CN1738799A - Methods for preparing phenylalkyne derivatives - Google Patents

Methods for preparing phenylalkyne derivatives Download PDF

Info

Publication number
CN1738799A
CN1738799A CNA038258978A CN03825897A CN1738799A CN 1738799 A CN1738799 A CN 1738799A CN A038258978 A CNA038258978 A CN A038258978A CN 03825897 A CN03825897 A CN 03825897A CN 1738799 A CN1738799 A CN 1738799A
Authority
CN
China
Prior art keywords
phenyl
heterocyclic radical
group
alkyl
independently
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CNA038258978A
Other languages
Chinese (zh)
Inventor
R·阿波达卡
X·邓
J·A·雅布罗诺夫斯基
N·马尼
C·R·潘迪特
W·肖
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceuticals Inc
3 Dimensional Pharmaceuticals Inc
Original Assignee
3 Dimensional Pharmaceuticals Inc
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 PCT/US2002/038480 external-priority patent/WO2003050099A1/en
Application filed by 3 Dimensional Pharmaceuticals Inc filed Critical 3 Dimensional Pharmaceuticals Inc
Publication of CN1738799A publication Critical patent/CN1738799A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • 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
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no 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 the ring nitrogen atom
    • C07D203/12—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • 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
    • 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
    • C07D215/04—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/02—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • 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
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other 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
    • C07D295/02—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon 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
    • C07D295/096—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
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyridine Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Indole Compounds (AREA)

Abstract

A method for preparing substituted phenylalkyne derivatives of the formula (I) is provided.

Description

The preparation method of benzyne derivative
Invention field
The present invention relates to benzyne, they synthetic and in disease of for example treating the Histamine Receptors mediation and the application in the illness.
Background of invention
Histamine { 2-(imidazol-4 yl) ethamine } is a transmitter substance.Histamine is by many different g protein coupled receptors performance physiological effects.It works in immediate hypersensitivity, and discharges from mastocyte after antigen I gE antibody interacts.The histamine that discharges acts on vascular system and level and smooth musculation, produces symptoms of allergic.These effects betide H 1Acceptor (Ash, A.S.F. and Schild, H.O., Br.J.Pharmac.Chemother.1966 27:427-439) and by standard antihistaminic (for example diphenhydramine) blocks.Histamine also is to regulate the important conditioning agent of gastric acid secretion by acting on parietal cell.These effects of histamine are passed through H 2It is receptor-mediated that (Nature 1972 for Black, J.W. etc., 236:385-390) and by H 2Receptor antagonist (for example Cimitidine Type A/AB) blocking-up.The third Histamine Receptors H 3, promptly be called as the earliest presynaptic autoreceptor in the synthetic and central nervous system (CNS) that discharges of control histamine (Arrang, J.-M. etc., Nature1983,302:832-837).The evidence that occurs shows recently: H 3Acceptor also can (containing γ-An Jidingsuan) neuronic presynaptic multiple receptor as being positioned at serotonin energy, norepinephrine energy, dopaminergic, cholinergic and GABA.Also identify these H recently in peripheral tissues such as vascular smooth muscles 3Acceptor.Therefore, histamine H 3Agonist, antagonist and inverse agonist have many potential therepic use.(referring to " The Histamine H 3Receptor-A Target forNew Drugs (histamine H 3Acceptor-new drug target) ", Leurs, R. and Timmerman, H. (editor), Elsevier, 1998; Morisset, S. etc., Nature 2000,408:860-864).Recently, Oda, T. etc. have described the 4th kind of Histamine Receptors H 4, (J.Biol.Chem.2000,275 (47): 36781-36786).
Histamine H 3Agonist proposes (Lin, J.-S. etc., Brain Res.1990,523:325-330 in sleep/Arousal disorders and the potential use that wakes up/wake up with a start in the obstacle according to animal experiment; Monti, J.M. etc., Eur.J.Pharmacol.1991,205:283-287).It treats migrainous purposes, and (Soc.Neurosci.Abstr.1996 22:2010) suppresses the neurogenic inflammation ability according to it and proposes for McLeod, R.L. etc.Other application can be that myocardial ischemia and hypertension are shielded, and wherein blocking norepinephrine release is useful (Imamura, M. etc., J.Pharmacol.Exp.Ther.1994,271 (3): 1259-1266).Someone proposes histamine H 3Agonist may be useful to asthma, because it can reduce non-adrenergic-non-cholinergic in the respiratory tract (NANC) neurotransmission, and can reduce microvascular leakage (Ichinose, M. and Barnes, P.J., Eur.J.Pharmacol.1989,174:49-55).
Histamine H 3Some indications of antagonist and inverse agonist are equally according to known histamine H 3The animal pharmacology experiment of antagonist (for example Thioperamide) proposes.These comprise dementia, alzheimer's disease (Panula, P. etc., Soc.Neurosci.Abstr.1995,21:1977), epilepsy (Yokoyama, H. etc., Eur.J.Pharmacol.1993,234:129-133), narcolepsy, eating disorder (Machidori, H. etc., Brain Res.1992,590:180-186), motion sickness, dizzy, scatterbrained hyperactivity disorder (ADHD), learning and memory obstacle (Barnes, J.C. etc., Soc.Neurosci.Abstr.1993,19:1813) and schizophrenia (Schlicker, E. and Marr, I., Naunyn-Schmiedebeg ' s Arch.Pharmacol.1996,353:290-294).(also referring to Stark, H. etc., Drugs Future 1996,21 (5): 507-520; And Leurs, R. etc., Prog.Drug Res.1995,45:107-165 and the reference of wherein quoting).It is reported histamine H 3The antagonist list is used or and histamine H 1The antagonist coupling can be used for treating upper respiratory tract hypersensitivity reaction (U.S. Patent number 5,217,986; 5,352,707 and 5,869,479).Recently, histamine H 3Antagonist (GT-2331) has obtained identifying and by Gliatech company (Gliatech Inc. news release, on November 5th, 1998; Bioworld Today, on March 2nd, 1999) exploitation is used for the treatment of the CNS disease.
It should be noted that relevant histamine H 3The prior art of part has had summary extensively and profoundly (" THe Histamine H 3Recptor-A Target For New Drugs (histamine H 3Acceptor-new drug target) ", Leurs, R. and Timmerman, H. (editor), Elsevier, 1998).In this reference to histamine H 3The pharmaceutical chemistry of agonist and antagonist done summary (respectively referring to Krause, M. etc. and Phillips, J.G. and Ali, S.M.).Noticed in the imidazoles part and only contained 4 mono-substituted importance, noticed that simultaneously extra replacement is to active deleterious effect.Specifically, it is reported imidazole ring any all the other do not methylate on the position of substitution and all can significantly reduce activity.Other publication is supported this hypothesis: imidazoles functional group is to the high-affinity histamine H 3Receptors ligand be absolutely necessary (referring to Ali, S.M. etc., J.Med.Chem.1999,42:903-909, and Stark, H. etc., and the reference wherein quoted).Yet many imidazo-containing compounds are substrates of histamine methyl transferase, this enzyme is human main histamine metabolic enzymes, it can cause half life to shorten and the bioavailability reduction (referring to Rouleau, A. etc., J.Pharmacol.Exp.Ther.1997,281 (3): 1085-1094).In addition, contain of the interaction of imidazoles medicine by itself and cytochrome P 450 monooxygenases system, can be owing to enzyme induction or enzyme suppress to cause unfavorable bio-transformation (referring to Kapetanovic, I.M. and Kupferberg, H.J., Drug Metab.Dispos.1984,12 (5): 560-564; Sheets, J.J. and Mason, J.I., Drug Metab.Dispos.1984,12 (5): 603-606; Back, D.J. and TJia, J.F., Br.J.Pharmacol.1985,85:121-126; Lavrijsen, K. etc., Biochem.Pharmacol.1986,35 (11): 1867-1878; Albengres, E. etc., Drug Safety, 1998,18 (2): 83-97).Early stage histamine H 3The bad hemato encephalic barrier penetrance of receptors ligand also may be relevant with imidazole fragments (Ganellin, C.R. etc., Arch.Pharm.Pharm.Med.Chem. (Weinheim, Ger.) 1998,331:395-404).
Recently, some publications have been described the histamine H that does not contain the imidazoles part 3Part, for example: Ganellin, C.R. etc.; Walczynski, K. etc., Arch.Pharm.Pharm.Med.Chem. (Weinheim, Ger.) 1999,332:389-398; Walczynski, K. etc., Farmaco 1999,54:684-694; Linney, I.D. etc., J. Med. Chem.2000,43:2362-2370; Tozer, M.J. and Kalindjian, S.B., Exp.Opin.Ther.Patents 2000,10:1045-1055; United States Patent (USP) 5,352,707; PCT applies for WO 99/42458; PCT applies for WO 02/076925; With european patent application on February 9th, 0978512,2000.
The compounds of this invention does not contain the imidazoles part, does not have its inherent shortcoming yet, but according to people's histamine H 3The receptors bind of acceptor is measured, and it has still kept the histamine H to the people 3The effect of acceptor (referring to Lovenberg, T.W. etc., Mol.Pharmacol.1999,55:1101-1107).The new drug that the personnel selection acceptor screens identifying the treatment human diseases is even more important.Conventional combination test is measured with following material: rat synaptosome (Garbarg, M. etc., J.Pharmacol.Exp.Ther.1992,263 (1): 304-310), rat layer film (West, R.E. etc., Mol.Pharmacol.1990,38:610-613) and guinea pig brain (Korte, A. etc., Biochem.Biophys.Res.Commun.1990,168 (3): 979-986).Before had only limited research to use tissue to test, but the remarkable pharmacology difference (West that is present in rodent acceptor and primates acceptor has but been mentioned in these researchs indirectly, R.E. etc., Eur.J.Pharmacol.1999,377:233-239).
Below we have described and a series ofly have the adjusting Histamine Receptors and (say it is H exactly 3Acceptor) active ability and do not have the intrinsic problem of imidazolyl part correlation benzyne.
Summary of the invention
The present invention relates to medical active benzyne and preparation method thereof and using method.The invention is characterized in following formula (I) compound or the acceptable salt of its medicine, ester or acid amides:
Figure A0382589700231
Wherein n is the integer of 0-1;
R 1And R 2Independently be selected from C 1-3Alkyl, allyl group and C 3-8Cycloalkyl, perhaps the nitrogen that is connected with them combines, and they form optional 2 the first heterocyclic radicals of extra heteroatomic non-aromatics 4-7 that independently are selected from O, S and N at the most that comprise;
R 3, R 4And R 5One of be G, one in all the other two is hydrogen, and another is selected from hydrogen, fluorine and chlorine;
G is L 2Q;
L 2Be methylene radical;
Q is NR 8R 9, R wherein 8Independently be selected from hydrogen, C 1-6Alkyl, C 3-6Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical (preferred 5-9 or 5-8 unit heterocyclic radical), phenyl, (5-9 unit heterocyclic radical) C 1-6Alkylidene group and (phenyl) C 1-6Alkylidene group; R 9Independently be selected from C 1-6Alkyl, C 3-6Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical (preferred 5-9 or 5-8 unit heterocyclic radical), phenyl, (5-9 unit heterocyclic radical) C 1-6Alkylidene group and (phenyl) C 1-6Alkylidene group;
Or
Q is the heterocyclic radical that the saturated N of 3-13 unit connects, and wherein, except that N connected nitrogen, 3-13 unit heterocyclic radical also can be chosen wantonly and contain 1-3 extra heteroatoms that independently is selected from O, S and N;
Each abovementioned alkyl, alkylidene group, thiazolinyl, heterocyclic radical, cycloalkyl, carbocylic radical and aryl can independently separately and optional independently be selected from following substituting group replacement by 1-3 in its Chinese style (I): methoxyl group, halogen, amino, nitro, hydroxyl and C 1-3Alkyl;
Wherein the 1-3 of a Q substituting group can further independently be selected from (except the paragraph of front) tert-butoxycarbonyl, formamido-, C 1-6Alkyl, 5-9 unit heterocyclic radical, N (C 1-6Alkyl) (5-9 unit heterocyclic radical), NH (5-9 unit heterocyclic radical), O (5-9 unit heterocyclic radical), (5-9 unit heterocyclic radical) C 1-3Alkylidene group, phenyl, C 1-2-hydroxy alkylidene, C 2-6Alkoxyl group, (C 3-6Cycloalkyl)-O-, phenyl, (phenyl) C 1-3Alkylidene group and (phenyl) C 1-3Alkylidene group-O-, wherein the described substituting group of Q can be chosen wantonly and have 1-3 and independently be selected from following substituting group: trifluoromethyl, halogen, nitro, cyano group and hydroxyl.
