸乙酯； _ 4-(7- {2-[(2R)-2-甲基-1-吡咯啶基]乙基} -3-異喹啉基） 苯基氰； 89248.doc -15- 200418454 6- {2-[(211)-2-甲基-1-说咯啶基]乙基}-2-(4-曱氧苯基） p奎口咢琳； 7- {2-[(211)-2-甲基-1^比咯啶基]乙基}-2-(4-甲氧苯基） 口奎口咢琳； 6- {2-[(2R)-2-甲基-1^比咯啶基]乙基}-2-苯基喹崎啉； 7- {2-[(211)-2-甲基-1-吡咯啶基]乙基}-2-苯基喹噚啉； 6-{2-[(2R)-2-甲基-1·吡咯啶基]乙基}-2-(3-吡啶基）4 峻琳； 6-¾基-2-{6-[2-((2R)-2-甲基-吡咯啶-1-基）-乙基]-萘 -2-基}-211-嗒呼-3-酮； 5-{6-[2-((2R)-2-甲基-吡咯啶-1-基）-乙基]-萘-2-基卜嘧 淀-2 -腈； 1- {6-[2-(2(R) -甲基-p比洛淀-1 -基）-乙基]奈-2-基}-1Η-ρ比- 2 -酉同， 5-{6-[2-(2(R)-甲基-吡咯啶-1-基）-乙基]-莕-2-基卜菸 基采； 4-甲基-l-{6-[2-(2 (R)-甲基-吡咯啶-1-基）-乙基]-莕-2-基卜1H-吡啶-2-酮； 2- {6-[2-((2R)-2-甲基^比咯啶-1-基）-乙基]-莕-2-基卜吡 畊； 2-{6-[2-((2R)-2-甲基-2,5-二氫-吡咯-1-基）-乙基]莕 -2-基卜2H-嗒畊-3-酮； _ 4-(6-{2-[(2 -二甲基胺基-乙基）-甲基-胺基]-乙基}-蕃 -2-基苯基氰； 89248.doc -16- 200418454 4-{6-[2-(4 -甲基-六氮7比喷-1-基）-乙基]奈-2-基}-苯基 氰·· 2-(2,5-二甲基-呋喃-3-基）-6-{2-[(2R)-2-曱基-1-吡咯 咬基]乙基} - P奎淋； 6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基}-2-(4-曱硫烷基-苯基）奎淋； 2-(6-甲基-批啶-3-基）-6-{2-[(2R)-2-甲基-1-吡咯啶基] 乙基卜喹啉； 2-(U3-二甲基-1H-吡唑-4-基）-6-{2-[(2幻-2-甲基-1-吡 嘻淀基]乙基}-p奎琳； 6-{2-[(2R)-2-甲基- Ι- p比洛淀基]乙基}-2 -石見苯-3-基-p奎 口林； 6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜2-嘧啶-5-基^奎 淋； 2-(2,6-二甲基-吡啶-3-基）-6-{2-[(2R)-2-甲基-1^比洛 啶基]乙基卜喹啉； 1 - [2,6-二甲基-5-(6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基} _ ρ奎pr林_ 2 -基）-口比淀-3 -基]-乙酉同， 6-{2-[(2R)-2-甲基-1 -峨洛淀基]乙基} - 2- (2H_ p比 σ坐_3·» 基）-^奎4木， 2-(3-溴-異哼唑-5-基）-6-{2-[(2R)-2_甲基-1-吡咯啶基] 乙基卜喳啉； - 2-(6-氯^比啶-3-基）-6-{2-[(2R)-2-甲基-1-吨咯啶基]乙 基} - ΪΤ奎淋， 89248.doc -17- 200418454 2-(3,5-二甲基-硫苯基-2-基）-6-{2-[(211)-2-甲基-1-吡 洛淀基]乙基} - ρ奎琳； 6-{2-[(2R)-2-甲基-1-外匕咯啶基]乙基}-2-硫苯-2-基-喳 淋； 2-呋喃-3-基-6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基}-喹 琳； 2- (4,5-二氫-嘧唑-2-基）-6-{2-[(2R)-2-甲基-1-吡咯啶 基]乙基} - p奎淋； 1- [4-(6-{2-[(2R)-2-甲基-1-吡咯啶基]乙基}-喹啉-2-基) -苯基]-乙酮； 3- (6-{2-[(2R)-2-甲基-1-说咯啶基]乙基卜喳啉-2-基） 三氟甲基比咱&gt;4-醇； 2- (3,5-二甲基-1H-吡唑-4-基）-6-{2-[(2R)-2-甲基-1-吡 咯啶基]乙基卜喳啉； 6_{2-[(2R)-2_甲基-卜吡咯啶基]乙基卜2-(1Η-吡唑-4-基）-峻琳； 2,6-二甲基-5_(6_{2-[(2R)-2-甲基-1-吡咯啶基]乙基卜 口奎啉-2-基）-菸醯胺； 2-[2-(2R-甲基-p比p各淀-1-基）-乙基]_6·^比淀-4-基套11林； 6-(6•甲氧-吡啶_3_基）_2-[2(R)-(2-甲基-吡咯啶-1-基）-乙基]-p套淋； 6_(2,6-二氟-p比啶-3-基）-2-[2-(2(R)-甲基-吡咯啶-1-基) -乙基]奎琳； 6-(6-氣比啶_3-基）_2-[2-(2(R)-甲基-P比咯啶-1-基）-乙 89248.doc -18 - 200418454 基p奎琳； 6-(2,6-二氯-说啶-3-基）-2-[2-(2(R)-甲基-吡咯啶-1-基) -乙基]-喹啉； 2-[2-(2(R)-甲基-吡咯啶-1-基）-乙基]-6-吡畊-2-基-喳 口林， 2-[2-(2(R)-甲基-吡咯啶-1-基）-乙基]-6-嘧啶-5-基-喳 淋； 6-(2,4-二甲氧-嘧啶-5-基）-2-[2-(2(R)-甲基比咯啶-1-基）-乙，基]^奎淋； 二甲基-(4-{2-[2-(2(R)_甲基-吡咯啶-1-基）-乙基]-喹啉 -6-基}-本基）-胺， 1- (4-{2-[2-(2(R)-甲基-吡咯啶-1-基）-乙基]-喹啉-6-基} -苯基）-乙酮； 6-(4_氯-苯基）-2-[2-(2(R)-甲基-外1:咯啶-1-基）-乙基]-喳 口林， 6-(2,6-二甲基-吡啶-3-基）-2-[2-(2(R)-甲基-吡咯啶-1-基）-乙基]-p奎4 ; 6-(5-甲氧-吡啶-3-基）-2-[2-(2(R)-甲基-吡咯啶-1-基）- 乙基]-口奎p林； 6-(3,5-二甲基-異哼唑-4-基）-2-[2-(2(11)-甲基-吡咯啶 -1-基）-乙基]-喹啉； 4-{2-[2-(2(R)-甲基-说咯啶-1-基）-乙基]-喹啉-6-基ί-苯甲酸甲酯； 2- [2-(2(R)-甲基咯啶-1-基）-乙基]-6-(4-甲硫烷基- 89248.doc -19- 200418454 苯基）-ρ奎17林； 6-(6-氟-吡啶-3-基）-2-[2-(2(R)-甲基-说咯啶-1-基）-乙 基]-口奎4木； 5-{2-[2-(2(R)-甲基^比咯啶-1-基）-乙基]-喳啉-6-基卜 菸基氰； 2,4-二甲氧-5-{6-[2-((2R)-甲基-说咯啶-1-基）-乙基]-萘-2-基}-喊淀； 2,6-二氟-3-{6-[2-((2R)-2-甲基^比咯啶-1-基）-乙基]-莕 _2-基比淀； 環丙基-(4-{6-[2-((2R)2-甲基-吡咯啶-1-基）-乙基]-莕 -2-基}-苯基）甲酮； 3- 甲氧-6-{6-[2-((2R)2-甲基-吡咯啶-1-基）-乙基]-莕-2- 基}-嗒畊； 4- {6-[2-(2-甲基-六氫吡啶-1-基）-乙基]-莕-2-基卜苯基 氰； 4-{6-[2-((2R)-2-乙基-吡咯啶-1-基）-乙基]-莕-2-基卜苯 基氰； 2-{6-[2-((2S)-2-甲基-p比洛淀-1-基）-乙基]-奈-2-基} -2H-嗒畊-3-酮； 2-[6-((2R)-2-tt 氣 p 比淀-1-基-乙基）-奈-2 -基]-211-塔 口井 -3-酮； 2-{6-[2-(第三丁基-甲基-胺基）-乙基]-茬-2-基}-2H-嗒 畊-3-酮； 2-[6-(2-二乙基胺基-乙基）-萘-2-基]-2H-嗒畊-3-酮； 89248.doc -20- 200418454 2-[6-(2-嗎啉-4-基-乙基）-莕-2-基]-2H-嗒畊-3-酮； 2-{6-[2-(乙基-甲基-胺基）-乙基]-莕-2-基}-2仏嗒啡-3-酮； 2-{6-[2-((23)-2-氟甲基-吡咯啶-1-基）-乙基]-萘-2-基} -2H-嗒畊-3-酮； 2-{6-[2-(2-羥基甲基-峨咯啶-1-基）-乙基]-莕-2-基} -2H-嗒畊-3-酮； 2_ {6-[2-((R)-2-乙基-p比洛淀-1-基）-乙基]•奈-2-基} -2H-嗒畊-3-酮； 2一[6-(2-吖口旦-1-基-乙基）_莕-2-基]-2H-嗒啩-3-酮； 2- {6-[2-((2S)-2-氟甲基-吖哩-1-基）-乙基]-莕-2-基} -2H-嗒畊-3-酮； 2-{6-[2-((2S)-2-羥甲基-吖吸-1-基）-乙基]-萘-2-基} -2H-嗒畊-3-酮； 2-{6-[2-((2尺，511)-2,5-二甲基-吡咯啶-1-基）-乙基]-萘 -2-基}-211-嗒畊-3-酮； 2-{6-[2-((211，63)-2,6-二甲基-六氫被啶-1-基）-乙基]-莕-2-基}-2；«-嗒畊-3-酮； 2-{6_[2-((R)-3-羥基-六氫吡啶-1-基）-乙基]-莕-2-基} -2H-嗒畊-3-酮； 2-{6-[2-((R)-2-甲基-六氫吡啶-1-基）-乙基]-莕-2-基} -2H-嗒畊-3-酮； &quot; 2,6-二甲基-3-{6-[2-((2R)-2-甲基-吡咯啶-1-基）-乙基]-萘-2-基}-7比淀； 89248.doc -21 - 200418454 5-{6-[2-((R)-2-甲基-峨咯啶-1-基）-乙基]-莕-2-基卜噻 口坐； 2- {6-[2-((11)-2-甲基-吡咯啶-1-基）-乙基卜莕-2-基卜嘧 淀； 3- 氯-6-{6-[2-((R)-2-甲基-吡咯啶-1-基）-乙基]-萘-2-基} -嗒畊； 5-{6-[2-((R)-2-甲基-吡咯啶-1-基）-乙基]-萘-2-基卜嘧 啶-2-基胺； 2- 甲，基-5-{6-[2-((2R)2-甲基-吡咯啶-1-基）-乙基]-莕-2- 基} ** 0比 ， 3- 溴-7-(2-吡咯啶-1-基-乙基）-[1，5]莕啶； 3-溴-7-[2-(2R-2-甲基-吡咯啶-1-基）-乙基；]-[1，5]萘啶； 3-溴-7-(2-六氫吡啶-1-基-乙基）-[1，5]莕啶； 3-(2,6-二甲基-吡啶-3-基）-7-[2-(2R-2-甲基-吡咯啶-1-基）-乙基]-[1，5]莕啶； 3-(2,4-二甲氧-嘧啶-5-基）-7-[2-(2R-2-甲基-吡咯啶-1-基）-乙基]-[1，5]莕啶； 3-(2,6-二甲基-吡啶-3-基）-7-(2-吡咯啶-1-基-乙基） -[1，5]莕啶； 3-(2,4- &gt;—甲氧-^淀-5 -基）-7 - (2 - p比洛淀-1 -基-乙基） -[1，5]莕啶； 3-(2,6-二甲基-吡啶-3-基）-7-(2-六氫吡啶-1-基-乙基） _[1，5]苯啶； 3-(2,4-二甲氧-嘧啶-5-基）-7-(2-六氫吡啶-1-基-乙基） 89248.doc -22- 200418454 - [1，5]莕啶； 3-[2-(2(R)-甲基^比咯啶-1-基）-乙基]-7-吡啶-4-基-異 喹啉； 7-(6-甲氧^比啶-3-基）-3-[2-(2(R)-甲基^比咯啶-1-基）-乙基]-異峻淋； 3- [2-(2(R)-甲基-吡咯啶-1-基）-乙基]-7-嘧啶-5-基-異 p奎琳； 7-(6-氟-吡啶-3-基）-3-[2-(2(R)-甲基-吡咯啶-1-基）-乙 基]-異/奎啉； 5-{3-[2-(2 (R)-甲基-吡咯啶-1-基）-乙基]-異喳啉-7-基} -菸基氰； 7-(3-氯-吡啶-4-基）-3-[2-(2(R)-甲基-吡咯啶-1-基）-乙 基]-異喳啉； 7-溴-3-[2-((2R)-2-甲基咯啶-1-基）-乙基]-噌啉-4-醇； 4- {3-[2-(2-甲基^比咯啶-1-基）-乙基]-噌啉-7-基卜苯基 氰； 7-溴-4-氯-3-[2-((2R)-2-甲基^比咯啶-1-基）-乙基]-噌 口林； 4-{4-羥基-3-[2-((2R)-2-甲基-吡咯啶-1-基）-乙基]-噌 啉-7-基卜苯基氰； 4-{4-異丙氧-3-[2-((211)-2-甲基-吡咯啶-1-基）-乙基&gt; 噌啉-7-基} •苯基氰； 4-{3-[2-(4-甲基-六氫吡畊-1-基）-乙基]-噌啉-7-基卜苯 89248.doc -23 - 200418454 基氰； 4-[3-(2-六氫吡啶-1-基-乙基）-噌啉-7-基]苯基氰； 4-[3-(2-吡咯啶-1-基-乙基）-噌啉-7-基]-苯基氰； 4-{3-[2-((211)-2-甲基-吡咯啶-1-基）-乙基]-噌啉-7-基}-苯基孩1， 4-{3-[2-((2R)-2-羥甲基比咯啶-1-基）-乙基]-噌啉-7- 基}-冬基氣， 4-[3-(2-嗎啉-4-基-乙基）-噌啉-7-基]-苯基氰； 4-U-[2-(4-甲基-六氫吡啶-1-基）-乙基]-噌啉-7-基}-苯 基氰； 4- {3-[2-(乙基-甲基-胺基）-乙基]-噌啉-7-基卜苯基氰； 7-(2,6-二甲基-吡啶-3-基）-3-[2-((2R)-2-甲基-吡咯啶 -1-基）-乙基]-噌啉； 7-(2,4-二甲氧-嘧啶-5-基）-3-[2-((2R)-2-甲基-p比咯啶 -1-基）-乙基]-噌啉；⑼ &gt; Aryl, heteroaryl, heterocyclic and ring R r R 8, R 9 and R 丨. Each occurrence is independently selected from the group consisting of: m group, fluorocarbon group and alkynyl group; or-R_R8 or a pair of R9 and R10 together form a C3_C6 ring, in which 0, 2 are selected from 0, N A heteroatom of S replaces a carbon atom in the ring; Ru, Ru, R13, and R4 are each independently selected from the group consisting of hydrogen, hydroxyl, hydroxyalkyl, alkyl, and fluorine; Q is selected from the group consisting of Middle: one bond, 0, s and nr15; L is-[C (R16) (Rl7)] n- or-[C (R16) (R17)] p〇-; L2 is selected from the group consisting of : One-bond, -〇-, -C (= 〇)-, -S-,-[C (R18) (Ri9)] q-, · 〇-[(: (Κ18) (Ι119) ν, -NH -And-N (alkyl)-; R! 5 is selected from the group consisting of hydrogen, alkyl, amino group, amine group, and methylamine group; Ru and R17 are independently selected each time they appear From the following groups of feet: 89248.doc 200418454 hydrogen, alkyl, alkoxy and fluorine; each occurrence of ruler 18 and 1 ^ 9 is independently selected from the group consisting of: lice, meridian, alkyl, Alkoxy and fluorine; each occurrence of I and Ry is selected from the group consisting of nitrogen, fluorenyl, alkyl, Oxygen, alkylamino, dialkylamino and fluorine, or Rx or Ry &lt; one and Rx or Ry on adjacent carbon atoms together represent a covalent bond, so a double bond is formed between adjacent carbon atoms; m Is an integer from 1 to 5; η is an integer from 1 to 6; ρ is an integer from 2 to 6; and q is an integer from 1 to 4; where X, X ', Y, γ', 2 and 2, among which Or, it can be nitrogen; but its limiting condition is that I does not exist when X, 4N; does not exist when Z * N, I does not exist when Z 'is N; and R3b does not exist when χ is N Existing. 2. The compound according to the scope of the patent application, wherein & is bromine, cyano, or l2r6. 3. The compound according to the scope of the patent application, i. Wherein R ^ L is also, and L2 is -CH ( OH)-, -CbO)-or one bond, and r6 is aryl, heteroaryl, heterocyclic or cycloalkyl. 4. The compound according to item 1 of the scope of patent application, wherein 1 is L2R6, l2 is a bond 'and R6 is an aryl group' wherein the aryl group is substituted with 0, 1 or 2 substituents selected from the group consisting of Phenyl · · cyano, halogen, -NRaL, acyloxy, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, alkanesulfonyl, haloalkyl, and thioalkoxy. 89248.doc 200418454 5. The compound according to item i of the scope of patent application, the center of which is ^! ^, L2 is a bond, and R6 is selected from the group consisting of p-furanyl, imidyl, IsoPetyl, Isopentyl, Isobutyl, P-Noctyl, P-Phenyl, Pyrazolyl, Daphnyl, Dafenone, Pyridone, Pyridyl, Pyridyl, Rotyl, tetrazolyl, pyrimidiazolyl, thiazolyl, pyrimilyl, diphenylsyl, and trisyl, which are substituted with 0, 1, 2 or 3 substituents selected from the group consisting of : -NRARB, halide, alkyl, cyano, alkoxyimino, alkoxycarbonyl, (NRARB) carbonyl, alkylcarbonyl, haloalkyl, and alkylcyano. 6. The compound according to item 1 of the scope of patent application, wherein Ri is L2r6, L2 is a single bond, and R6 is selected from the group consisting of acryl, acryl, acryl, and acryl 4 , Dihydrooxazolyl, morpholinyl 'hexahydropyridyl, hexahydropyridyl, p-bihalidyl, p-bilopridyl, thiomorpholinyl, tetrahydropyridyl, tetrahydrofuranyl and Tetrahydropyranyl. 7. The compound according to item 1 of the scope of patent application, wherein the compound is independently selected from methyl, ethyl and propyl. 8. The compound according to item 1 of the scope of patent application, wherein & 4 and the nitrogen atom attached thereto form a 4- to 8-membered non-aromatic ring represented by formula (a). 9. The compound according to item 8 of the scope of patent application, in which the 4- to 8-membered non-aromatic ring system is selected from the group consisting of acryl, acryl, 4-hexyl, &lt; p than hep p linki, hexahydro? Than Yodo-based, hexahydro? Bi p and tetrahydroeridinyl are replaced by 0, 1 or 2 substituents selected from the group consisting of alkyl, hydroxyalkyl, fluoroalkyl, and -NRARB-. 10. The compound according to item 8 of the scope of patent application, wherein at least one substituent represented by h, ruler 8, ^ and 89248.doc 200418454 1 〇 is selected from the group consisting of alkyl, halogen, and halothane And at least one substituent represented by hydroxyalkyl, or Rx or R is selected from the group consisting of hydrogen, hydroxyl, and fluorine. 11. 12. 13. 14. 15. 16. 17. 18. 