Feature of the present invention also is the preparation method of formula (I) compound and the acceptable salt of medicine, ester or acid amides, and described method comprises at least one following step: make following formula (VI) compound and following formula V compound reaction:
Figure A0382589700241
With
With organic bases R 1R 2NH is at the X of formula (VIII) compound 1On carry out nucleophilic substitution, wherein with the linked reaction of alkynes in, X 2Be suitable leavings group, and with the nucleophilic substitution reaction of amine in, X 1Be suitable leavings group.
Feature of the present invention also is the preparation method of formula (I) compound and the acceptable salt of medicine, ester or acid amides, wherein more particularly, and R 3And R 5One of be G, all the other one and R 4One of be H, and another is selected from hydrogen, fluorine and chlorine, described method comprises: make the reaction of at least one following formula (XXIIIw) compound and following formula (XXIIIow) compound and formula V compound:
Figure A0382589700252
Wherein W is that C (O) H (is meant ) or G, X 2With the linked reaction of alkynes in be suitable leavings group.
Feature of the present invention also is the preparation method of formula (I) compound and the acceptable salt of medicine, ester or acid amides, wherein more particularly, and R 4Be G, remaining R 3And R 5One of be hydrogen, and another is selected from hydrogen, fluorine and chlorine, G is the meta-substituent with respect to the alkynes chain substituent, described method comprises: make the reaction of following formula (XXIIImw) compound and formula V compound:
Figure A0382589700254
Wherein W is C (O) H or G, X 2For with the linked reaction of alkynes in suitable leavings group.
Feature of the present invention also is the preparation method of formula (I) compound and the acceptable salt of medicine, ester or acid amides, and described method comprises: in the presence of halogenation San Wan Ji Phosphonium and alkali, make following formula (VII) compound and organic bases R 1R 2The NH reaction:
Feature of the present invention also is to comprise pharmaceutical composition and the preparation or the compound method of The compounds of this invention and medicine acceptable carrier.Composition of the present invention can also comprise more than a kind of compound of the present invention, or conjoint therapy (combination of the promoting agent of compound formulation or different methods preparation).
The present invention also provides the method for some illness of treatment and disease, and every kind of method comprises The compounds of this invention or the composition that needs the patient treatment of this treatment significant quantity (or associating significant quantity).Disclosed compound can be used for treating or preventing the patient's of this needs neurology department's disease and other histamine H 3The method of receptor-mediated disease, described neurology department disease comprise sleep/Arousal disorders and wake/wake up with a start obstacle (for example insomnia and trouble with jet lag), scatterbrained hyperactivity disorder (ADHD), learning and memory obstacle, cognition dysfunction, migraine, neurogenic inflammation, dementia, mild cognitive go down (forerunner's dementia), alzheimer's disease, epilepsy, narcolepsy, eating disorder, obesity, motion sickness, dizzy, schizophrenia, substance abuse, two-phase obstacle, mania and dysthymia disorders up; Described histamine H 3Receptor-mediated disease is upper respiratory tract hypersensitivity reaction, asthma, itch, nasal congestion and allergic rhinitis for example.For example, the invention is characterized in prevention, suppress following advancing of disease or following disease treated: the method for upper respiratory tract hypersensitivity reaction, asthma, itch, nasal congestion and allergic rhinitis.
In yet another embodiment, disclosed compound can be used for conjoint therapy, and described method comprises the H of associating effective dose 3Antagonist and unite the histamine H of effective dose 1Antagonist, for example Loratadine (CLARITIN TM), Desloratadine (CLARINEX TM), fexofenadine (ALLEGRA TM) and cetirizine (ZYRTEC TM), be used for the treatment of allergic rhinitis, nasal congestion and supersensitivity hyperemia.
In yet another embodiment, disclosed compound can be used for conjoint therapy, and described method comprises the H of associating effective dose 3Antagonist and unite effective dose neurotransmitter re-uptake retarding agent, for example selective serotonin reuptake inhibitor (SSRI) or non-selective serotonin, Dopamine HCL or NRI comprise fluoxetine (PROZAC TM), Sertraline (ZOLOFT TM), paroxetine (PAXIL TM) and amitriptyline, be used for the treatment of dysthymia disorders, mood disorder or schizophrenia.
According to hereinafter detailed Description Of The Invention and embodiment and appended claims, the extra feature and advantage of the present invention will become apparent.
Detailed Description Of The Invention
The invention provides and be applicable to that treatment is subjected to the disease of Histamine Receptors adjusting and the benzyne compound of illness.
A. term
Some terms of definition in the whole specification sheets, use described usage below.
" halogen " used herein is meant the univalent perssad of chlorine, bromine, fluorine and iodine.
Used herein is that the term " alkyl " that uses separately or use as substituent integral part all comprises straight chain and side chain carbochain.For example, alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group etc.Except as otherwise noted, when being used for alkyl, " rudimentary " implication is the carbochain of being made up of 1-4 carbon atom." alkylidene group " refers to bivalent hydrocarbon radical, for example methylene radical (CH 2), ethylidene (CH 2-CH 2-) or propylidene ((CH 2CH 2CH 2-) etc.
Except as otherwise noted, " thiazolinyl " used herein is meant that its at least two hydrogen atoms are replaced the straight or branched alkyl that forms carbon-to-carbon double bond, for example propenyl, butenyl, pentenyl etc. by the π key.When thiazolinyl is R 8Or R 9The time, open base (tie point of molecule rest part) is at sp 3On the carbon, be example with the allyl group, therefore one or more pairs of keys are α (if not the words of β, γ etc.) positions to open base at least.
Except as otherwise noted, " alkoxyl group " used herein is meant the oxygen ether of above-mentioned straight or branched alkyl.For example, methoxyl group, oxyethyl group, positive propoxy, sec-butoxy, tert.-butoxy, positive hexyloxy etc.
Except as otherwise noted, " cycloalkyl " used herein is meant the saturated monocycle carbocyclic ring structure of 3-8 unit.Suitable example comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.
Except as otherwise noted, " cycloalkenyl group " used herein is meant the unsaturated monocycle carbocyclic ring of 3-8 unit's part structure, and wherein ring structure contains a two key at least.Suitable example comprises cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctene base, hexamethylene-butadienyl etc.
Except as otherwise noted, " aryl " used herein is meant isocyclic aryl, for example phenyl, naphthyl etc.Divalent radical comprises phenylene (C 6H 4-), wherein preferred inferior benzene-1,4-two bases, but also can be inferior benzene-1,3-two bases.
Except as otherwise noted, " aralkyl " used herein is meant any alkyl that is replaced by aryl such as phenyl, naphthyls.The example of aralkyl comprises benzyl, styroyl and hydrocinnamyl.
Except as otherwise noted, " carbocylic radical " used herein is meant in any one or a plurality of framework ring by 3-13 carbon atom, preferred 6-9 cyclic group that carbon atom is formed, even described carbocyclic ring is to condense or screw togather dicyclo or three cyclic groups.Carbocyclic ring can be saturated, unsaturated, part is unsaturated or fragrant.Example comprises cycloalkyl, cycloalkenyl group, cycloalkynyl radical; Specific examples comprises phenyl, benzyl, indanyl and xenyl.Carbocyclic ring can have the substituting group that is not carbon or hydrogen, for example the hydroxyl that provides of this paper other parts, halogen, halogenated methyl etc.
Except as otherwise noted, term used herein " heterocycle " and " heterocyclic radical " are meant any 3,4,5,6,7 or 8 yuan of monocycles that are selected from following heteroatom moiety that contain at least, 8 or 9 or 10 or 11 yuan of dicyclos, 12 or 13 or 14 yuan of tricyclic structure: N, O, SO, SO 2, (C=O) and S, preferred N, O or S optionally in each ring contain 1-4 extra heteroatoms.In some embodiments, described heterocyclic radical contains 1-3 or 1-2 extra heteroatoms.Unless otherwise indicated, heterocyclic radical can be saturated, part is undersaturated, fragrant or part fragrance.Heterocyclic radical can be connected with any heteroatoms or carbon atom, forms rock steady structure.
Exemplary monocyclic heterocycles base can comprise pyrrolidyl, pyrryl, indyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidyl oxazolyl oxazolidinyl isoxazoline-3-yl isoxazolyl, thiazolyl, thiadiazolyl group, thiazolidyl, isothiazolyl, the isothiazole alkyl, furyl, tetrahydrofuran base, thienyl oxadiazole base, piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxa-azepines base, the azepines base, the hexahydroazepine base, the 4-piperidyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, THP trtrahydropyranyl, tetrahydro thiapyran base, the tetrahydro thiapyran base sulfone, morpholinyl, thio-morpholinyl, the thio-morpholinyl sulfoxide, the thio-morpholinyl sulfone, 1,3-dioxolane base and tetrahydrochysene-1,1-dioxo thienyl, the dioxane base, the isothiazole alkyl, the Thietane base, the thiirane base, triazinyl, triazolyl, tetrazyl, azetidinyl etc.
For example, if Q is the heterocyclic radical that the N-of saturated 3-13 unit connects, then Q must contain at least one nitrogen and carbon atom is sp 3Hydridization.
Generally speaking, exemplary bicyclic heterocyclic radical comprises benzothiazolyl benzoxazolyl benzoxazinyl, benzothienyl, quinuclidinyl, quinolyl, quinolyl-N-oxide compound, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl-, benzopyranyl, the indolizine base, benzofuryl, the chromone base, the tonka bean camphor base, the cinnolines base, quinoxalinyl, indazolyl, pyrrolopyridinyl, (for example furo { 2 for the furo pyridyl, the 3-c} pyridyl, furo { 3,1-b} pyridyl or furo { 2, the 3-b} pyridyl), dihydro-iso indolyl, dihydroquinazoline base (for example 3,4-dihydro-4-oxo-quinazolyl), tetrahydric quinoline group (for example 1,2,3, the 4-tetrahydric quinoline group), tetrahydro isoquinolyl (for example 1,2,3, the 4-tetrahydro isoquinolyl), the benzisothiazole base, the benzoisoxazole base, the benzodiazine base, benzo furazan base, the benzo thiapyran base, the benzotriazole base, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thienyl, the thiochroman base, thiochroman base sulfone, the dihydrobenzopyrans base, indolinyl, pseudoindoyl, tetrahydrochysene indazole base (for example 4,5,6,7-tetrahydrochysene indazole base), different chromanyl, iso-dihydro-indole-group, naphthyridinyl, phthalazinyl, piperonyl, purine radicals, the pyridopyridine base, quinazolyl, tetrahydric quinoline group, the thienofuran base, the thienopyridine base, the thienothiophene base;
Figure A0382589700301
Deng.
Exemplary tricyclic heterocyclic base comprises acridyl, phenoxazinyl, phenazinyl, phenothiazinyl, carbazyl, our pyridine base, phenanthroline base, carbolinyl, aphthothiophenes base, thianthrenyl etc.
Preferred heterocyclic radical comprises morpholinyl, piperidyl, piperazinyl, pyrrolidyl, pyrimidyl, pyridyl, pyrryl, imidazolyl, oxazolyl, isoxazolyl, acridyl, azepines base, hexahydroazepine base, azetidinyl, indyl, pseudoindoyl, thiazolyl, thiadiazolyl group, quinolyl, isoquinolyl, 1,2,3,4-tetrahydric quinoline group, 1,3,4-three hydrogen isoquinoline bases, 4,5,6,7-tetrahydrochysene indazole base, benzoxazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl-, tetrazyl, di azoly,
Figure A0382589700302
With
Figure A0382589700303
Except as otherwise noted, term used herein " heterocyclic radical-alkyl " or " heterocyclic radical-alkylidene group " are meant any alkyl that is replaced by heterocyclic radical, and wherein said heterocyclic radical-alkyl is by the centre portions bonding of moieties and molecule.The suitable example of heterocyclic radical-alkyl includes but not limited to piperidino methyl, pyrrolidyl methyl, piperidyl ethyl, piperazinyl methyl, pyrryl butyl, piperidyl isobutyl-, pyridylmethyl, pyrimidinylethyl etc.
If concrete group is " replacement " (for example alkyl, alkylidene group, cycloalkyl, aryl, heterocyclic radical, heteroaryl), then this group can have one or more substituting groups that independently are selected from the substituting group catalogue, preferred 1-5 substituting group, more preferably 1-3 substituting group, most preferably 1-2 substituting group.
Any substituting group in the regulation molecule on the specific position or the definition of variable group are independent of the definition of its other position in this molecule.Be appreciated that substituting group and replacement mode on the The compounds of this invention can be selected by those of ordinary skills, with those compounds of the easy synthetic of those methods that provide chemically stable and available technology known in the art and this paper to provide.
According to standard naming rule used in the disclosure text, the terminal portions of specifying side chain is at first described, the adjacent functional group towards tie point is described then.Therefore, for example " phenyl (alkyl) amide group (alkyl) " substituting group is meant the group of following formula:
Term used herein " patient " is meant the animal into treatment, observation or experimental subjects, and preferably Mammals most preferably is the people.
Term used herein " treatment significant quantity " be meant by the determined every kind of active compound of researchist, animal doctor, the doctor of medicine or other clinicist or medicine list with or in tissue system, animal or human, cause biologically or the drug reaction amount of (comprise prevention, suppress to fall ill or alleviate the symptom of the disease for the treatment of) during coupling.
Term used herein " composition " is meant any goods of combination results directly or indirectly of the predetermined component of the goods that comprise the predetermined component that contains prescribed dose and prescribed dose.
In this manual, particularly used abbreviation in scheme and embodiment, see the following form:
DBAD ＝ Azo-2-carboxylic acid's di tert butyl carbonate
DCE ＝ 1, the 2-ethylene dichloride
DCM ＝ Methylene dichloride
DEAD ＝ The diethylazodicarboxylate
DIPEA Diisopropylethylamine
DMAC or DMA ＝ N, the M N,N-DIMETHYLACETAMIDE
DMAP ＝ 4-N, N-dimethylamino-pyridine
DME ＝ 1, the 2-glycol dimethyl ether
DMF ＝ Dimethyl formamide
DMSO ＝ Dimethyl sulfoxide (DMSO)
TEA ＝ Triethylamine
TFA ＝ Trifluoroacetic acid
THF ＝ Tetrahydrofuran (THF)
Next joint more detailed description compound provided by the invention.
B. compound
The invention is characterized in formula (I) compound of describing in above overview section and the claim.Preferred compound comprises following compound or the acceptable salt of its medicine, ester or acid amides, wherein:
(a) NR 1R 2Be combined together to form piperidyl, methyl piperidine base, dimethylamino, pyrrolidyl, diethylamino, methylethyl amino, ethyl propyl amino or dipropyl amino;
(b) NR 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin;
(c) NR 1R 2Be combined together to form piperidyl or pyrrolidyl;
(d) R 4And R 5One of be G;
(e) R 4Be G;
(f) R 5Be G;
(g) n is 1;
(h) Q is the nitrogen heterocycle that saturated N connects;
(i) Q is selected from and replaces or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl;
(j) replace Q and be selected from N-(C 1-6Alkyl) piperazinyl, N-phenyl-Piperazine base, 1,3,8-three azepines-spiral shell [4.5] decyl and 1,4-two oxa-s-8-azepine-spiral shell [4.5] decyl;
(k) Q is the univalent perssad that is selected from following amine: aziridine, 1,4,7-trioxa-10-azepine-cyclododecane, thiazolidine, 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone, piperidines-3-formic acid diethylamide, 1,2,3,4,5,6-six hydrogen-[2,3 '] dipyridyl, 4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazine-1-base-pyrimidine, piperidines-4-methane amide, methyl-(2-pyridine-2-base-ethyl)-amine, [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine, thio-morpholinyl, allyl group-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine, 1-piperidin-4-yl-1,3-dihydro-benzimidazolyl-2 radicals-ketone, 2-(piperidin-4-yl oxygen base)-pyrimidine, piperidin-4-yl-pyridine-2-base-amine, aniline and pyridine-2-base amine;
(l) Q is selected from optional by 1-3 N-morpholinyl and N-piperidyl that independently is selected from following substituting group replacement: hydroxyl, formamido-, C 1-6Alkyl, 5-9 unit or 6-9 unit heterocyclic radical, N (C 1-6Alkyl) (5-9 unit or 6-9 unit heterocyclic radical), NH (5-9 unit or 6-9 unit heterocyclic radical), (5-9 unit or 6-9 unit heterocyclic radical) C 1-3Alkylidene group, 5-9 unit or 6-9 unit heterocyclic radical-O-, C 1-6Alkoxyl group, (C 3-6Cycloalkyl)-O-, phenyl, (phenyl) C 1-3Alkylidene group and (phenyl) C 1-3Alkylidene group-O-, wherein above-mentioned heterocyclic radical, phenyl and alkyl can choose wantonly separately by 1-3 and independently be selected from following substituting group replacement: halogen, nitro, cyano group and C 1-3Alkyl;
(m) Q is comprised that the substituting group that is selected from following 5-9 unit or 6-9 unit heterocyclic radical replaces: pyridyl, pyrimidyl, furyl, thienyl, imidazolyl, (imidazolyl) C 1-6Alkylidene group, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl-, 2-oxo benzimidazolyl-, (tetrazyl) C 1-6Alkylidene group, tetrazyl, (triazolyl) C 1-6Alkylidene group, triazolyl, (pyrryl) C 1-6Alkylidene group and pyrryl;
(n) Q is for replacing or unsubstituted N-morpholinyl;
(o) R 8Be hydrogen;
(p) R 9Be selected from phenyl or 5-9 unit aromatic heterocyclic radical, wherein said phenyl or aromatic heterocyclic radical are optional to be selected from following substituting group replacement by 1-3: halogen, nitro, cyano group and C 1-3Alkyl;
(q) R 9Be selected from replacement or unsubstituted phenyl, pyridyl, pyrimidyl, furyl, thienyl, imidazolyl, (imidazolyl) C 1-6Alkylidene group, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl-, 2-oxo benzimidazolyl-, (tetrazyl) C 1-6Alkylidene group, tetrazyl, (triazolyl) C 1-6Alkylidene group, triazolyl, (pyrryl) C 1-6Alkylidene group and pyrryl;
(r) R 9For replacing or unsubstituted phenyl;
(s) R 9For replacing or the unsubstituted pyridine base;
(t) wherein n is 1; R 1And R 2Independently be selected from C 2Alkyl, perhaps the nitrogen that is connected with them combines, and they form the optional first heterocyclic radical of extra heteroatomic non-aromatics 5-6 that independently is selected from O, S and N that comprises; R 3, R 4And R 5One of be G, all the other two is hydrogen; G is L 2Q; L 2Be methylene radical; Q is NR 8R 9, R wherein 8Independently be selected from hydrogen, C 1-2Alkyl, C 3Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical (preferred 5-9 or 6-9 unit heterocyclic radical), phenyl, (5-9 unit heterocyclic radical) C 1-6Alkylidene group and (phenyl) C 1-6Alkylidene group; R 9Independently be selected from C 1-2Alkyl, C 3Thiazolinyl, 5-9 unit carbocylic radical, 3-12 unit heterocyclic radical (for example 5-9 or 6-9 unit heterocyclic radical, preferred in some cases 6 yuan of heterocyclic radicals), phenyl, (5-9 unit heterocyclic radical) C 1-6Alkylidene group and (phenyl) C 1-6Alkylidene group; Perhaps Q is the heterocyclic radical (preferred 5-9 or 6-9 heterocyclic radical) that the saturated N of 3-13 unit connects, and wherein, except that N connected nitrogen, 3-13 unit heterocyclic radical also can be chosen wantonly and contain 1-3 extra heteroatoms that independently is selected from O, S and N; Wherein each abovementioned alkyl, alkylidene group, thiazolinyl, alkenylene, heterocyclic radical, cycloalkyl and aryl can independently separately and optional independently be selected from following substituting group replacement by 1-3: methoxyl group, halogen, amino, nitro, hydroxyl and C 1-3 alkaneBase; Wherein the substituting group of Q can further independently be selected from tert-butoxycarbonyl, formamido-, 6-9 unit heterocyclic radical, NH (6 yuan of heterocyclic radicals), O (6 yuan of heterocyclic radicals), phenyl, C 2-hydroxy alkylidene, hydroxyl and benzyl, and wherein each above-mentioned heterocyclic radical, phenyl and the alkyl substituent of Q can be chosen wantonly by trifluoromethyl and replace;
(u) (1) NR 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin and (2) Q and be selected from replacement or unsubstituted piperidyl, piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl;
(v) (1) NR 1R 2Be combined together to form piperidyl or pyrrolidyl, (2) n be 1 and (3) Q be selected from morpholinyl and piperidyl;
(w) Q is morpholinyl or replaces morpholinyl;
(x) NR 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin, n be 1 and
Wherein Q is NR 8R 9, R 8Be H, R 9Be selected from phenyl or aromatics 5-9 unit heterocyclic radical, wherein said phenyl or heterocyclic radical are optional to be selected from following substituting group replacement by 1-3: halogen, nitro, cyano group and C 1-3Alkyl; Or
(y) or the combination of above-mentioned each component.
The example of The compounds of this invention comprises:
1) 1-[4-(4-piperidines-1-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines;
2) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines;
3) 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine;
4) 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-the morpholine dihydrochloride;
5) 1-[4-(4-tetramethyleneimine-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines;
6) diethyl-[4-(4-piperidines-1-ylmethyl-phenyl)-Ding-3-alkynyl]-amine;
7) 4-[4-(4-piperidines-1-ylmethyl-phenyl)-Ding-3-alkynyl]-thiomorpholine;
8) 4-[4-(4-piperidines-1-ylmethyl-phenyl)-Ding-3-alkynyl]-morpholine;
9) 1-methyl-4-[4-(4-piperidines-1-ylmethyl-phenyl)-Ding-3-alkynyl]-piperazine;
10) 1-[4-(4-tetramethyleneimine-1-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines;
11) 4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine;
12) diethyl-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
13) 1-{4-[4-(4-benzyl-piperidines-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-piperidines;
14) 1-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-alcohol;
15) 2-{1-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-2-yl }-ethanol;
16) 1-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-decahydro-quinoline;
17) 1-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-methane amide;
18) 8-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-1,4-two oxa-s-8-azepine-spiral shell [4.5] decane;
19) 1-methyl-4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine;
20) cyclohexyl-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
21) indane-1-base-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
22) 1-phenyl-4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine;
23) 1-benzyl-4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine;
24) 4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine-1-t-butyl formate;
25) 1-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine;
26) 1-sec.-propyl-4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine;
27) 1-phenyl-8-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone;
28) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-3-formic acid diethylamine;
29) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-1,2,3,4,5,6-six hydrogen-[2,3 '] dipyridyl;
30) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-4-(3-trifluoromethyl-phenyl)-piperazine;
31) 2-{4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine-1-yl }-pyrimidine;
32) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-methane amide;
33) methyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-(2-pyridine-2-base-ethyl)-amine;
34) [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
35) 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-thiomorpholine;
36) allyl group-cyclopentyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
37) 10-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-1,4,7-trioxa-10-azepine-cyclododecane;
38) 1-[4-(3-thiazolidine-3-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines;
39) [2-(1H-indol-3-yl)-ethyl]-methyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
40) 1-{1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidin-4-yl }-1,3-dihydro-benzimidazolyl-2 radicals-ketone;
41) phenyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
42) 1-[4-(3-tetramethyleneimine-1-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines;
43) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-the nitrogen heterocyclic tridecane;
44) dimethyl-[4-(4-piperidines-1-ylmethyl-phenyl)-Ding-3-alkynyl]-amine;
45) dimethyl-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
46) phenyl-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
47) 1-[4-(3-aziridine-1-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines;
48) 2-{1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl-1 piperidin-4-yl oxygen base }-pyrimidine;
49) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidin-4-yl }-pyridine-2-base-amine;
50) 4-[4-(3-morpholine-4-ylmethyl-phenyl)-Ding-3-alkynyl]-morpholine;
51) 4-[3-(4-thiomorpholine-4-Ji-Ding-1-alkynyl)-benzyl]-morpholine;
52) 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-thiomorpholine;
53) 4-[4-(3-thiomorpholine-4-ylmethyl-phenyl)-Ding-3-alkynyl]-morpholine;
54) 4-[3-(4-thiomorpholine-4-Ji-Ding-1-alkynyl)-benzyl]-thiomorpholine;
55) 4-{4-[3-(4-methyl-piperazine-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-morpholine;
56) 4-{4-[3-(4-methyl-piperazine-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-thiomorpholine;
57) 1-methyl-4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine;
58) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-alcohol;
59) 1-[3-(4-morpholine-4-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-alcohol;
60) 1-[3-(4-thiomorpholine-4-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-alcohol;
61) 1-{4-[3-(4-methoxyl group-piperidines-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-piperidines;
62) 4-{4-[3-(4-methoxyl group-piperidines-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-morpholine; With
63) 4-{4-[3-(4-methoxyl group-piperidines-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-alkali is for morpholine.