19. The compound according to item 8 of the patent application range, wherein the 4 to 8 member non-aromatic mounting system is selected from the group consisting of methyl Pyrrolidinyl, ethylpyrrolidinyl-methylamino, phenyl, isopropyl, and isopropyl: methyl, isobutyl, p, p, and other methyl groups, hydroxymethyl pyrrolidyl, and fluoromethylpyrrole Pyridyl. A compound according to item i of the scope of patent application, wherein 4 and 1 together with the oxygen atom to which it is attached form a morpholinyl or thiomorpholinyl group. · The compound according to item i of the scope of patent application, wherein at least one of the substituents represented by R7, R8, 1 and is hydroxyalkyl, fluoroalkyl or alkyl. According to the scope of patent application! The compound of the above item, wherein at least one substituent represented by R7, h, ^ and Rio is methyl, ethyl, fluoromethyl, or hydroxymethyl. According to the compound in the scope of application for item i, at least one of the substituents represented by R7, R8, Xin and Rio is an alkyl group, and the other three substituents are hydrogen. According to the compound in the scope of patent application, R11, R12, R13 and R14 are hydrogen respectively. The compound according to item 1 of the patent application, wherein R &quot; and R12 are each hydrogen, and R13 and R4 are independently selected from hydrogen and alkyl, respectively. The compound according to item} of the application, which is selected from the group consisting of hydrogen, alkyl, amido, and formamidine. The compound according to item 1 of the patent application, wherein R! 6 and R17 are hydrogen. 89248.doc 200418454 20. Compound according to item 1 of the scope of patent application, wherein R18 and R19 are 21. Compound according to item 1 of the scope of patent application, where m is 2 or 3. 22. The compound according to item 1 of the scope of patent application, wherein η is 2 or 3. 23. The compound according to item 1 of the patent application, wherein ρ is 2. 24. The compound according to item 1 of the scope of patent application, wherein q is 1. 25. The compound according to item 1 of the scope of patent application, wherein Y and y 'are CH; X, X, Z and Z are C; and R &quot; 2, and R3, R3a and R3b are hydrogen. 26. The compound according to item 1 of the scope of patent application, wherein Y and Y 'are CH; X, X' and Z are C; R3, R3a and R3b are hydrogen; Z is N; and R2 does not exist. 27. The compound according to item 1 of the scope of patent application, wherein Y and y 'are CH; X', Z, and Z are C; R2, R3 and R3a are hydrogen; X is N; and R3b does not exist. 28. The compound according to item 1 of the scope of patent application, wherein Y and Y 'are CH; X, X, and Z' are C; 89248.doc -6- 200418454 R2, R3 and R3b are nitrogen; Z is N; and R3a does not exist. 29. The compound according to item 1 of the application, wherein Y is CH; X, X ', Z, and Z are C; R2, R3, and R3b are nitrogen; and Y is N. 30. The compound according to item 1 of the patent claim, wherein Y and Yf are CH; X and π are C; R2 and R3b are hydrogen; X 丨 is N; Z is N; and R3 and R3 do not exist. 3 1. The compound according to item 1 of the scope of patent application, wherein X, Xf, Z and Z 'are C; R2, R3, R3a and R3b are hydrogen; Y is N; and Yf is N. 32. The compound according to item 1 of the scope of patent application, wherein Y is CH; X, X 'and Z are C; R3, R3a and R3b are hydrogen; 89248.doc 200418454 Y is N; Z% N; and R2 is not presence. 33. The compound according to item 1 of the scope of patent application, wherein Y is CH; X, Z and Z 'are C; R2, R3a and R3b are hydrogen; Y is N; X, $ N; and R3 does not exist. 34. The compound according to item 1 of the scope of patent application, wherein Yf is CH; X, X 'and Z1 are C; R2, R3 and R3b are gas; Y is N; Z is N; and R3a does not exist. 3 5. The compound according to item 1 of the scope of patent application, wherein Y is CH; X, 乂 'and B are C; K · 3, R3a and R3b are hydrogen; Y is N; Zf is N: and R2 does not exist . 89248.doc 200418454 36. The compound according to item 1 of the scope of patent application, wherein Y and Y 'are CH; Zf and Z are C; R2 and R3a are hydrogen; X 丨 is N; X is N; and R3 and R3b are not presence. 37. The compound according to item 1 of the scope of patent application, wherein Y ^ CH; X, X ', Z and Zf are 0; R2, R3, R3a and R3b are nitrogen; and Y is N. 3 8. The compound according to item 1 of the scope of patent application, wherein Y and Yf are CH; X 'and ζ'Λc; R2 and R3 are hydrogen; X is N; Z is N; and R3b does not exist. 39. The compound according to item 1 of the scope of patent application, wherein Y is CH; X, Zf and Z are C; R2, R3a and R3b are nitrogen; Y 'is N; 89248.doc 200418454 X' is N; and I is not presence. 40. 41. 42. The compound according to item 1 of the scope of the patent application, wherein R4L2R6 'wherein L4-bonded, R64 heteroaryl or heterocyclic ring; R2, R3, R3a and R3b are hydrogen; L is-[C (R16) (R17)] n-; η is 2; Rl6 and Rl7 are hydrogen each time; Han 4 and R5 together form a methyl pyrrolidinyl ring of formula (a), where R7 ,, 1 and chi 1 ( 1) is a methyl group, and the remaining three substituents are hydrogen; Y and Y 'are CH; and X, X, Z, and Z are c. The compound according to item 40 of the scope of patent application, wherein Ri is a heteroaryl group selected from 2H_daquin-3-one-2-yl. The compound according to item 1 of the scope of patent application, which is selected from the group consisting of: 4- (6- {2-[(2R) -2-methyl + errolyl] ethyl} _2_ ) Phenyl cyanide; (2R) -l- [2- (6-bromo-2-fluorenyl) ethyl] -2-methylpyrrolidine; l_ [3- (6- {2-[(2R)- 2-methyl-1-pyrrolidinyl] ethyloxanyl) phenyl] ethanone; 2- [3- (6- {2-[(2R) -2-methyl-1-pyrrolidinyl ] Ethyl ethyl fluorenyl) phenyl] -2-propanol; 6- {2-[(2R) -2-methyl-1-t: Bihadinyl] ethyl triphenylamine; 89248.doc -10- 200418454 4- (6- {[((2R) -2 -methyl-lp than pyrrolidinyl] methylb-2-fluorenyl) phenyl cyanide; 3- (6- {2- [ (2R) -2 -Methyl-1-t-lodonyl] ethylbutan-2-phenyl) phenyl cyanide; 4- (6- {2-[(211) -2-methyl-14pyrrolidine Phenyl] ethylpyridinyl) eridine; 3- (6- {2-[(2R) -2-amidino-1-pyrrolidinyl] ethylpyridinyl) pyridine; ( 3 -fluorophenyl) (6- [2-[(2R) -2 -methyl-l-p-pyrrolidyl] ethylbu 2-fanyl) methanol; 