Extra compound comprises:
1) 1-[4-(4-piperidines-1-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines;
2) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines;
3) 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine;
4) 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-the morpholine dihydrochloride;
5) 1-[4-(4-tetramethyleneimine-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines;
6) 1-[4-(4-tetramethyleneimine-1-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines;
7) diethyl-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
8) 1-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-alcohol;
9) 2-{1-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-2-yl }-ethanol;
10) 1-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-decahydro-quinoline;
11) 1-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-methane amide;
12) 8-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-1,4-two oxa-s-8-azepine-spiral shell [4.5] decane;
13) 1-methyl-4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine;
14) cyclohexyl-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
15) indane-1-base-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
16) 1-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine;
17) 1-sec.-propyl-4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine;
18) 1-phenyl-8-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone;
19) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-methane amide;
20) 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-thiomorpholine;
21) allyl group-cyclopentyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
22) 10-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-1,4,7-trioxa-10-azepine-cyclododecane;
23) 1-[4-(3-thiazolidine-3-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines;
24) [2-(1H-indol-3-yl)-ethyl]-methyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
25) 1-{1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidin-4-yl }-1,3-dihydro-benzimidazolyl-2 radicals-ketone; With
26) 1-[4-(3-tetramethyleneimine-1-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines.
Preferred compound comprises: 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine and 4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine; Particularly the former.
Extra examples of compounds comprises:
1) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines;
2) 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine;
3) 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-the morpholine dihydrochloride;
4) 1-phenyl-8-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone;
5) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-3-formic acid diethylamine;
6) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-1,2,3,4,5,6-six hydrogen-[2,3 '] dipyridyl;
7) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-4-(3-trifluoromethyl-phenyl)-piperazine;
8) 2-{4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine-1-yl }-pyrimidine;
9) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-methane amide;
10) methyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-(2-pyridine-2-base-ethyl)-amine;
11) [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
12) 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-thiomorpholine;
13) allyl group-cyclopentyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
14) 10-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-1,4,7-trioxa-10-azepine-cyclododecane;
15) 1-[4-(3-thiazolidine-3-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines;
16) [2-(1H-indol-3-yl)-ethyl]-methyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
17) 1-{1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidin-4-yl }-1,3-dihydro-benzimidazolyl-2 radicals-ketone;
18) phenyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
19) 1-[4-(3-tetramethyleneimine-1-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines; With
20) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-the nitrogen heterocyclic tridecane.
More example comprises:
1) dimethyl-[4-(4-piperidines-1-ylmethyl-phenyl)-Ding-3-alkynyl]-amine;
2) dimethyl-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
3) phenyl-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine;
4) 1-[4-(3-aziridine-1-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines;
5) 2-{1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidin-4-yl oxygen base }-pyrimidine;
6) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidin-4-yl }-pyridine-2-base-amine;
7) 4-[4-(3-morpholine-4-ylmethyl-phenyl)-Ding-3-alkynyl]-morpholine;
8) 4-[3-(4-thiomorpholine-4-Ji-Ding-1-alkynyl)-benzyl]-morpholine;
9) 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-thiomorpholine;
10) 4-[4-(3-thiomorpholine-4-ylmethyl-phenyl)-Ding-3-alkynyl]-morpholine;
11) 4-[3-(4-thiomorpholine-4-Ji-Ding-1-alkynyl)-benzyl]-thiomorpholine;
12) 4-{4-[3-(4-methyl-piperazine-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-morpholine;
13) 4-{4-[3-(4-methyl-piperazine-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-thiomorpholine;
14) 1-methyl-4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine;
15) 1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-alcohol;
16) 1-[3-(4-morpholine-4-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-alcohol;
17) 1-[3-(4-thiomorpholine-4-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-alcohol;
18) 1-{4-[3-(4-methoxyl group-piperidines-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-piperidines;
19) 4-{4-[3-(4-methoxyl group-piperidines-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-morpholine; With
20) 4-{4-[3-(4-methoxyl group-piperidines-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-thiomorpholine.
The present invention also provides the compound as the The compounds of this invention synthetic intermediate.Itself can be with or without medical active this compounds, and comprises the compound that provides among scheme and the synthetic embodiment.
The present invention also considered can by positron emission computerized tomography (PET) or single photon emission computed tomoscan (SPECT) detect to research H 3The useful isotope-labeled compound of disease of-mediation.
In any technology of preparation The compounds of this invention, have sensitivity or active group on essential and/or the related any molecule of better preserved.In addition, The compounds of this invention can be modified with protecting group; Such compound, precursor or prodrug are also within the scope of the invention.This can obtain the method for describing in for example following document by using the GPF (General Protection False base: " Protective Groups in Organic Chemistry (vitochemical protecting group) ", and J.F.W.McOmie edits, Plenum Press, 1973; With T.W.Greene ﹠amp; P.G.M.Wuts, " Protective Groups in Organic Synthesis (protecting group of organic synthesis) ", the third edition, John Wiley ﹠amp; Sons, 1999.Can use methods known in the art, remove described protecting group in follow-up phase easily.
Hydroxyl protecting group
Hydroxyl protecting group comprises methyl ether, substituent methyl ether, replaces ethyl ether, substituted benzyl ether and silyl ether.
Substituent methyl ether
The example of substituent methyl ether comprises methoxymethyl, methylthiomethyl, uncle's butylthio methyl, (phenyl dimetylsilyl) methoxymethyl, benzyloxymethyl, to methoxyl group benzyloxy ylmethyl, (4-methoxyl group phenoxy group) methyl, the methyl catechol methyl, the tert.-butoxy methyl, 4-pentenyl oxygen ylmethyl, the siloxy-methyl, 2-methoxy ethoxy methyl, 2,2,2-trichlorine ethoxyl methyl, two (2-chloroethoxy) methyl, 2-(trimethyl silyl) ethoxyl methyl, THP trtrahydropyranyl, 3-bromine THP trtrahydropyranyl, tetrahydro thiapyran base, 1-methoxyl group cyclohexyl, 4-methoxyl group THP trtrahydropyranyl, 4-methoxyl group tetrahydro thiapyran base, 4-methoxyl group tetrahydro thiapyran base S, the S-bicyclic oxygen, 1-[(2-chloro-4-methyl) phenyl]-4-methoxyl group piperidin-4-yl, 1,4-diox-2-base, tetrahydrofuran base, tetrahydro-thienyl and 2,3,3a, 4,5,6,7,7a-octahydro-7,8,8-trimethylammonium-4,7-methylene radical benzo furans-2-base.
Replace ethyl ether
The example that replaces ethyl ether comprises 1-ethoxyethyl group, 1-(2-chloroethoxy) ethyl, 1-methyl isophthalic acid-methoxy ethyl, 1-methyl isophthalic acid-benzyloxy ethyl, 1-methyl isophthalic acid-benzyloxy-2-fluoro ethyl, 2,2,2-three chloroethyls, 2-trimethyl silyl ethyl, 2-(phenyl selenyl) ethyl, the tertiary butyl, allyl group, rubigan, p-methoxyphenyl, 2,4-dinitrophenyl and benzyl.
Substituted benzyl ether
The example of substituted benzyl ether comprises methoxy-benzyl; 3; the 4-dimethoxy-benzyl; adjacent nitrobenzyl; to nitrobenzyl; to halogeno-benzyl; 2; the 6-dichloro benzyl; to the cyano group benzyl; to phenylbenzyl; 2-picolyl and 4-picolyl; 3-methyl-2-picolyl N-epoxy group(ing); diphenyl methyl; p; p '-dinitrobenzene diphenyl-methyl; 5-dibenzo suberyl; trityl group; the Alpha-Naphthyl diphenyl methyl; the p-methoxyphenyl diphenyl methyl; two (p-methoxyphenyl) phenyl methyl; three (p-methoxyphenyl) methyl; 4-(4 '-bromobenzene formyl methyl oxygen base) the phenyl diphenyl methyl; 4; 4 '; 4 " three (4; 5-dichloro phthaloyl imino phenyl) methyl; 4; 4 '; 4 "-three (levulinic acyl group oxygen base phenyl) methyl; 4; 4 '; 4 " three (benzoyl oxygen base phenyl) methyl; 3-(imidazoles-1-ylmethyl) two (4 '; 4 "-Dimethoxyphenyl) methyl; 1; two (the 4-p-methoxy-phenyls)-1 of 1-'-the pyrenyl methyl; the 9-anthryl; 9-(9-phenyl) xanthenyl; 9-(9-phenyl-10-oxo) anthryl; 1; 3-benzo dithia ring penta-2-base and benzisothiazole base S, the S-bicyclic oxygen.
Silyl ether
The example of silyl ether comprises trimethyl silyl, triethylsilyl, triisopropyl silyl, dimethyl sec.-propyl silyl, diethyl sec.-propyl silyl, dimethyl hexyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzyl silyl, three p-Xylol base silyls, triphenyl silyl, diphenyl methyl silyl and tertiary butyl p-methoxy-phenyl silyl.
Ester
Except that ether, hydroxyl can be protected and be ester.The example of ester comprises manthanoate; the benzoyl manthanoate; acetic ester; chloracetate; the dichloro acetic acid ester; trichloroacetic esters; trifluoro-acetate; the methoxyacetic acid ester; triphenyl methoxyacetic acid ester; the phenylium ester; the parachlorophen-oxyacetic acid ester; p-P-phenylacetic acid ester; 3-phenylpropionic acid ester; 4-oxopentanoie acid ester (levulinate); 4; 4-(ethylene sulfo-) valerate; pivalate; the adamantane acid ester; crotonate; 4-methoxyl group crotonate; benzoic ether; to phenylbenzoate; 2; 4,6-trimethylbenzoic acid ester (keto ester).
Carbonic ether
The example of carbonic ether comprises methyl carbonate, carbonic acid 9-fluorenyl methyl esters, ethyl-carbonate, carbonic acid 2; 2; 2-trichloro ethyl ester, carbonic acid 2-(trimethyl silyl) ethyl ester, carbonic acid 2-(phenyl sulfonyl) ethyl ester, carbonic acid 2-(triphenyl phosphorus base) ethyl ester, isobutyl carbonate butyl ester, NSC 11801, allyl carbonate, p-nitrophenyl carbonate ester, carbon acid benzyl ester, carbonic acid are to methoxy benzyl ester, carbonic acid 3, and 4-dimethoxy benzyl ester, the adjacent nitrobenzyl ester of carbonic acid, carbonic acid are to nitrobenzyl ester, thiocarbonic acid SOH S-benzyl ester, carbonic acid 4-oxyethyl group-1-naphthalene ester and dithiocarbonic acid methyl esters.
Auxiliary cracking agent
The example of auxiliary cracking agent comprises 2-iodobenzoic acid ester, 4-nitrine butyric ester, 4-nitro-4-methyl valerate, neighbour's (two brooethyls) benzoic ether, 2-formyl radical benzene sulfonate, 2-(methylthio group methoxyl group) ethyl carbonate ester, 4-(methylthio group methoxyl group) butyric ester and 2-(methylthio group methoxymethyl) benzoic ether.
Other ester
The example of other ester comprises 2,6-two chloro-2-methylenedioxy phenoxy yl acetates, 2,6-two chloro-4-(1,1,3, the 3-tetramethyl butyl) phenylium ester, 2,4-two (1, the 1-dimethyl propyl) phenylium ester, the chlorodiphenyl yl acetate, isobutyrate, the monosuccinic acid ester, (E)-2-methyl-2-butene acid esters (tiglate), adjacent (methoxycarbonyl) benzoic ether, the p-P-benzoic ether, the α-Nai Jiasuan ester, nitric ether, N, N, N ', N '-tetramethyl-diamino alkyl phosphate, the N-phenylcarbamate, boric acid ester, sulfenic acid dimethyl sulphide see ester and sulfenic acid 2,4 dinitrobenzene phenyl esters.
Sulphonate
The example of sulphonate comprises sulfuric ester, methanesulfonates, benzyl sulfonic acid ester and tosylate.To 1,2-two is pure and mild 1, the protection of 3-glycol
Cyclic acetal and ketal
The example of cyclic acetal and ketal comprises methylene radical, ethylidene, 1-tertiary butyl ethylidene, 1-phenyl ethylidene, (4-p-methoxy-phenyl) ethylidene, 2,2,2-three chlorethylidenes, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, inferior suberyl, benzylidene, to methoxyl group benzylidene, 2,4-dimethoxybenzylidenegroup group, 3,4-dimethoxybenzylidenegroup group and 2-nitro benzylidene.
Cyclic ortho ester
The example of cyclic ortho ester comprises methoxyl group methylene radical, oxyethyl group methylene radical, dimethoxy methylene radical, 1-methoxyl group ethylidene, 1-oxyethyl group ethylidene, 1,2-dimethoxy ethylidene, α-methoxyl group benzylidene, 1-(N, the N-dimethylamino) ethidene derivant, α-(N, N-dimethylamino) benzylidene derivatives and 2-oxa-cyclopentylidene.
The silyl derivative
The example of silyl derivative comprises di-t-butyl silicylene and 1,3-(1,1,3,3-tetra isopropyl two inferior siloxaness) derivative.
Amino protecting group
Amino protecting group comprises carbamate, acid amides and special-NH protecting group.
The example of carbamate comprises Urethylane and urethanum, the urethanum of replacement, auxiliary cracking ammonia carbamate, photodissociation cracking ammonia carbamate, urea type derivative and other carbamate.
Carbamate
The example of Urethylane and urethanum comprises Urethylane and urethanum, carboxylamine 9-fluorenyl methyl esters, carboxylamine 9-(2-sulphur) fluorenyl methyl esters, carboxylamine 9-(2; the 7-dibromo) fluorenyl methyl esters, carboxylamine 2; the 7-di-t-butyl-{ 9-(10; 10-dioxo-10; 10; 10, the 10-tetrahydrochysene thia chlorine anthryl of mixing) methyl esters and carboxylamine 4-anisoyl methyl esters.
Replace ethyl ester
The example of substituted-amino ethyl formate comprises 2; 2; 2-three chloroethyls; 2-trimethyl silyl ethyl; the 2-phenylethyl; 1-(1-adamantyl)-1-methylethyl; 1; 1-dimethyl-2-halogenated ethyl; 1; 1-dimethyl-2; 2-two bromotrifluoromethanes; 1; 1-dimethyl-2; 2; 2-three chloroethyls; 1-methyl isophthalic acid-(4-xenyl) ethyl; 1-(3; the 5-di-tert-butyl-phenyl)-the 1-methylethyl; 2-(2 '-pyridyl) ethyl and 2-(4 '-pyridyl) ethyl; 2-(N; N-dicyclohexyl formamido-) ethyl; the tertiary butyl; the 1-adamantyl; vinyl; allyl group; 1-sec.-propyl allyl group; cinnamyl; 4-nitro cinnamyl; the 8-quinolyl; N-hydroxy piperidine base; the alkyl dithio; benzyl; to methoxy-benzyl; to nitrobenzyl; to bromobenzyl; p-chlorobenzyl; 2, the 4-dichloro benzyl; 4-methylsulfinyl benzyl; 9-anthryl methyl and diphenyl methyl.
Auxiliary cracking agent
The example of auxiliary cracking agent comprises 2-methylmercaptoethyl, 2-methyl sulphonyl ethyl, 2-(p-toluenesulfonyl) ethyl, [2-(1; 3-dithiane base)] methyl, 4-methylthio group phenyl, 2; 4-diformazan sulfenyl phenyl, 2-phosphorus base ethyl, 2-triphenyl phosphorus base sec.-propyl, 1,1-dimethyl-2-cyano ethyl, a chloro-are to the acyloxy benzyl, to (dihydroxyl boryl) benzyl, 5-benzoisoxazole ylmethyl and 2-(trifluoromethyl)-6-chromone ylmethyl.
The photodissociation cracking agent
The example of photodissociation cracking agent comprises m-nitro base, 3,5-dimethoxy-benzyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl and phenyl (ortho-nitrophenyl base) methyl.
Urea type derivative
The example of urea type derivative comprises phenothiazinyl-(10)-carbonyl derivative, N '-p-toluenesulfonyl aminocarboxyl and N '-phenyl amino thiocarbonyl.
Other carbamate
The example of other carbamate comprises tert.-amyl carbamate; thiocarbamate S-benzyl ester; carboxylamine is to cyano group benzyl ester; carboxylamine ring butyl ester; the carboxylamine cyclohexyl; carboxylamine ring pentyl ester; carboxylamine cyclopropyl methyl esters; carboxylamine is to decyl oxygen base benzyl ester; carboxylamine di-isopropyl methyl esters; carboxylamine 2; 2-dimethoxy carbonyl ethenyl ester; carboxylamine neighbour (N; the dinethylformamide base) benzyl ester; carboxylamine 1; 1-dimethyl-3-(N; the dinethylformamide base) propyl ester; carboxylamine 1; 1-alkynyl dimethyl ester; carboxylamine two (2-pyridyl) methyl esters; carboxylamine 2-furyl methyl esters; carboxylamine 2-iodo-ethyl ester; carboxylamine isocamphanyl ester; isobutyl carbamate; the different nicotinoyl ester of carboxylamine; carboxylamine p-(p '-the anisole azo-group) the benzyl ester; carboxylamine 1-methyl ring butyl ester; carboxylamine 1-methyl cyclohexane ester; carboxylamine 1-methyl isophthalic acid-cyclopropyl methyl esters; carboxylamine 1-methyl isophthalic acid-(3; the 5-Dimethoxyphenyl) ethyl ester; carboxylamine 1-methyl isophthalic acid-(to the phenylazo-phenyl) ethyl ester; carboxylamine 1-methyl isophthalic acid-phenyl chlorocarbonate; carboxylamine 1-methyl isophthalic acid-(4-pyridyl) ethyl ester; phenyl carbamate; carboxylamine is to (phenylazo-) benzyl ester; carboxylamine 2; 4; 6-tri-tert phenyl ester; carboxylamine 4-(trimethyl ammonium) benzyl ester and carboxylamine 2; 4,6-trimethylammonium benzyl ester.
The example of acid amides comprises:
Acid amides
N-formyl radical, N-ethanoyl, N-chloracetyl, N-tribromo-acetyl base, N-TFA base, N-phenyl acetyl, N-3-phenyl propionyl, N-pieolinyl, N-3-pyridyl formamido-, N-benzoyl phenylalanyl radical derivative, N-benzoyl, N-are to the phenyl benzoyl.
Auxiliary cracking agent
N-ortho-nitrophenyl base ethanoyl; N-ortho-nitrophenyl oxygen base ethanoyl; the N-acetoacetyl; (N '-dithio benzyloxycarbonyl amino) ethanoyl; N-3-(p-hydroxybenzene) propionyl; N-3-(ortho-nitrophenyl base) propionyl; N-2-methyl-2-(ortho-nitrophenyl oxygen base) propionyl; N-2-methyl-2-(adjacent phenylazo-phenoxy group) propionyl; the N-4-chlorobutyryl; N-3-methyl-3-nitro butyryl radicals; the adjacent nitro cinnamoyl of N-; N-acetyl methionine derivative; the N-o-nitrobenzoyl; N-neighbour's (benzoyloxy methyl) benzoyl and 4,5-phenylbenzene-3-oxazoline-2-ketone.
The cyclic imide derivative
N phlhalimide, N-dithia succinyl, N-2,3-phenylbenzene maleoyl, N-2,5-dimethyl pyrrole, N-1; 1; 4,1 of 4-tetramethyl-dimethyl silanyl aza-cyclopentane adducts, 5-replacement, 3-dimethyl-1; 3; 1 of 5-Trianacyclohexane-2-ketone, 5-replacement, 3-dibenzyl-1,3; 3 of 5-Trianacyclohexane-2-ketone and 1-replacement, 5-dinitrobenzene-4-pyriconyl.
Special-the NH protecting group
The example of special NH protecting group comprises:
N-alkyl and N-arylamines
N-methyl, N-allyl group, N-[2-(trimethyl silyl) oxyethyl group] methyl, N-3-acetoxyl group propyl group, N-(1-sec.-propyl-4-nitro-2-oxo-3-pyrroline-3-yl), quaternary ammonium salt, N-benzyl, N-4-methoxy-benzyl, N-two (4-p-methoxy-phenyl) methyl, N-5-dibenzo suberyl, N-trityl group, N-(4-p-methoxy-phenyl) diphenyl methyl, N-9-phenyl fluorenyl, N-2,7-two chloro-9-fluorenyl methylene radical, N-ferrocenyl methyl and N-2-picolyl amine N '-oxide compound.
Imine derivative
N-1,1-methyl-sulfide methylene, N-benzylidene, N-are to methoxyl group benzylidene, N-phenylbenzene methylene radical, N-[(2-pyridyl) the sym-trimethylbenzene base] methylene radical and N-(N ', N '-dimethylaminomethylene).
Protection to carbonyl
Acyclic acetal and ketal
The example of acyclic acetal and ketal comprises dimethyl, two (2,2,2-three chloroethyls), dibenzyl, two (2-nitrobenzyls) and diacetyl.
Cyclic acetal and ketal
The example of cyclic acetal and ketal comprises 1,3-diox, 5-methylene radical-1,3-diox, 5,5-two bromo-1,3-diox, 5-(2-pyridyl)-1,3-diox, 1,3-dioxolane, 4-brooethyl-1,3-dioxolane, 4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane, 4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxy-methyl-1,3-dioxolane, O, O '-phenylene dioxy base and 1,5-dihydro-3H-2,4-benzo dioxepine.
Acyclic dithio acetal and ketal
The example of acyclic dithio acetal and ketal comprises S, S '-dimethyl, S, S '-diethyl, S, S '-dipropyl, S, S '-dibutyl, S, S '-diamyl, S, S '-phenylbenzene, S, S '-dibenzyl and S, S '-diacetyl.
Ring-type dithio acetal and ketal
The example of ring-type dithio acetal and ketal comprises 1,3-dithiane, 1,3-dithiolane and 1,5-dihydro-3H-2,4-benzo two thiepins.
Acyclic single sulfo-acetal and ketal
The example of acyclic single sulfo-acetal and ketal comprise O-trimethyl silyl-S-alkyl, O-methyl-S-alkyl or-S-phenyl and O-methyl-S-2-(methylthio group) ethyl.
Single sulfo-acetal of ring-type and ketal
The example of single sulfo-acetal of ring-type and ketal comprises 1,3-oxygen Thiophane.
Other derivative
The cyanohydrin that O-replaces
The example of the cyanohydrin that O-replaces comprises O-ethanoyl, O-trimethyl silyl, O-1-ethoxyethyl group and O-THP trtrahydropyranyl.
Replace hydrazone
The example that replaces hydrazone comprises N, N-dimethyl and 2,4-dinitrophenyl.
9 oxime derivate
The example of 9 oxime derivate comprises O-methyl, O-benzyl and O-thiophenyl methyl.
Imines
Substituted methylene derivative, cyclic derivatives
The example Bao Kuo oxazolidine of substituted methylene and cyclic derivatives, 1-methyl-2-(1 '-hydroxyalkyl) imidazoles, N, N '-methylimidazole alkane, 2,3-dihydro-1,3-benzothiazole, diethylamine adducts and two (2,6 di tert butyl 4 methyl phenol) aluminium trimethide (MAD) complex compound.
Monobasic protection to dicarbonyl compound
α-and the selective protection of beta-diketon
α-and the example of the selective protection of beta-diketon comprise enamine, acetate enol ester, enol ether, methyl, ethyl, isobutyl-, piperidyl, morpholinyl, 4-methyl isophthalic acid, 3-dioxolanyl, pyrrolidyl, benzyl, S-butyl and trimethyl silyl.
Cyclic ketal, single sulfo-and dithio ketal
The example of cyclic ketal, single sulfo-and dithio ketal comprises dimethylene dioxy radical derivative and tetramethyl-dimethylene dioxy radical derivative.
Protection to carboxyl
Ester
The substituent methyl ester
The example of the methyl ester that replaces comprises 9-fluorenyl methyl, methoxymethyl, methylthiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, methoxy ethoxy methyl, 2-(trimethyl silyl) ethoxyl methyl, benzyloxymethyl, phenacyl, to bromobenzene formyl methyl, Alpha-Methyl phenacyl, to methoxybenzoyl methyl, formamido-methyl and N-phthalimido methyl.
The ethyl ester that 2-replaces
The example of the ethyl ester that 2-replaces comprises 2; 2; 2-three chloroethyls; the 2-halogenated ethyl; ω-chlorine alkyl; 2-(trimethyl silyl) ethyl; 2-methylmercaptoethyl; 1,3-dithiane base-2-methyl; 2-(p-nitrophenyl sulfinyl) ethyl; 2-(p-toluenesulfonyl) ethyl; 2-(2 '-pyridyl) ethyl; 2-(diphenylphosphine) ethyl; 1-methyl isophthalic acid-phenylethyl; the tertiary butyl; cyclopentyl; cyclohexyl; allyl group; 3-butene-1-Ji; 4-(trimethyl silyl)-2-butylene-1-base; cinnamyl; the Alpha-Methyl cinnamyl; phenyl; to (methyl mercapto) phenyl and benzyl.
The substituted benzyl ester
The example of substituted benzyl ester comprises trityl group, diphenyl methyl, two (ortho-nitrophenyl base) methyl, 9-anthryl methyl, 2-(9; the 10-dioxo) anthryl methyl, 5-dibenzo suberyl, 1-pyrenyl methyl, 2-(trifluoromethyl)-6-chromyl methyl, 2; 4; the 6-trimethyl benzyl, to bromobenzyl, adjacent nitrobenzyl, to nitrobenzyl, to methoxy-benzyl, 2,6-dimethoxy-benzyl, 4-(methylsulfinyl) benzyl, 4-sulphur benzyl, piperonyl, 4-picolyl and p-P-benzyl.