3,5-dimethyl-4- (6- {2-[(2R) -2-methyl_1_ehazidinyl] ethyl} _2-fluorenyl) isoindazole; 4- (6- {2-[(2S) -2- (Light methyl) -1-pyrrolidinyl] ethyl Phenyl cyanide; 4- (6- {2-[(3R) -3-Light group, smaller p than hexanoyl] ethyl p-hexyl) phenyl cyanide; 4- {6- [2- (2-isobutyl-1-pyrrolidinyl) ethyl] _2_fluorenyl} phenylcyanide; 4- {6- [2- (2-isopropyl-1-pyrrolidinyl) ethyl] _2 _Fluorenyl} phenyl cyanide; 4- (6- {2-[(3R) -3- (dimethylamino) -1-p-pylonidyl] ethyl} _2_yl) phenyl cyanide ; 4- {6- [2- (diethylamino) ethyl] -2-fluorenyl} phenylcyanide; 4- {6- [2- (dimethylamino) ethyl; μ2-fluorene Yl} phenyl cyanide; 4- (6- {2- [ethyl (isopropyl) amino] ethylb-2-fluorenyl) phenyl cyanide; 4- (6- {2- [third butyl (Methyl) amino] ethyl 2-naphthyl) phenyl cyanide; 4- (6- {2-[(2S) -2-methyl-1-pyrrolidinyl] ethyl 2-diphenyl ) Phenyl cyanide; 4- (6- {2-[(2R) -2 -methyl-1-hexahydropyridyl] ethylbu 2-fanyl) benzene 89248.doc -11-200418454 radical i; 4- {6- [2- (2,5-dihydro-1H-pyrrole-1-yl) ethyl] -2-naphthyl} phenylcyanide; 4- (6- {2- [methyl (propyl (Amino) amino] ethylphenyl 2-fluorenyl) phenyl cyanide; 4- (6- {2-[(2- # to ethyl) (methyl) amino] ethyl} -2-theanyl) Phenyl cyanide; 5- (6- {2-[(2R) -2 -methyl-I -p-pylonidyl] ethyl] »-2-theanyl) p dense lake; 4- (6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} · 2 -Fluorenyl) morpholine; 2- (6- {2-[(2R) -2-methyl-l-p-pylonidyl] ethylbu 2-theyl) _1,3_pyrimazole; 4- ( &amp; {2-[(2S) -2- (Fluorofluorenyl) -1-pyrrolidinyl] ethylbu 2-fluorenyl) phenylcyanide; (3-fluorophenyl) (6- {2- [ (2R) -2-methyl-1-pyrrolidinyl] ethyl} _2_fluorenyl) methanone; 2- (6- {2--((2R) -2-methyl-l-p-pyridine) -1-yl] -ethyl] ·-2-tri-2-yl) -2H-dagen-3-one; 2 -methyl milk_5- (6- {2-[(2 R)-2- Methyl-Ethylyl] ethyl} -2-ylphenyl p-pyridine; 4- (6- {2-[(2R) -2- (hydroxymethyl) -1-pyrrolidinyl] ethyl 2-fluorenyl) phenyl cyanide; 4- {6- [2- (2-methyl-I-p than 17 each) ethyl] -2-naphthyl} phenyl gas; 4- {6- [2- (1-pyrrolidinyl) ethyl] -2-fluorenyl} phenylcyanide; 4- (6- {2-[(2R) _2-methyl-1-exo [: pyridinyl] ethyl Bu 2_fluorenyl) thiomorphine; 1- {2-[(6-bromo-2-stubyl) oxy] ethyl} pyrrolidine; 3- {6- [2- (1-pyrrolidinyl) Ethoxy] -2-fluorenyl} phenyl cyanide; 89248.doc -12- 200418454 3- {6- [2- (l-orbiloxyl) ethoxy ] -2 -fluorenyl} p ratio bite; 3- (6- {2-[(2R) -2 -fluorenyl-1 -ppyridyl group] ethoxy group 2-theyl) phenyl cyanide; 3- (6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethoxy} _2-naphthyl) pyridine; 4- (2- {2-[(2R) -2- Methyl-1-pyrrolidinyl] ethylbu 6-fluorinyl) phenyl cyanide; 6- (4-fluorophenyl) -2- {2-[(2-2--2-methyl-1-? Bipyridyl] ethyl} ?? Querin, ^ 3- (2- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethylbu 6-fluorinyl) phenyl cyanide ; 1- [3- (2- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethylbu 6-quinolinyl) phenyl] ethanone; 6- (4-methoxy Phenyl) -2- {2 _ [(2R) -2-methylmethylpyrrolidinyl] ethyl} guolin; 2- {2-[(2R) -2-methyl-1-pyrrolidinyl] Ethyl} -6- [4- (trifluoromethyl) phenyl] pentazone; 2- {2-[(211) -2-methyl-14pyrrolidinyl] ethyl} -6- [4 -(Methylsulfonyl) phenyl] quinoline; 6- (3,5-difluorophenyl) -2- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} Kwoklin; (3-fluorophenyl) (2- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethylbu 6-quinolinyl) methanone; 2- {2- [(2R) -2-methyl-1 ^ pyrrolidinyl] ethyl} -6- (3-pyridinyl) fluorene 89248.doc -13-200418454 Leaching; 4- (3- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} -7-isofluorinyl) phenyl cyanide; 3- (3- {2- [ (2R) -2-methyl-1-pyrrolidinyl] ethyl} -7-isoquinolinyl) phenyl gas, 6- {2-[(2R) -2-methyl-1-p-p-p Each Yodo group] ethyl} -2- (3-p than Yodo group) oral Chakulin, 6- {2-[(2R) -2-methyl-l-p-Bilododonyl] ethyl}- 2- (4-p than yodoyl) quinine; 6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} -2- (2-pyridyl) fluorene Lin, 6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} -2- (1,3-oxazol-2-yl) quinoline; 2- (2,4 -Dimethyl-i, 3-pyrazol-5-yl) -6- {2-[(211) -2-methyl-1-methyl-1-pyridyl] ethyl} p-quinine; 6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} -2- (2-pyridyl) quinine; l- [6- (6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethylbu 2-phosphonyl) -2 -17 is more than ethyl] 4 (2 {2-[(2 R)-2-methyl-1_ρ Bilodoyl] ethyl} -6-Kou Kui (Linyl) phenyl cyanide; 4- (3_ {2-[(2R) -2-methyl-1-exo [: pyridinyl] ethyl Bu 6-fluorenyl-) phenyl cyanide; 7- (2,6-difluoro-3-pyridyl) -3_ {2acryl-1βpyrrolidinyl] 89248.doc -14- 200418454 ethyl} isojunlin; 3-{2-[(2 R)-2-methyl-lp bilocidyl] ethyl} -7- (3-ρ biidyl) Kou Lin; 3- (benzyloxy) -2-methyl-6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl}; -6- {2-[(2R) -2_methyl-1-pyrrolidinyl] ethyl} pyridin; 4- (6- {2-[(2R) -2 -methyl-l-p ratio p each ytyl] ethyl} -2-p quinolyl) winteryl cyanide; 2,6-, dimethyl-5- (6- {2-[(2R) -2-methyl-1-syl) Pyridinyl] ethyl} -2 -bendolinyl) in cyanocyanate; 2- (3-methyl-2_metyl) _6- {2-[(2R) -2-methyl-1- Pyrrolidinyl] ethyl} pentin; 5- (6- {2-[(2R) -2 -methyl-1-erlotinyl] ethyl} -2-ρquinyl) -3- Isoroxazole ethyl carboxylate; 5- (6- {2-[(2R) -2 -methyl-l-p to p each yl] ethyl} -2-junlinyl) -2-pyrimidine Nitrile; 5- (6- {2-[(2R) -2 -Methyl-I-p-bilodolide] ethyl} -2_ (quinolyl))-2 · thiophene carboxyimidic acid ethyl ester; 2 -(2,4-dimethyl-1,3-oxazol-5-yl) -6- {2-[(211) -2-methyl-1-pyrrolidinyl] ethyl} quinoline; 3 -Methyl- 5- (6- {2-[(2R) -2-methyl-l-p-p-p-phenyl] ethyl-bromo-2) Ethyl-4-iso-4-ammonioic acid; _ 4- (7- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} -3-isoquinolinyl) phenyl cyanide 89248.doc -15- 200418454 6- {2-[(211) -2-methyl-1-salrolidinyl] ethyl} -2- (4-fluorenylphenyl) 7- {2-[(211) -2-methyl-1 ^ pyrrolidinyl] ethyl} -2- (4-methoxyphenyl) guokuilin; 6- {2-[(2R ) -2-methyl-1 ^ pyrrolidinyl] ethyl} -2-phenylquinazolin; 7- {2-[(211) -2-methyl-1-pyrrolidinyl] ethyl} 2-phenylquinoline; 6- {2-[(2R) -2-methyl-1 · pyrrolidinyl] ethyl} -2- (3-pyridyl) 4 -2- {6- [2-((2R) -2-methyl-pyrrolidin-1-yl) -ethyl] -naphthalene-2-yl} -211-dahu-3-one; 5- { 6- [2-((2R) -2-methyl-pyrrolidin-1-yl) -ethyl] -naphthalene-2-ylpyrimidine-2 -nitrile; 1- {6- [2- (2 (R) -Methyl-p-Bilodo-1 -yl) -ethyl] naphthalenyl-2-yl} -1Η-ρ ratio- 2 -same, 5- {6- [2- (2 (R) -Methyl-pyrrolidin-1-yl) -ethyl] -fluoren-2-ylpyridinyl; 4-methyl-l- {6- [2- (2 (R) -methyl-pyrrolidine -1-yl) -ethyl] -fluoren-2-ylb 1H-pyridin-2-one; 2- {6- [2-((2R) -2-methyl ^ pyrrolidin-1-yl) -Ethyl] -fluoren-2-yl Pycnogenol; 2- {6- [2-((2R) -2-methyl-2,5-dihydro-pyrrole-1-yl) -ethyl] pyridin-2-ylbuth 2H-Dagen-3 -Ketone; _ 4- (6- {2-[(2-dimethylamino-ethyl) -methyl-amino] -ethyl} -fan-2-ylphenyl cyanide; 89248.doc- 16- 200418454 4- {6- [2- (4- -methyl-hexaaza 7-pyron-1-yl) -ethyl] naphthalen-2-yl} -phenylcyanide 2- (2,5- Dimethyl-furan-3-yl) -6- {2-[(2R) -2-fluorenyl-1-pyrroleyl] ethyl} -Pquinium; 6- {2-[(2R)- 2-methyl-1-pyrrolidinyl] ethyl} -2- (4-methylsulfanyl-phenyl) quinone; 2- (6-methyl-pyridin-3-yl) -6- { 2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl quinoline; 2- (U3-dimethyl-1H-pyrazol-4-yl) -6- {2-[( 2-Homo-2-methyl-1-pyridinyl] ethyl} -p quinine; 6- {2-[(2R) -2-methyl-l-p-bilodino] ethyl}- 2-Ishibenzyl-3-yl-p-kuikoulin; 6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl 2-pyrimidin-5-yl ^ quinine; 2 -(2,6-dimethyl-pyridin-3-yl) -6- {2-[(2R) -2-methyl-1 ^ pyridinyl] ethyl quinoline; 1-[2, 6-Dimethyl-5- (6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} _ ρ-Pr-prin_ 2 -yl) -Kipido- 3- Base]-Ethyl Similarly, 6- {2-[(2R) -2-methyl-1 -erodondyl] ethyl}-2- (2H_ p ratio σ sitting _3 · »group)-^ Kui 4 wood, 2- (3-bromo-isohumazol-5-yl) -6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethylpyridinium;-2- (6-chloro ^ ratio Pyridin-3-yl) -6- {2-[(2R) -2-methyl-1-tyrrolidinyl] ethyl} -Hydroxyl, 89248.doc -17- 200418454 2- (3,5 -Dimethyl-thiophenyl-2-yl) -6- {2-[(211) -2-methyl-1-pyridolyl] ethyl}-ρ Quilin; 6- {2- [ (2R) -2-methyl-1-exopyridinyl] ethyl} -2-thiophen-2-yl-pyrene; 2-furan-3-yl-6- {2-[(2R) 2-methyl-1-pyrrolidinyl] ethyl} -quinine; 2- (4,5-dihydro-pyrazol-2-yl) -6- {2-[(2R) -2-methyl -Yl-1-pyrrolidinyl] ethyl} -p-quinine; 1- [4- (6- {2-[(2R) -2-methyl-1-pyrrolidinyl] ethyl} -quinolin- 2-yl) -phenyl] -ethanone; 3- (6- {2-[(2R) -2-methyl-1-salrolidinyl] ethylpyridin-2-yl) trifluoromethane Bibitan &gt;4-ol; 2- (3,5-dimethyl-1H-pyrazol-4-yl) -6- {2-[(2R) -2-methyl-1-pyrrolidinyl ] Ethylpyridinium; 6_ {2-[(2R) -2_methyl-pyrrolidinyl] ethylpyridin-2- (1Η-pyrazol-4-yl) -Junlin; 2,6-di Methyl-5_ (6_ { 2-[(2R) -2-methyl-1-pyrrolidinyl] ethylbuquinol-2-yl) -nicotinamine; 2- [2- (2R-methyl-p to p each -1-yl) -ethyl] -6. ^ Biyodo-4-yl-tall 11 lin; 6- (6 • methoxy-pyridine_3-yl) _2- [2 (R)-(2-methyl- Pyrrolidin-1-yl) -ethyl] -p mantle; 6_ (2,6-difluoro-p than pyridin-3-yl) -2- [2- (2 (R) -methyl-pyrrolidine -1-yl) -ethyl] quinine; 6- (6-Gapyridin-3-yl) _2- [2- (2 (R) -methyl-P than pyridin-1-yl) -ethyl 89248.doc -18-200418454 p-quinine; 6- (2,6-dichloro-saldin-3-yl) -2- [2- (2 (R) -methyl-pyrrolidin-1-yl ) -Ethyl] -quinoline; 2- [2- (2 (R) -methyl-pyrrolidin-1-yl) -ethyl] -6-pyracin-2-yl-Hokolin, 2- [2- (2 (R) -methyl-pyrrolidin-1-yl) -ethyl] -6-pyrimidin-5-yl-pyridine; 6- (2,4-dimethoxy-pyrimidine-5- (Yl) -2- [2- (2 (R) -methylpyrrolidin-1-yl) -ethyl, yl] quinine; dimethyl- (4- {2- [2- (2 (R ) _Methyl-pyrrolidin-1-yl) -ethyl] -quinolin-6-yl} -benzyl) -amine, 1- (4- {2- [2- (2- (2 (R) -methyl -Pyrrolidin-1-yl) -ethyl] -quinolin-6-yl} -phenyl) -ethanone; 6- (4-chloro-phenyl) -2- [2- (2 (R)- Methyl-exo 1: pyridin-1-yl) -ethyl ]-喳 口 林, 6- (2,6-dimethyl-pyridin-3-yl) -2- [2- (2 (R) -methyl-pyrrolidin-1-yl) -ethyl]- p-quinone 4; 6- (5-methoxy-pyridin-3-yl) -2- [2- (2 (R) -methyl-pyrrolidin-1-yl) -ethyl] -quinone plin; 6- (3,5-dimethyl-isohumazol-4-yl) -2- [2- (2 (11) -methyl-pyrrolidin-1-yl) -ethyl] -quinoline; 4 -{2- [2- (2 (R) -methyl-salrolidin-1-yl) -ethyl] -quinolin-6-yl-benzoic acid methyl ester; 2- [2- (2 ( R) -methylpyridin-1-yl) -ethyl] -6- (4-methylsulfanyl- 89248.doc -19- 200418454 phenyl) -p-quinone 17 Lin; 6- (6-fluoro- Pyridin-3-yl) -2- [2- (2 (R) -methyl-salrolidin-1-yl) -ethyl] -tauquinol; 5- {2- [2- (2 ( R) -methyl ^ pyrrolidin-1-yl) -ethyl] -pyridin-6-ylpicotinyl cyanide; 2,4-dimethoxy-5- {6- [2-((2R) -Methyl-salrolidin-1-yl) -ethyl] -naphthyl-2-yl} -dimethylol; 2,6-difluoro-3- {6- [2-((2R) -2-methyl ^ Pyrrolidin-1-yl) -ethyl] -fluorene_2-ylpyridine; cyclopropyl- (4- {6- [2-((2R) 2-methyl-pyrrolidin-1- (Yl) -ethyl] -fluoren-2-yl} -phenyl) methanone; 3-methoxy-6- {6- [2-((2R) 2-methyl-pyrrolidin-1-yl)- Ethyl] -fluorenyl-2-yl} -Dagen; 4- {6- [2 -(2-methyl-hexahydropyridin-1-yl) -ethyl] -fluoren-2-ylphenylphenyl cyanide; 4- {6- [2-((2R) -2-ethyl-pyrrolidine -1-yl) -ethyl] -fluoren-2-ylphenylphenyl cyanide; 2- {6- [2-((2S) -2-methyl-p-pylonol-1-yl) -ethyl ] -Naphthalenyl-2-yl} -2H-dagen-3-one; 2- [6-((2R) -2-tt gas p ratio -1-yl-ethyl) -naphthalene-2 -yl] -211-Taguchi-3-one; 2- {6- [2- (Third-butyl-methyl-amino) -ethyl] -stub-2-yl} -2H-Dagen-3- Ketones; 2- [6- (2-diethylamino-ethyl) -naphthalene-2-yl] -2H-da-gen-3-one; 