Silyl ester
The example of silyl ester comprises trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, sec.-propyl dimetylsilyl, phenyl dimetylsilyl and di-t-butyl methyl-silicane base.
Active ester
The example of active ester comprises mercaptan.
Other derivative
The example Bao Kuo oxazole of other derivative, 2-alkyl-1,3-oxazoline, 4-alkyl-5-oxo-1,3-oxazolidine, 5-alkyl-4-oxo-1,3-dioxolane, ortho ester, phenyl and pentaamino cobalt (III) complex compound.
The stannyl ester
The example of stannyl ester comprises triethyl stannyl and three normal-butyl stannyls.
Acid amides and hydrazides
Acid amides
The example of acid amides comprises N, N-dimethyl, pyrrolidyl, piperidyl, 5,6-dihydro phenanthridinyl, o-Nitraniline, N-7-nitroindoline base, N-8-nitro-1,2,3,4-tetrahydric quinoline group and p-P-benzsulfamide.
Hydrazides
The example of hydrazides comprises N-phenyl and N, N '-di-isopropyl.
Can prepare compound of the present invention according to the method that next trifle is described.
C. synthetic
Can be according to conventional methodology of organic synthesis and matrix or combinational chemistry, the preparation The compounds of this invention, described as following scheme 1-5 and embodiment 1-76.Those of ordinary skills will know, can make amendment and change described scheme and embodiment, and precondition is still can obtain compound of the present invention.
It will be recognized by those skilled in the art that The compounds of this invention synthetic may be subjected to the intermediate of being bought described in arbitrary scheme disclosed herein or the influence of shielded midbody compound.In whole proposal, when reactive functionality is positioned at R 3The time, it will be recognized by those skilled in the art, select R 3Only be used for illustrating that reactive functionality also may be at R 4Or R 5On.
Those skilled in the art also will recognize that, in any technology of preparation The compounds of this invention, may be essential and/or the related any molecule of better preserved on sensitivity or reactive group.This can be achieved by the GPF (General Protection False base, for example the protecting group of describing in following document: " Protective Groups in Organic Chemistry ", and J.F.W.McOmie edits, PlenumPress, 1973; With T.W.Greene ﹠amp; P.G.M.Wuts, " Protective Groups inOrganic Synthesis ", John Wiley ﹠amp; Sons, 1991.Can use methods known in the art, remove these protecting groups in follow-up phase easily.
In whole proposal, when reactive functionality is positioned at R 5The time, it will be recognized by those skilled in the art, select R 5Only be used for illustrating that reactive functionality also may be at R 3And/or R 4On.
Can be according to the method for scheme 1 general introduction, the compound of preparation formula V.
Scheme 1
Figure A0382589700511
The method of being summarized according to scheme 1 is from the compound of the compound formula V of formula (II).Under the hydroxyl activation condition, make formula (II) compound and hydroxy functional group can be changed into leavings group X 1Reagent react.
With amine amine R for example 1R 2In the nucleophilic substitution reaction that NH carries out, leavings group X 1It is suitable leavings group.In a preferred embodiment,, under-78 ℃ to 50 ℃ temperature, make the reaction of formula (III) compound and alkyl chloride or aryl sulfonyl chloride, obtain leavings group X by in non-alcoholic solvent, in the presence of organic bases or mineral alkali 1Be sulphonate.The example of described solvent is benzene, DCM, DCE, THF, DMF, acetonitrile, hexamethylphosphoramide (HMPA), hexane, pentane and composition thereof.The example of organic bases is pyridine, TEA and composition thereof.The example of mineral alkali is KOH, NaOH, Na 2CO 3, K 2CO 3Or its mixture.
In an especially preferred embodiment, in the presence of TEA, under the temperature between 0 ℃ and the room temperature, make Tosyl chloride or methylsulfonyl chloride reaction among formula (II) compound and the DCM.
Under the nucleophilic substitution condition, alkali exist or non-existent condition under, under 0 ℃ to 100 ℃ temperature, make formula (IV) compound and formula (III) compound with pure form or in solvent, react, obtain the formula V compound from formula (III) compound.The example of described solvent is methyl alcohol, ethanol, propyl alcohol, propyl carbinol, DMF, DMSO, DME and compatibility mixture thereof.The example of described alkali (if present) is yellow soda ash, salt of wormwood, cesium carbonate, triethylamine, tetramethyl guanidine and compatibility mixture thereof.
In these reactions, use high polar solvent, can improve speed and reduce the generation of by product.So high polar solvent with form of mixtures is provided in some embodiments, and described mixture is the mixture that first kind of solvent and (with respect to the specific inductivity of first kind of solvent) increase the solubility promoter of this mixture dielectric constant.For example, it will be recognized by those of ordinary skills, according to disclosure text, in these reactions, water can improve speed as such solubility promoter and reduce the generation of by product.In a preferred embodiment, described solvent is the mixture of water, ethanol or water and ethanol and/or propyl alcohol, and described alkali is yellow soda ash or salt of wormwood or do not exist, and temperature is a room temperature to 80 ℃.
In an especially preferred embodiment, described solvent is an ethanol, does not add alkali, temperature be 0 ℃ to room temperature.
At halogenation San Wan for example iodate of Ji Phosphonium (cyano methyl) San Jia Ji Phosphonium and alkali for example in the presence of the DIPEA, for example in the propionitrile,, make the reaction of formula (IV) compound and formula (II) compound at solvent at 90 ℃, also can obtain the formula V compound by formula (II) compound.
Can be according to the method for scheme 2 general introductions, preparation formula (I) compound.
Scheme 2
Figure A0382589700531
With formula (VI) compound formula (I) compound, shown in scheme 2.
Radicals X 2, the radicals X in the compound (VI) for example 2, be meant the suitable leavings group in the linked reaction of carrying out with alkynes, wherein the definition of " alkynes " is meant replacement or the unsubstituted chain with carbon-to-carbon triple bond.The example of such leavings group comprises sulfonic groups such as halogens such as iodine, bromine and chlorine and trifluoromethanesulfonic acid base.
At palladium-containing catalyst and alkali for example in the presence of triethylamine, DIEA, Diisopropylamine, yellow soda ash, salt of wormwood, cesium carbonate and composition thereof, at solvent for example in THF, DME, diox, DCE, DCM, toluene, acetonitrile and composition thereof, under 0 ℃ to 100 ℃ temperature, under the Sonogashira condition, make the reaction of formula (VI) compound and formula (II) compound; Wherein, for example palladium on carbon, Pd (PPh of described palladium-containing catalyst 3) 2Cl 2, Pd 2(dba) 3, Pd 2(dba) 3CHCl 3, Pd (P tBu 3) 2, Pd 2(dba) 3CHCl 3/ Pd (P tBu 3) 2, Pd (OAc) 2, Pd (PhCN) 2Cl 2And PdCl 2
In this reaction, use copper compound, for example Cu (I) compound as catalyzer.This Cu (I) catalyzer preferably is incorporated in the reaction medium as substoichiometric mantoquita, for example CuI or CuBrMe 2S.Adopt for example PPh of phosphine part 3Or P ( tBu) 3, be the part of the method for some embodiments of the present invention.
The same with other method steps in the embodiment of the present invention text, as in these reactions, to use high polar solvent can improve speed and reduce by product generation.So high polar solvent with form of mixtures is provided in some embodiments, and described mixture is the mixture that first kind of solvent and (with respect to the specific inductivity of first kind of solvent) increase the solubility promoter of this mixture dielectric constant.For example, it will be recognized by those of ordinary skills, according to disclosure text, in these reactions, water can improve speed as such solubility promoter and reduce the generation of by product.
In a preferred embodiment, described palladium source is Pd 2(dba) 3CHCl 3/ Pd (PtBu 3) 2, Pd (PPh 3) 2Cl 2Or palladium on carbon, described alkali is triethylamine or salt of wormwood, and described solvent is the mixture of THF or DME and water, and described temperature is between room temperature to 80 ℃.In an especially preferred embodiment, described palladium source is Pd (PPh 3) 2Cl 2, described alkali is triethylamine, described solvent is THF, uses the CuI or the CuBrMe of catalytic amount 2S, described temperature of reaction is that room temperature is to reflux temperature.
According to the method for steps A that is similar to scheme 1 and B, perhaps, obtain formula (I) compound from formula (VII) compound according to the method for the step C of similar scheme 1.Also can directly obtain formula (I) compound by under the Sonogashira condition, reacting with the formula V compound from formula (VI) compound.
Can be according to the method for scheme 3 general introductions, preparation formula (XII) compound.
Scheme 3
According to the method for scheme 3 general introductions, from formula (IX) compound formula (XII) compound.Those skilled in the art can select suitable protecting group P for formula (IX) compound 1Under the reductive amination reaction conditions, at reductive agent NaBH (OAc) for example 3Exist down, in DCE, THF and composition thereof equal solvent, under 0 ℃-80 ℃ temperature, make the reaction of formula (IX) compound and formula (X) compound.In such reductive amination reaction, amine (X) and aldehyde (IX) reaction form the imonium ion.According to disclosure text, it will be recognized by those skilled in the art, add for example acetate of acid, will speed up the generation of this reaction and reduction by product.So the imonium ion that forms is subsequently by NaBH (OAc) 3Be reduced into required product.In an especially preferred embodiment, at NaBH (OAc) 3Exist down with acetate, in DCE, at room temperature, make the reaction of formula (IX) compound and formula (X) compound.
Under the condition that those skilled in the art were familiar with, by removing protecting group P 1, obtain formula (XII) compound from formula (XI) compound.Protecting group P is determined in the description of reference that those of ordinary skills quote according to for example this paper (for example works of Greene etc. and McOmie) and the protecting group that this paper provided 1Selection and remove.
Can be according to the method for scheme 4 general introductions, preparation formula (XVI) compound.
Scheme 4
Figure A0382589700552
According to the method for scheme 4 general introductions, from formula (XIII) compound formula (XVI) compound.As mentioned above, those skilled in the art can select suitable protecting group P for formula (XIII) compound 2
At alkali for example in the presence of sodium hydride, potassium hydride KH, sodium hydroxide, potassium hydroxide, DBU, triethylamine and the butyllithium, at solvent for example in DMF, THF, toluene, DMAC, acetonitrile and composition thereof, under the temperature of room temperature to 140 ℃, make the reaction of formula (XIII) compound and formula (XIV) compound, wherein X 3Be leavings groups such as halogen or Acibenzolar.
Perhaps, formula (XIII) compound and formula (XIV) compound are reacted, wherein X under the Mitsunobu condition 3Be hydroxyl, R 22Be aryl.By under the condition that those skilled in the art were familiar with, removing protecting group P 2, obtain formula (XVI) compound from formula (XV) compound.
Can be according to the method for scheme 5 general introductions, preparation formula (XXVI) compound.
Scheme 5
Figure A0382589700571
From formula (XXIII) compound formula (XXVI) compound, shown in scheme 5.Radicals X in formula (XXIII) compound 2Be meant leavings group, such as in the scheme 2 definition.
Formula (XXIII) compound and formula (II) compound are reacted under the Sonogashira condition, obtain formula (XXVIII) compound, as described in scheme 2 steps A.Formula (XXVIII) compound and formula (XXIV) compound are reacted under the reductive amination condition, obtain formula (XXIX) compound, as described in scheme 3 steps A.It will be recognized by those skilled in the art, contain the replacement or the unsubstituted non-aromatic heterocyclic of secondary amine functional groups, piperidine derivative for example, for example formula (XII) and (XVI) compound can be used for replacement formula (XXIV) compound.
Formula (XXIX) compound is reacted under scheme 1 step C or scheme 1 steps A and the described condition of B, obtain formula (XXVI) compound.Perhaps, formula (XXV) and formula V compound are reacted under the Sonogashira condition of scheme 2 steps A, obtain formula (XXVI) compound.Formula (XXIII) compound is reacted under the described reductive amination condition of scheme 3 steps A, obtain formula (XXV) compound.Perhaps, formula (XXVII) compound and formula (XXIV) compound are reacted under the described reductive amination condition of scheme 3 steps A, obtain formula (XXVI) compound.Formula (XXIII) compound and formula V compound are reacted under the described Sonogashira condition of scheme 2 steps A, obtain formula (XXVII) compound.
In compound (XXIII), substituent X 2Demonstrate each other with aldehyde radical and to arrange with contraposition.In extra scheme, clearly do not demonstrate other scheme of the scheme of being similar to 5, wherein substituent X 2Arrange with an ortho position and a position each other with aldehyde radical.Be appreciated that according to described herein, embodiment of the present invention comprise such scheme: wherein compound (XXIII) is similar to compound shown in the scheme 5, wherein substituent X 2Arrange with the ortho position each other with aldehyde radical.Be appreciated that equally also embodiment of the present invention comprise such scheme: wherein compound (XXIII) is similar to compound shown in the scheme 5, wherein substituent X 2Arrange with a position each other with aldehyde radical.This paper provides the specific examples of arranging with position between such, because compare with the para-orientation condition with the ortho position, has different activities under a position replacement condition.