89248.doc -20- 200418454 2- [6- (2 -Morpholin-4-yl-ethyl) -fluoren-2-yl] -2H-daikon-3-one; 2- {6- [2- (ethyl-methyl-amino) -ethyl] -Fluoren-2-yl} -2 piperidin-3-one; 2- {6- [2-((23) -2-fluoromethyl-pyrrolidin-1-yl) -ethyl] -naphthalene- 2-yl} -2H-dagen-3-one; 2- {6- [2- (2-hydroxymethyl-errolidin-1-yl) -ethyl] -fluoren-2-yl} -2H -Dagen-3-one; 2_ {6- [2-((R) -2-ethyl-p-bilodine-1-yl) -ethyl] • naphthalene-2-yl} -2H-dagen -3-ketone; 2- [6- (2-azolodan-1-yl-ethyl) _fluoren-2-yl] -2H-daquan-3-one; 2- {6- [2- ( (2S) -2-fluoromethyl-azir-1-yl) -ethyl] -fluoren-2-yl} -2H-dagen-3-one; 2- {6- [2-((2S) -2-hydroxymethyl-azor-1-yl) -ethyl] -naphthalene-2-yl} -2H- Dagen-3-one; 2- {6- [2-((2 feet, 511) -2,5-dimethyl-pyrrolidin-1-yl) -ethyl] -naphthalene-2-yl}- 211-dagen-3-one; 2- {6- [2-((211,63) -2,6-dimethyl-hexahydropyridin-1-yl) -ethyl] -fluorene-2- } -2; «-dagen-3-one; 2- {6_ [2-((R) -3-hydroxy-hexahydropyridin-1-yl) -ethyl] -fluoren-2-yl}- 2H-Dagen-3-one; 2- {6- [2-((R) -2-methyl-hexahydropyridin-1-yl) -ethyl] -fluoren-2-yl} -2H-Da Phen-3-one; &quot; 2,6-dimethyl-3- {6- [2-((2R) -2-methyl-pyrrolidin-1-yl) -ethyl] -naphthalene-2- Yl} -7 Biyodo; 89248.doc -21-200418454 5- {6- [2-((R) -2-methyl-errolidin-1-yl) -ethyl] -fluoren-2-yl Buthiazoline; 2- {6- [2-((11) -2-methyl-pyrrolidin-1-yl) -ethylbuzo-2-ylpyrimidine; 3-chloro-6- { 6- [2-((R) -2-methyl-pyrrolidin-1-yl) -ethyl] -naphthyl-2-yl} -daqin; 5- {6- [2-((R)- 2-methyl-pyrrolidin-1-yl) -ethyl] -naphthyl-2-ylpyrimidin-2-ylamine; 2-methyl, yl-5- {6- [2-((2R) 2- Methyl-pyrrolidin-1-yl) -ethyl] -fluoren-2-yl} ** 0 ratio, 3-bromo-7- ( 2-pyrrolidin-1-yl-ethyl)-[1,5] pyridine; 3-bromo-7- [2- (2R-2-methyl-pyrrolidin-1-yl) -ethyl;] -[1,5] naphthyridine; 3-bromo-7- (2-hexahydropyridine-1-yl-ethyl)-[1,5] pyridine; 3- (2,6-dimethyl-pyridine -3-yl) -7- [2- (2R-2-methyl-pyrrolidin-1-yl) -ethyl]-[1,5] pyridine; 3- (2,4-dimethoxy- Pyrimidin-5-yl) -7- [2- (2R-2-methyl-pyrrolidin-1-yl) -ethyl]-[1,5] pyrimidine; 3- (2,6-dimethyl -Pyridin-3-yl) -7- (2-pyrrolidin-1-yl-ethyl)-[1,5] pyrimidine; 3- (2,4- &gt; -methoxy- ^ dian-5- Yl) -7-(2-p-bilodine-1 -yl-ethyl)-[1,5] pyridine; 3- (2,6-dimethyl-pyridin-3-yl) -7- ( 2-hexahydropyridin-1-yl-ethyl) _ [1,5] phenylidine; 3- (2,4-dimethoxy-pyrimidin-5-yl) -7- (2-hexahydropyridine-1 -Yl-ethyl) 89248.doc -22- 200418454-[1,5] pyridine; 3- [2- (2 (R) -methyl ^ pyrrolidin-1-yl) -ethyl] -7 -Pyridin-4-yl-isoquinoline; 7- (6-methoxy ^ pyridin-3-yl) -3- [2- (2 (R) -methyl ^ pyridin-1-yl)- Ethyl] -Isoprene; 3- [2- (2 (R) -methyl-pyrrolidin-1-yl) -ethyl] -7-pyrimidin-5-yl-isop-quinine; 7- ( 6-fluoro-pyridine- 3-yl) -3- [2- (2 (R) -methyl-pyrrolidin-1-yl) -ethyl] -iso / quinoline; 5- {3- [2- (2 (R)- Methyl-pyrrolidin-1-yl) -ethyl] -isofluorin-7-yl} -nicotinyl cyanide; 7- (3-chloro-pyridin-4-yl) -3- [2- (2 ( R) -Methyl-pyrrolidin-1-yl) -ethyl] -isophosphorin; 7-bromo-3- [2-((2R) -2-methylpyridin-1-yl) -ethyl ] -Porphyrin-4-ol; 4- {3- [2- (2-methyl ^ pyrrolidin-1-yl) -ethyl] -pyridin-7-ylphenylphenylcyanide; 7-bromo 4-Chloro-3- [2-((2R) -2-methyl ^ pyrrolidin-1-yl) -ethyl] -Houkoulin; 4- {4-hydroxy-3- [2- ( (2R) -2-methyl-pyrrolidin-1-yl) -ethyl] -pyridin-7-ylphenylphenyl cyanide; 4- {4-isopropoxy-3- [2-((211) -2-methyl-pyrrolidin-1-yl) -ethyl &gt; fluorin-7-yl} • phenyl cyanide; 4- {3- [2- (4-methyl-hexahydropyridine-1 -Yl) -ethyl] -pyridin-7-ylbenzene benzene 89248.doc -23-200418454 cyano; 4- [3- (2-hexahydropyridin-1-yl-ethyl) -pyridin-7 -Yl] phenylcyanine; 4- [3- (2-pyrrolidin-1-yl-ethyl) -pyridin-7-yl] -phenylcyanine; 4- {3- [2-((211) -2-methyl-pyrrolidin-1-yl) -ethyl] -pyridin-7-yl} -phenylene 1,4- {3- [2-((2R) -2-hydroxymethyl ratio Pyridin-1-yl) -B ] -Pyridin-7-yl} -dongyl, 4- [3- (2-morpholin-4-yl-ethyl) -pyridin-7-yl] -phenylcyanide; 4-U- [ 2- (4-methyl-hexahydropyridin-1-yl) -ethyl] -fluorin-7-yl} -phenylcyanide; 4- {3- [2- (ethyl-methyl-amino) ) -Ethyl] -pyridin-7-ylphenylphenyl cyanide; 7- (2,6-dimethyl-pyridin-3-yl) -3- [2-((2R) -2-methyl- Pyrrolidin-1-yl) -ethyl] -pyridoline; 7- (2,4-dimethoxy-pyrimidin-5-yl) -3- [2-((2R) -2-methyl-p ratio Pyridin-1-yl) -ethyl] -pyridinium; 7-(6-甲氧-吡啶-3-基）-3-[2-((2R)-2-甲基-吡咯啶-1-基） _乙基卜噌啉； 3-{3-[2-((21〇-2-甲基4比咯啶-1-基）-乙基]-噌啉-7-基卜 苯基氰； 5- {3-[2-((2R)-2-甲基^比咯啶-1-基）-乙基]_噌啉-7-基卜 菸基氰； 7-(4-氟-苯基）-3-[2-((2R)-2-甲基^比咯啶-1-基）-乙基&gt; 噌淋； 2-{3-[2-((2R)-2-甲基-吡咯啶-1-基）-乙基]-噌啉-7-基卜 89248.doc -24- 吡咯-1-羧酸第三丁酯； (3-{3-[2-((211)-2-甲基-叶1：咯啶-1-基）-乙基]-噌啉冬基} -苯基）-甲醇； 7-(3,5-二氟-苯基）-3_[2-((2幻_2_甲基_吡咯啶_1_基）_乙 基]-嗜琳； 3-[2-((2R)_2-甲基-ίτ比洛淀-1-基）_乙基]_7-硫苯基一 噌口林； 7-(4-氯-苯基）-3-[2-((2R)-2-甲基峨咯啶小基）_乙基]_ 噌4 ·、 7-(4-乙氧基-苯基）_3-[2_((2Κ)-2-甲基_吡咯啶_丨_基）_ 乙基]-嗜琳； 3-[2-((2R)-2-甲基-吡咯啶-丨-基）·乙基]-7_(1η_吡咯_2_ 基）-噌啉；與 2-(1，5-二甲基-1Η-吡唑-4-基）_6-{2-[(2R)-2-甲基-1-吡 。各淀基]乙基}-?奎琳。 43·根據申請專利範圍第1項之化合物，其係2-(6_{2_[(2r&gt;孓 甲基-1胃吡咯啶-i-基]-乙基卜2_莕-2-基）-211_嗒畊_3_酮或 2-(6-{2-[(2R)_2-甲基-吡咯啶基]乙基卜2_萘基） 塔啡酮。 44. -《藥組合物’其包含醫療有效量之根據中請專利範 圍第1項之化合物，與醫藥上可接受之載劑組合。 45 · —種選擇性調節哺乳動物中組織胺_3受體之功效之方、— ，其包括投與有效量之根據申請專利範圍第丨項之化人物 46· —種治療哺乳動物受組織胺_3受體調節之病症或病：、° 89248.doc -25- 418454 方法，其包括技與有效量之根據申請專利範圍第1項之化 合物。 4入根據申請專利範圍第46項之方法，其中該病症或病變係 選自下列組成 &lt; 群中··急性心肌梗塞、阿茲海默氏症、 氣喘、注意力缺乏之過動異常、兩極化病變、認知功能 障礙、精神病之認知能力缺陷、記憶力缺陷、學習力缺 陷、癡呆、皮膚癌瘤、嗑藥、糖尿病、„型糖尿病、抑 鬱症、癲癇、胃腸病變、發炎、胰島素抗性症候群、噴 射遲滯、髓質甲狀腺癌瘤、黑色素瘤、梅尼爾氏症 (Meniere’s disease)、代謝症候群、中度認知受損、偏頭 痛、情緒與注意力改變、動暈症、發作性睡眠、神經性 發炎、肥胖、強迫觀念與強迫行為性異常、疼痛、巴金 森氏症、多囊性卵巢症候群、精神分裂症、精神分裂症 H忍知力缺陷、發作、敗血性休克、χ症候群、妥瑞特 氏（Tourette's)症候群、眩暈與睡眠障礙。 伙根據中請專利範圍第46項之方法，其中該病症或病變會 影響1己憶力或認知力。 伙根據中請專利第則之方法，纟中該病症或病變為 阿兹海默氏症、注意力缺乏之過動異常、精神分裂症或 精神分裂症之認知力缺陷。 5〇· -種製備式⑴化合物或其醫藥上可接受之鹽類、酷類、 醯胺類或前藥之方法， 89248.doc -26- 2004184547- (6-methoxy-pyridin-3-yl) -3- [2-((2R) -2-methyl-pyrrolidin-1-yl) _ethylpyridinium; 3- {3- [ 2-((21〇-2-methyl 4-pyrrolidin-1-yl) -ethyl] -pyridin-7-ylphenylphenyl cyanide; 5- {3- [2-((2R) -2 -Methyl ^ pyrrolidin-1-yl) -ethyl] -pyridin-7-ylbicotinyl cyanide; 7- (4-fluoro-phenyl) -3- [2-((2R) -2 -Methyl ^ pyrrolidin-1-yl) -ethyl &gt;Glycol; 2- {3- [2-((2R) -2-methyl-pyrrolidin-1-yl) -ethyl]- Pyridin-7-jib 89248.doc -24-Pyrrole-1-carboxylic acid tert-butyl ester; (3- {3- [2-((211) -2-methyl-leaf 1: pyridine-1 -Yl) -ethyl] -pyridoordinyl} -phenyl) -methanol; 7- (3,5-difluoro-phenyl) -3_ [2-((2-2-_2methyl_pyrrolidin) _1_yl) _ethyl] -philimine; 3- [2-((2R) _2-methyl-ίτ Billotian-1-yl) _ethyl] _7-thiophenyl-amylolamine; 7- (4-chloro-phenyl) -3- [2-((2R) -2-methylerrolidine small group) _ethyl] _ 噌 4 ·, 7- (4-ethoxy-benzene Group) _3- [2 _ ((2Κ) -2-methyl_pyrrolidine_ 丨 _yl) _ethyl] -lin; 3- [2-((2R) -2-methyl-pyrrolidine- 丨-Yl) · ethyl] -7_ (1η_pyrrole_2_yl) -pyridoline; and 2- (1,5-dimethyl-1Η-pyrazol-4-yl) _6 -{2-[(2R) -2-methyl-1-pyridine. Each ytyl] ethyl}-? Quinine. 43. The compound according to item 1 of the scope of patent application, which is 2- (6_ {2_ [(2r &gt; fluorenylmethyl-1 gastric pyrrolidin-i-yl] -ethylbumin-2-yl-2-yl) -211_dagen_3_one or 2- (6- {2-[(2R ) _2-Methyl-pyrrolidinyl] ethylbu-2-naphthyl) Talphone. 44.-"Pharmaceutical composition 'which contains a medically effective amount of a compound according to item 1 of the patent claim, and medically Acceptable combination of vehicles 45 · —A method for selectively regulating the effect of the histamine_3 receptor in mammals, which includes administering an effective amount of a person according to the scope of the patent application item 46 · — A method for treating mammalian disorders or diseases regulated by the histamine_3 receptor: ° 89248.doc -25- 418454 method, which includes a technical and effective amount of a compound according to item 1 of the scope of patent application. The method according to item 46, wherein the disorder or disease is selected from the group consisting of: · acute myocardial infarction, Alzheimer's disease, asthma, hyperactivity disorder due to lack of attention, bipolar disorder, cognitive function obstacle, Cognitive deficits in mental illness, memory deficits, learning deficits, dementia, skin cancer, peony, diabetes, diabetes, depression, epilepsy, gastrointestinal disorders, inflammation, insulin resistance syndrome, jet retardation, medullary thyroid cancer Neoplasm, melanoma, Meniere's disease, metabolic syndrome, moderate cognitive impairment, migraine, mood and attention change, motion sickness, narcolepsy, neurological inflammation, obesity, obsessions and Obsessive-compulsive behavior abnormalities, pain, Parkinson's disease, polycystic ovary syndrome, schizophrenia, schizophrenia, H-tolerance deficiency, seizures, septic shock, χ syndrome, Tourette's syndrome, vertigo and sleep disorder. The method according to item 46 of the patent application, wherein the disorder or disease affects memory and cognition. According to the method of the patent claim, the disease or disease is Alzheimer's disease, attention deficit hyperactivity disorder, schizophrenia or cognitive impairment of schizophrenia. 50. A method for preparing a compound of formula VII or a pharmaceutically acceptable salt, cool, amidine or prodrug thereof, 89248.doc -26- 200418454 R3b (丨） 其中R3b (丨) where Ri為L2R6，其中L2為一鍵結，以6為3(2H)_嗒崎酮-2-基’ R*2、R3、R3a與 R3b為氫； L為；[C(R16)(R17)]n-; η為2 ; R16與R17每次出現時分別為氫； R»4與R5共同形成式（a)甲基峨ρ各淀基環，其中r7、R8、 R9與Rio中之一為甲基，其餘三個取代基為氫； Y與Yf為CH ;與 X、X，、Z與 Z，為 c ;Ri is L2R6, where L2 is a bond, and 6 is 3 (2H) _dastilbone-2-yl 'R * 2, R3, R3a, and R3b are hydrogen; L is; [C (R16) (R17) ] n-; η is 2; R16 and R17 are hydrogen each time they appear; R »4 and R5 together form a methyl ring of formula (a), wherein one of r7, R8, R9, and Rio Is methyl, and the remaining three substituents are hydrogen; Y and Yf are CH; and X, X, and Z and Z are c; 該方法包括下列步驟： (a) 提供化合物（η):The method includes the following steps: (a) providing a compound (η): HO (N) I (b) 由化合物⑴）經BH3-THF還原，產生化合物（III): 89248.docHO (N) I (b) is reduced from compound ⑴) via BH3-THF to give compound (III): 89248.doc (III) -27- 200418454 (c)由式（III)化合物經3 (2H)-嗒畊酮、銅粉與鹼處理， 產生化合物（IV):(III) -27- 200418454 (c) Treatment of a compound of formula (III) with 3 (2H) -dacrotonone, copper powder and alkali to produce compound (IV): (d)活化化合物（IV)之羥基；及由所得化合物與甲基吡 咯啶反應，產生式（I)化合物。(d) activating the hydroxyl group of compound (IV); and reacting the obtained compound with methylpyrrolidine to produce a compound of formula (I). 89248.doc 28- 200418454 柒、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件代表符號簡單說明： 捌、本案若有化學式時，請揭示最能顯示發明特徵的化學式：89248.doc 28- 200418454 柒. Designated representative map: (1) The designated representative map in this case is: (none) (II) The component representative symbols of this representative map are simply explained: 捌 If there is a chemical formula in this case, please reveal the best display Inventive chemical formula: 89248.doc89248.doc
TW092131661A 2002-11-12 2003-11-12 Bicyclic-substituted amines as histamine-3 recepto TWI359658B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10/292,422 US20040092521A1 (en) 2002-11-12 2002-11-12 Bicyclic-substituted amines as histamine-3 receptor ligands
US10/689,735 US7153889B2 (en) 2002-11-12 2003-10-22 Bicyclic-substituted amines as histamine-3 receptor ligands