The example of the extra embodiment of the different compounds (XXIII) that replace arrangement type is illustrated with the following formula (XXIIIw) that suitably replaces, (XXIIIow) with (XXIIImw):
Except the method for being implemented according to content of the present invention and those of ordinary skills for preparing The compounds of this invention as herein described, the embodiment for preparing the method for The compounds of this invention also comprises following embodiment.
Some embodiments comprise the preparation method of formula (I) compound, the acceptable salt of its medicine, ester or acid amides, and described method comprises at least one following step: make the reaction of following formula (VI) compound and formula V compound and formula (VIII) compound:
With
Figure A0382589700592
With organic bases R 1R 2NH is at the X of formula (VIII) compound 1On carry out nucleophilic substitution, wherein with the linked reaction of alkynes in, X 2Be suitable leavings group, and with the nucleophilic substitution reaction of amine in, X 1Be suitable leavings group.More particularly, extra embodiment comprises such method: NR wherein 1R 2Be combined together to form piperidyl, methyl piperidine base, dimethylamino, pyrrolidyl, diethylamino, methylethyl amino, ethyl propyl amino or dipropyl amino, more particularly, NR wherein 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin, more more particularly, NR wherein 1R 2Be combined together to form piperidyl or pyrrolidyl.Extra embodiment comprises wherein R 4And R 5One of be the method for G, more particularly, R wherein 4Be G, perhaps R wherein 5Be G.Extra embodiment comprises that n wherein is 1 method.Extra embodiment comprises that wherein Q is the method for the nitrogen heterocycle of saturated N connection, and more particularly, wherein Q is selected from and replaces or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl; Perhaps wherein replace Q and be selected from N-(C 1-6Alkyl) piperazinyl, N-phenyl-Piperazine base, 1,3,8-three azepines-spiral shell [4.5] decyl and 1,4-two oxa-s-8-azepine-spiral shell [4.5] decyl; Perhaps wherein Q is the univalent perssad that is selected from following amine: aziridine, 1,4,7-trioxa-10-azepine-cyclododecane, thiazolidine, 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone, piperidines-3-formic acid diethylamide, 1,2,3,4,5,6-six hydrogen-[2,3 '] dipyridyl, 4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazine-1-base-pyrimidine, piperidines-4-methane amide, methyl-(2-pyridine-2-base-ethyl)-amine, [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine, thio-morpholinyl, allyl group-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine, 1-piperidin-4-yl-1,3-dihydro-benzimidazolyl-2 radicals-ketone, 2-(piperidin-4-yl oxygen base)-pyrimidine, piperidin-4-yl-pyridine-2-base-amine, aniline, pyridine-2-base amine; Perhaps wherein Q is selected from optional by 1-3 N-morpholinyl and N-piperidyl that is selected from following substituting group replacement: hydroxyl, formamido-, C 1-6Alkyl, 5-9 unit heterocyclic radical, N (C 1-6Alkyl) (5-9 unit heterocyclic radical), NH (5-9 unit heterocyclic radical), (5-9 unit heterocyclic radical) C 1-3Alkylidene group, C 1-2-hydroxy alkylidene, O (5-9 unit heterocyclic radical), C 1-6Alkoxyl group, (C 3-6Cycloalkyl)-O-, phenyl, (phenyl) C 1-3Alkylidene group and (phenyl) C 1-3Alkylidene group-O-, wherein above-mentioned heterocyclic radical, phenyl and alkyl can choose wantonly separately by 1-3 and independently be selected from following substituting group replacement: halogen, nitro, cyano group and C 1-3Alkyl; Perhaps wherein Q is comprised and is selected from following C 1-6The substituting group of heterocyclic radical replaces: pyridyl, pyrimidyl, furyl, thienyl, imidazolyl, (imidazolyl) C 1-6Alkylidene group, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl-, 2-oxo benzimidazolyl-, (tetrazyl) C 1-6Alkylidene group, tetrazyl, (triazolyl) C 1-6Alkylidene group, triazolyl, (pyrryl) C 1-6Alkylidene group and pyrryl; Perhaps more particularly, wherein Q is replacement or unsubstituted N-morpholinyl.Other embodiment comprises such method: wherein
N is 1;
R 1And R 2Independently be selected from C 2Alkyl, perhaps the nitrogen that is connected with them combines, and they form optional 1 the first heterocyclic radical of extra heteroatomic non-aromatics 5-6 that independently is selected from O, S and N that comprises;
R 3, R 4And R 5One of be G, all the other two is hydrogen;
G is L 2Q;
L 2Be methylene radical;
Q is NR 8R 9, R wherein 8Independently be selected from hydrogen, C 1-2Alkyl, C 3Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 2Alkylidene group and (phenyl) C 2Alkylidene group; R 9Independently be selected from C 1-2Alkyl, C 3Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 2Alkylidene group and (phenyl) C 2Alkylidene group;
Or
Q is the heterocyclic radical that the saturated N of 3-13 unit connects, and wherein, except that N connected nitrogen, 3-13 unit heterocyclic radical also can be chosen wantonly and contain 1-3 extra heteroatoms that is selected from O, S and N;
Wherein each abovementioned alkyl, alkylidene group, thiazolinyl, alkenylene, heterocyclic radical and carbocylic radical can independently separately and optional independently be selected from following substituting group replacement by 1-3: methoxyl group, halogen, amino, nitro, hydroxyl and C 1-3Alkyl;
Wherein the substituting group of Q can further be selected from tert-butoxycarbonyl, formamido-, 5-9 unit heterocyclic radical, NH (6 yuan of heterocyclic radicals), O (6 yuan of heterocyclic radicals), phenyl, C 2-hydroxy alkylidene, hydroxyl and benzyl, and wherein each above-mentioned heterocyclic radical, phenyl and the alkyl substituent of Q can be chosen wantonly by trifluoromethyl and replace.
Some embodiments comprise such method again: NR wherein 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin, Q is selected from and replaces or unsubstituted piperidyl, piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl; Perhaps wherein said organic bases R 1R 2NH is a piperidines, and described nucleophilic substitution is at room temperature to carry out; Perhaps wherein in the presence of ethanol, at room temperature carry out described nucleophilic substitution with 10 equivalent piperidines; Perhaps wherein in the presence of ethanol, at room temperature carry out described nucleophilic substitution (X with 10 equivalent piperidines 1Be the methylsulfonic acid ester group), obtain replacing alkali and eliminate mixture of products; And comprise further or do not comprise the steps: described mixture is exposed among the HCl and obtain salts solution that selective precipitation and crystallization make the benzyne dihydrochloride from described salts solution; More particular embodiment is that wherein said benzyne dihydrochloride is 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl] the morpholine dihydrochloride.Other embodiment comprises the method that wherein satisfies following arbitrary condition:
NR 1R 2Be combined together to form piperidyl or pyrrolidyl, n is 1, and Q is selected from morpholinyl and piperidyl;
NR 1R 2Be combined together to form piperidyl or pyrrolidyl, n is 1, and Q is morpholinyl or replaces morpholinyl;
N=1, R 3Be H, R 5Be H, R 4Be L 2Q, wherein Q is a morpholinyl, L 2As above definition, and NR 1R 2Be combined together to form piperidyl;
Described organic bases R 1R 2NH is a piperidines;
In the presence of ethanol, at room temperature carry out described nucleophilic substitution;
In the presence of ethanol, at room temperature carry out described nucleophilic substitution, and described organic bases R 1R 2NH is a piperidines, comprises when the consumption of described piperidines is 10 equivalents:
N=1, R 3Be H, R 5Be H, R 4Be L 2Q, wherein Q is a morpholinyl, L 2As above definition, described organic bases R 1R 2NH is a piperidines, in the presence of ethanol, at room temperature carries out described nucleophilic substitution; Described nucleophilic substitution obtains substitution product and eliminates mixture of products, and in containing pure medium, obtaining carrying out under the temperature of at least 80% described substitution product;
Described nucleophilic substitution obtains substitution product and eliminates mixture of products, and in the presence of ethanol, at room temperature carry out described organic bases R 1R 2NH is a piperidines, described method also comprises makes described mixture and acid-respons obtain salts solution, and selective precipitation and the described salts solution of crystallization, obtain salt, described method comprises that wherein said acid is HCl, use ether and any method of alcoholic acid in described crystallization, under latter event, the feature of more particular embodiment is n=1 wherein again, R 3Be H, R 5Be H, R 4Be L 2Q, wherein Q is a morpholinyl, L 2As above definition, NR 1R 2Be combined together to form piperidyl, described substitution product is 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine, described salt is the dihydrochloride of described substitution product.Wherein said nucleophilic substitution reaction be in the presence of ethanol, at room temperature carry out, described organic bases R 1R 2NH is that the method for other embodiment of piperidines comprises that also the alcohol with formula (VII) compound is transformed into described formula (VIII) compound, and more particular embodiment also comprises following formula (VIIa) compound amine R 8R 9NH carries out reductive amination, obtains formula (VII) compound:
Figure A0382589700621
R wherein 3 ', R 4 'And R 5 'One of be C (O) H, all the other two are selected from H, chlorine and bromine, wherein R 3, R 4And R 5One of be NR 8R 9, all the other two are selected from H, chlorine and bromine.
Also more particularly, comprise such method: wherein satisfy following arbitrary condition: described amine is morpholine; And the mantoquita that is included in palladium-containing catalyst and formula (II) compound exists down and dibasic benzene carries out linked reaction, obtain formula (VIIa) compound, one in the wherein said benzene substituting group is C (O) H, and in the described benzene substituting group another is selected from chlorine and bromine.
Some embodiments comprise the preparation method of formula (I) compound and the acceptable salt of medicine, ester or acid amides, wherein more particularly, and R 3And R 5One of be G, all the other one and R 4One of be H, another is selected from hydrogen, fluorine and chlorine, these embodiments comprise makes at least one following formula (XXIIIw) compound and following formula (XXIIIow) compound and the reaction of formula V compound:
Wherein W is C (O) H or G, X 2Be with the linked reaction of alkynes in suitable leavings group.More particularly, extra embodiment comprises the method that wherein also satisfies following arbitrary condition: described W is C (O) H, and described method also comprises makes described W and organic bases R 9R 8NH carries out the reductive amination reaction; NR 1R 2Be combined together to form piperidyl, methyl piperidine base, dimethylamino, pyrrolidyl, diethylamino, methylethyl amino, ethyl propyl amino or dipropyl amino, the condition that comprises more specifically is NR wherein 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin, perhaps NR wherein 1R 2Be combined together to form piperidyl or pyrrolidyl;
R 5Be G;
R 3Be G;
N is 1;
Q is the nitrogen heterocycle that saturated N connects;
Q is selected from and replaces or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl, comprises for example following more specifically arbitrary feature: wherein replace Q and be selected from N-(C 1-6Alkyl) piperazinyl, N-phenyl-Piperazine base, 1,3,8-three azepines-spiral shell [4.5] decyl and 1,4-two oxa-s-8-azepine-spiral shell [4.5] decyl, wherein Q is the univalent perssad that is selected from following amine: aziridine, 1,4,7-trioxa-10-azepine-cyclododecane, thiazolidine, 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone, piperidines-3-formic acid diethylamide, 1,2,3,4,5,6-six hydrogen-[2,3 '] dipyridyl, 4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazine-1-base-pyrimidine, piperidines-4-methane amide, methyl-(2-pyridine-2-base-ethyl)-amine, [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine, thio-morpholinyl, allyl group-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine, 1-piperidin-4-yl-1,3-dihydro-benzimidazolyl-2 radicals-ketone, 2-(piperidin-4-yl oxygen base)-pyrimidine, piperidin-4-yl-pyridine-2-base-amine, aniline, pyridine-2-base amine; Q is selected from optional by 1-3 N-morpholinyl and N-piperidyl that is selected from following substituting group replacement: hydroxyl, formamido-, C 1-6Alkyl, 5-9 unit heterocyclic radical, N (C 1-6Alkyl) (5-9 unit heterocyclic radical), NH (5-9 unit heterocyclic radical), (5-9 unit heterocyclic radical) C 1-3Alkylidene group, C 1-2-hydroxy alkylidene, O (5-9 unit heterocyclic radical), C 1-6Alkoxyl group, (C 3-6Cycloalkyl)-O-, phenyl, (phenyl) C 1-3Alkylidene group and (phenyl) C 1-3Alkylidene group-O-, wherein above-mentioned heterocyclic radical, phenyl and alkyl can choose wantonly separately by 1-3 and independently be selected from following substituting group replacement: halogen, nitro, cyano group and C 1-3Alkyl;
Q is comprised being selected from following C 1-6The substituting group of heterocyclic radical replaces: pyridyl, pyrimidyl, furyl, thienyl, imidazolyl, (imidazolyl) C 1-6Alkylidene group, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl-, 2-oxo benzimidazolyl-, (tetrazyl) C 1-6Alkylidene group, tetrazyl, (triazolyl) C 1-6Alkylidene group, triazolyl, (pyrryl) C 1-6Alkylidene group and pyrryl;
Q is for replacing or unsubstituted N-morpholinyl;
NR 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin and
Q is selected from and replaces or unsubstituted piperidyl, piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl;
NR 1R 2Be combined together to form piperidyl or pyrrolidyl, n is 1, and Q is selected from morpholinyl and piperidyl;
NR 1R 2Be combined together to form piperidyl or pyrrolidyl, n is 1, and Q is morpholinyl or replaces morpholinyl;
N is 1, R 4Be H, R 3And R 5One of be H, R 3And R 5In all the other one be L 2Q, wherein Q is a morpholinyl, L 2As above definition, NR 1R 2Be combined together to form piperidyl;
N is 1, R 4Be H, R 3Be H, R 5Be C (O) H, NR 1R 2Be combined together to form piperidyl, wherein said reaction is at room temperature carried out;
N is 1, R 4Be H, R 3Be H, R 5Be C (O) H, NR 1R 2Be combined together to form piperidyl, wherein said reaction at room temperature, in the presence of palladium-containing catalyst and mantoquita, carry out, and described reaction obtains benzyne;
N is 1, R 4Be H, R 3Be H, R 5Be C (O) H, NR 1R 2Be combined together to form piperidyl, X 2Be bromine, wherein at room temperature, carry out described reaction in the presence of palladium-containing catalyst and mantoquita, and described reaction obtains benzyne; With
N is 1, R 4Be H, R 3Be H, R 5Be C (O) H, NR 1R 2Be combined together to form piperidyl, wherein said reaction at room temperature, in the presence of palladium-containing catalyst and mantoquita, carry out, and described reaction obtains benzyne, described method also comprises uses R 8R 9The described benzyne of NH reductive amination obtains alkali, and more particular embodiment satisfies at least one following condition again:
Described R 8R 9NH is a morpholine, and described alkali is 4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine; With
Described method also comprises and HCl forms salts solution, and also more particular embodiment also comprises the dihydrochloride that obtains described alkali by crystallization, again more particular embodiment to satisfy described alkali be 4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine.