Publications (2)

Publication Number Publication Date
TW200418454A true TW200418454A (en) 2004-10-01
TWI359658B TWI359658B (en) 2012-03-11

Family

ID=32314386

Family Applications (1)

Application Number Title Priority Date Filing Date
TW092131661A TWI359658B (en) 2002-11-12 2003-11-12 Bicyclic-substituted amines as histamine-3 recepto

Country Status (8)

Country Link
EP (1) EP1569637A1 (en)
JP (2) JP4820094B2 (en)
AU (1) AU2003291329A1 (en)
CA (2) CA2765093A1 (en)
MX (1) MXPA05005116A (en)
PL (1) PL376751A1 (en)
TW (1) TWI359658B (en)
WO (1) WO2004043458A1 (en)

Families Citing this family (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MXPA05011942A (en) * 2003-05-07 2006-02-02 Abbott Lab Fused bicyclic-substituted amines as histamine-3 receptor ligands.
US7094790B2 (en) 2003-05-07 2006-08-22 Abbott Laboratories Fused bicyclic-substituted amines as histamine-3 receptor ligands
US20040224952A1 (en) * 2003-05-07 2004-11-11 Cowart Marlon D. Fused bicyclic-substituted amines as histamine-3 receptor ligands
WO2005108370A1 (en) * 2004-04-16 2005-11-17 Ajinomoto Co., Inc. Benzene compounds
US20050256118A1 (en) * 2004-05-12 2005-11-17 Altenbach Robert J Bicyclic-substituted amines having cyclic-substituted monocyclic substituents
US7098222B2 (en) 2004-05-12 2006-08-29 Abbott Laboratories Bicyclic-substituted amines having cyclic-substituted monocyclic substituents
US20050256309A1 (en) * 2004-05-12 2005-11-17 Altenbach Robert J Tri-and bi-cyclic heteroaryl histamine-3 receptor ligands
US7205316B2 (en) 2004-05-12 2007-04-17 Abbott Laboratories Tri- and bi-cyclic heteroaryl histamine-3 receptor ligands
JP4594386B2 (en) 2004-06-02 2010-12-08 エフ．ホフマン−ラ ロシュ アーゲー Naphthalene derivatives useful as ligands for the histamine 3 receptor
ES2367515T3 (en) * 2004-10-19 2011-11-04 F. Hoffmann-La Roche Ag DERIVATIVES OF QUINOLINA.
EP1683523A1 (en) * 2005-01-25 2006-07-26 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. 2-Phenylquinoxalines as inhibitors for MPP1
EP1888523B1 (en) 2005-06-03 2011-10-26 Abbott Laboratories Cyclobutyl amine derivatives
ES2601178T3 (en) * 2005-09-01 2017-02-14 F. Hoffmann-La Roche Ag Diaminopyrimidines as modulators of P2X3 and P3X2 / 3
US7576110B2 (en) 2005-09-22 2009-08-18 Abbott Laboratories Benzothiazole cyclobutyl amine derivatives
EP2049472B1 (en) 2006-06-23 2015-01-21 AbbVie Bahamas Ltd. Cyclopropyl amine derivatives as histamin h3 receptor modulators
US9108948B2 (en) 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
US8153813B2 (en) 2007-12-20 2012-04-10 Abbott Laboratories Benzothiazole and benzooxazole derivatives and methods of use
US8383657B2 (en) 2007-12-21 2013-02-26 Abbott Laboratories Thiazolylidine urea and amide derivatives and methods of use thereof
US9186353B2 (en) 2009-04-27 2015-11-17 Abbvie Inc. Treatment of osteoarthritis pain
GB201104267D0 (en) 2011-03-14 2011-04-27 Cancer Rec Tech Ltd Pyrrolopyridineamino derivatives
RU2017140639A (en) * 2011-05-23 2019-02-12 Элан Фармасьютикалз, Инк. KINASE LRRK2 KINASE ACTIVITY INHIBITORS
US9181275B2 (en) 2011-08-11 2015-11-10 Abbvie Inc. Mercaptoamidine derivatives and methods of use
EP2825533B1 (en) 2012-03-13 2016-10-19 Basf Se Fungicidal pyrimidine compounds
GB201216017D0 (en) 2012-09-07 2012-10-24 Cancer Rec Tech Ltd Inhibitor compounds
GB201216018D0 (en) 2012-09-07 2012-10-24 Cancer Rec Tech Ltd Pharmacologically active compounds
WO2014086701A1 (en) * 2012-12-06 2014-06-12 F. Hoffmann-La Roche Ag Substituted thiazole compounds
ES2647965T3 (en) * 2013-01-09 2017-12-27 Arena Pharmaceuticals, Inc. Biphenyl-ethyl-pyrrolidine derivatives as histamine H3 receptor modulators for the treatment of cognitive disorders
WO2015036059A1 (en) 2013-09-16 2015-03-19 Basf Se Fungicidal pyrimidine compounds
WO2015036058A1 (en) 2013-09-16 2015-03-19 Basf Se Fungicidal pyrimidine compounds
GB201403536D0 (en) 2014-02-28 2014-04-16 Cancer Rec Tech Ltd Inhibitor compounds
EP3411374B9 (en) * 2016-02-04 2023-01-11 Raynergy Tek Inc. [1,5]naphthyridine compounds and polymers as semiconductors
WO2018226622A1 (en) * 2017-06-05 2018-12-13 Ptc Therapeutics, Inc. Compounds for treating huntington's disease
GB201709840D0 (en) 2017-06-20 2017-08-02 Inst Of Cancer Research: Royal Cancer Hospital Methods and medical uses
JP7399870B2 (en) 2018-03-27 2023-12-18 ピーティーシー セラピューティクス， インコーポレイテッド Compounds to treat Huntington's disease
CN110669504B (en) * 2019-11-15 2022-01-04 北京建筑大学 Fluorescent probe for detecting aldehyde characteristic odor substances in drinking water

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE556324C (en) * 1929-04-05 1932-08-10 Chemische Ind Ges Process for the preparation of halogen-containing basic ethers
CH149007A (en) * 1929-04-05 1931-08-15 Chem Ind Basel Process for the preparation of a halogen-containing basic ether.
US1860286A (en) * 1929-05-16 1932-05-24 Soc Of Chemical Ind Basic ethers of aryl-quinolines
US1949046A (en) * 1930-03-24 1934-02-27 Soc Of Chemical Ind Basic ether containing halogen
US3139430A (en) * 1960-12-20 1964-06-30 Merck & Co Inc 2-dialkylaminoalkoxy-6-substituted naphthalenes useful as new anticholesteremic agents
NL131915C (en) * 1966-07-27
DE1543360C2 (en) * 1966-07-27 1975-05-28 Boehringer Mannheim Gmbh, 6800 Mannheim N, N-disubstituted 2- (aminoalkoxy) naphthalenes and processes for their preparation
GB1166538A (en) * 1967-06-10 1969-10-08 Pfizer Ltd Substituted Tetrahydroquinolines
US3489756A (en) * 1967-07-10 1970-01-13 Merck & Co Inc 2-carbocyclic-6-tertiary amino alkoxy naphthalenes and tetralins
JPS5649357A (en) * 1979-09-28 1981-05-02 Otsuka Pharmaceut Co Ltd Quinoline derivative
JP2551298B2 (en) * 1991-04-25 1996-11-06 田辺製薬株式会社 Antidepressant
US5480883A (en) * 1991-05-10 1996-01-02 Rhone-Poulenc Rorer Pharmaceuticals Inc. Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
AU6753298A (en) * 1997-03-25 1998-10-20 Astra Pharmaceuticals Limited Novel pyridine derivatives and pharmaceutical compositions containing them
SK130599A3 (en) * 1997-03-25 2000-05-16 Astra Pharma Prod Novel pyridine derivatives and pharmaceutical compositions containing them
JP4370002B2 (en) * 1997-08-08 2009-11-25 富山化学工業株式会社 Quinolone carboxylic acid derivative or salt thereof
EP0982300A3 (en) * 1998-07-29 2000-03-08 Societe Civile Bioprojet Non-imidazole alkylamines as histamine H3 - receptor ligands and their therapeutic applications
JP2002275157A (en) * 1998-11-20 2002-09-25 Torii Yakuhin Kk New naphthalene derivative
AU4058399A (en) * 1998-11-20 2000-06-13 Torii Pharmaceutical Co., Ltd. Naphthalene derivatives
WO2002018335A1 (en) * 2000-08-28 2002-03-07 Yamanouchi Pharmaceutical Co., Ltd. Cyclic amine derivatives
AU2001293847B2 (en) * 2000-10-02 2007-05-24 Janssen Pharmaceutica N.V. Metabotropic glutamate receptor antagonists
EP1370546A2 (en) * 2001-03-16 2003-12-17 Abbott Laboratories Novel amines as histamine-3 receptor ligands and their therapeutic applications

Also Published As

Publication number Publication date
EP1569637A1 (en) 2005-09-07
CA2765093A1 (en) 2004-05-27
TWI359658B (en) 2012-03-11
JP4820094B2 (en) 2011-11-24
JP2011063594A (en) 2011-03-31
PL376751A1 (en) 2006-01-09
WO2004043458A1 (en) 2004-05-27
MXPA05005116A (en) 2005-07-01
JP2006514926A (en) 2006-05-18
CA2505427A1 (en) 2004-05-27
AU2003291329A1 (en) 2004-06-03
CA2505427C (en) 2012-04-03

Similar Documents

Publication Publication Date Title
TW200418454A (en) Bicyclic-substituted amines as histamine-3 receptor ligands
US7456196B2 (en) Bicyclic-substituted amines as histamine-3 receptor ligands
US7098222B2 (en) Bicyclic-substituted amines having cyclic-substituted monocyclic substituents
CA2566896C (en) Bicyclic-substituted amines having cyclic-substituted monocyclic substituents for modulating effects of histamine-3 receptor
AU2017287553B2 (en) Imidazopyrazinamine phenyl derivative and use thereof
TW200944520A (en) Spiro compounds as NPY Y5 receptor antagonists
TW201139427A (en) Pyridine and pyrazine derivative for the treatment of CF
US20050245543A1 (en) Histamine-3 receptor antagonists
TW200815412A (en) A pharmaceutical combination comprising 3-or 4-monosubstituted phenol and thiophenol derivatives
TW200911244A (en) New azabiphenylaminobenzoic acid derivatives
DE19637237A1 (en) Piperazine derivatives
CA2574361A1 (en) 1, 3 substituted cycloamino derivatives and their use as histamine-3 receptor antagonists
AU2011223976A1 (en) Inhibitors of catechol O-methyl transferase and their use in the treatment of psychotic disorders
TWI572592B (en) Pyridine derivatives and application of anti-macobacterium thereof
TW201002711A (en) Azacarboline derivatives, preparation and therapeutic use thereof
TWI290140B (en) 2-Substituted benzimidazole derivatives as selective melanin concentrating hormone receptor antagonists for thr treatment of obesity and related disorders
CN114174266A (en) Arylsulfonamide derivatives as MGLUR4 negative allosteric modulators
US20040092521A1 (en) Bicyclic-substituted amines as histamine-3 receptor ligands
EP3026043A1 (en) Glycine transporter inhibitor
KR20210022646A (en) Cyanotriazole compounds and uses thereof
JP2857693B2 (en) New pyridyl- and pyrimidyl derivatives
CN106604918B (en) Polycyclic hERG activators
TW200817361A (en) Substituted heterocyclic ethers and their use in CNS disorders
JP6199406B2 (en) Novel compounds as diacylglycerol acyltransferase inhibitors
CN110177784A (en) One kind containing aromatic compound, preparation method, pharmaceutical composition and application

Legal Events

Date Code Title Description
MM4A Annulment or lapse of patent due to non-payment of fees