Extra again embodiment comprises such method: wherein n is 1;
R 1And R 2Independently be selected from C 2Alkyl, perhaps the nitrogen that is connected with them combines, and they form the first heterocyclic radical of non-aromatics 5-6, choose wantonly to comprise an extra heteroatoms that independently is selected from O, S and N;
R 3And R 5One of be G, all the other one and R 4Be H;
G is L 2Q;
L 2Be methylene radical;
Q is NR 8R 9, R wherein 8Independently be selected from hydrogen, C 1-2Alkyl, C 3Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 2Alkylidene group and (phenyl) C 2Alkylidene group; R 9Independently be selected from C 1-2Alkyl, C 3Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 2Alkylidene group and (phenyl) C 2Alkylidene group;
Or
Q is the heterocyclic radical that the saturated N of 3-13 unit connects, and wherein, except that N connected nitrogen, 3-13 unit heterocyclic radical also can be chosen wantonly and contain 1-3 extra heteroatoms that independently is selected from O, S and N;
Wherein each abovementioned alkyl, alkylidene group, thiazolinyl, alkenylene, heterocyclic radical and carbocylic radical can independently separately and optional independently be selected from following substituting group replacement by 1-3: methoxyl group, halogen, amino, nitro, hydroxyl and C 1-3Alkyl;
And wherein the substituting group of Q can further be selected from tert-butoxycarbonyl, formamido-, 5-9 unit heterocyclic radical, NH (6 yuan of heterocyclic radicals), O (6 yuan of heterocyclic radicals), phenyl, C 2-hydroxy alkylidene, hydroxyl and benzyl, wherein the above-mentioned heterocyclic radical of each of Q, phenyl and alkyl substituent can be chosen wantonly by trifluoromethyl and replace.
Some embodiments comprise the preparation method of formula (I) compound and the acceptable salt of medicine, ester or acid amides, and described method is included in halogenation San Wan Ji Phosphonium and alkali exists down, makes following formula (VII) compound and organic bases R 1R 2The NH reaction:
Figure A0382589700661
More particularly, extra embodiment comprises the method that wherein satisfies following arbitrary condition:
Described halogenation San Wan Ji Phosphonium be iodate (cyano methyl) San Jia Ji Phosphonium and
Described alkali is DIPEA;
NR 1R 2Be combined together to form piperidyl, methyl piperidine base, dimethylamino, pyrrolidyl, diethylamino, methylethyl amino, ethyl propyl amino or dipropyl amino;
NR 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin;
NR 1R 2Be combined together to form piperidyl or pyrrolidyl;
R 4And R 5One of be G;
R 4Be G;
R 5Be G;
N is 1;
Q is the nitrogen heterocycle that saturated N connects;
Q is selected from and replaces or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl;
NR 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin and
Q is selected from and replaces or unsubstituted piperidyl, piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl;
NR 1R 2Be combined together to form piperidyl or pyrrolidyl, n is 1, and Q is selected from morpholinyl and piperidyl;
NR 1R 2Be combined together to form piperidyl or pyrrolidyl, n is 1, and Q is morpholinyl or replaces morpholinyl; With
N=1, R 3Be H, R 5Be H, R 4Be L 2Q, wherein Q is a morpholinyl, L 2As above definition, NR 1R 2Be combined together to form piperidyl.
Some embodiments comprise the preparation method of formula (I) compound and the acceptable salt of medicine, ester or acid amides, wherein more particularly, and R 4Be G, R 3And R 5One of be hydrogen, all the other one is selected from hydrogen, fluorine and chlorine, these embodiments comprise makes the reaction of following formula (XXIIImw) compound and formula V compound:
Figure A0382589700671
Wherein W is C (O) H or G, X 2With the linked reaction of alkynes in be suitable leavings group.More particularly, extra embodiment comprises the method that wherein satisfies following arbitrary condition:
Described W is C (O) H, and described method also comprises the organic bases R with described W 9R 8NH carries out reductive amination;
NR 1R 2Be combined together to form piperidyl, methyl piperidine base, dimethylamino, pyrrolidyl, diethylamino, methylethyl amino, ethyl propyl amino or dipropyl amino;
NR 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin;
NR 1R 2Be combined together to form piperidyl or pyrrolidyl;
N is 1;
Q is the nitrogen heterocycle that saturated N connects;
Q is selected from and replaces or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl;
Replace Q and be selected from N-(C 1-6Alkyl) piperazinyl, N-phenyl-Piperazine base, 1,3,8-three azepines-spiral shell [4.5] decyl and 1,4-two oxa-s-8-azepine-spiral shell [4.5] decyl;
Q is the univalent perssad that is selected from following amine: aziridine, 1,4,7-trioxa-10-azepine-cyclododecane, thiazolidine, 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone, piperidines-3-formic acid diethylamide, 1,2,3,4,5,6-six hydrogen-[2,3 '] dipyridyl, 4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazine-1-base-pyrimidine, piperidines-4-methane amide, methyl-(2-pyridine-2-base-ethyl)-amine, [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine, thio-morpholinyl, allyl group-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine, 1-piperidin-4-yl-1,3-dihydro-benzimidazolyl-2 radicals-ketone, 2-(piperidin-4-yl oxygen base)-pyrimidine, piperidin-4-yl-pyridine-2-base-amine, aniline and pyridine-2-base amine;
Q is selected from optional by 1-3 N-morpholinyl and N-piperidyl that independently is selected from following substituting group replacement: hydroxyl, formamido-, C 1-6Alkyl, 5-9 unit heterocyclic radical, N (C 1-6Alkyl) (5-9 unit heterocyclic radical), NH (5-9 unit heterocyclic radical), (5-9 unit heterocyclic radical) C 1-3Alkylidene group, C 1-2Hydroxy alkylidene, O (5-9 unit heterocyclic radical), C 1-6Alkoxyl group, (C 3-6Cycloalkyl)-O-, phenyl, (phenyl) C 1-3Alkylidene group and (phenyl) C 1-3Alkylidene group-O-, wherein above-mentioned heterocyclic radical, phenyl and alkyl can choose wantonly separately by 1-3 and independently be selected from following substituting group replacement: halogen, nitro, cyano group and C 1-3Alkyl;
Q is comprised being selected from following C 1-6The substituting group of heterocyclic radical replaces: pyridyl, pyrimidyl, furyl, thienyl, imidazolyl, (imidazolyl) C 1-6Alkylidene group, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl-, 2-oxo benzimidazolyl-, (tetrazyl) C 1-6Alkylidene group, tetrazyl, (triazolyl) C 1-6Alkylidene group, triazolyl, (pyrryl) C 1-6Alkylidene group and pyrryl;
Q is for replacing or unsubstituted N-morpholinyl;
NR 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin; With
Q is selected from and replaces or unsubstituted piperidyl, piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl; With
N=1, R 5Be H, R 3Be H, R 4Be L 2Q, wherein Q is a morpholinyl, L 2As above definition, NR 1R 2Be combined together to form piperidyl.
Other embodiment comprises the method that satisfies following condition:
n＝1；
R 1And R 2Independently be selected from C 2Alkyl, perhaps the nitrogen that is connected with them combines, and they form the optional first heterocyclic radical of extra heteroatomic non-aromatics 5-6 that independently is selected from O, S and N that comprises;
R 3And R 5Be hydrogen;
G is L 2Q;
L 2Be methylene radical;
Q is NR 8R 9, R wherein 8Independently be selected from hydrogen, C 1-2Alkyl, C 3Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 2Alkylidene group and (phenyl) C 2Alkylidene group; R 9Independently be selected from C 1-2Alkyl, C 3Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 2Alkylidene group and (phenyl) C 2Alkylidene group;
Or
Q is the heterocyclic radical that the saturated N of 3-13 unit connects, and wherein, except that N connected nitrogen, 3-13 unit heterocyclic radical also can be chosen wantonly and contain 1-3 extra heteroatoms that independently is selected from O, S and N;
Wherein each abovementioned alkyl, alkylidene group, thiazolinyl, alkenylene, heterocyclic radical and carbocylic radical can independently separately and optional independently be selected from following substituting group replacement by 1-3: methoxyl group, halogen, amino, nitro, hydroxyl and C 1-3Alkyl;
Wherein the substituting group of Q can further be selected from tert-butoxycarbonyl, formamido-, 5-9 unit heterocyclic radical, NH (6 yuan of heterocyclic radicals), O (6 yuan of heterocyclic radicals), phenyl, C 2-hydroxy alkylidene, hydroxyl and benzyl, wherein the above-mentioned heterocyclic radical of each of Q, phenyl and alkyl substituent can be chosen wantonly by trifluoromethyl and replace.
Other embodiment satisfies NR again 1R 2Be combined together to form piperidyl or pyrrolidyl, n is 1, and Q is selected from morpholinyl and piperidyl, and the some of them embodiment more specifically satisfies NR 1R 2Be combined together to form piperidyl or pyrrolidyl, n is 1, and Q is morpholinyl or replaces morpholinyl.To satisfy n be 1 to other embodiment again, R 3Be H, R 5Be H, W is C (O) H, X 2Be chlorine or bromine, the formula V compound is 1-fourth-3-alkynyl-piperidines, and to make benzyne, the some of them embodiment more specifically satisfies at least one following condition:
Carrying out described reaction and obtain the benzyne compound in the presence of tetramethyleneimine, under about 50 ℃ of temperature is again that some embodiments also satisfy wherein carry out described reaction in the presence of palladium-containing catalyst and mantoquita;
X 2Be bromine, be at least at the yield of described benzyne under 80% the condition and carry out described reaction;
Also comprise and use R 8R 9The described benzyne of NH reductive amination and obtain alkali, some more particular embodiments also satisfy at least one following condition:
Wherein said R 8R 9NH is a morpholine, and described alkali is 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine and
Also comprise with HCl and form salts solution, some embodiments in these embodiments also comprise the dihydrochloride that obtains described alkali by crystallization, and it is 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl that some embodiments also more specifically satisfy described alkali]-morpholine.
Herein disclosed is linear synthetic route, for example shown in the embodiment of step B, the C of scheme 2 and D, and shown in the embodiment of the step B of scheme 2 and E.The embodiment of the step C of scheme 5, D and E, and the combination of the step C of the step C of scheme 5 and D and scheme 2 and D provides the example of extra linear process.
Herein disclosed is the convergent synthesis route, for example shown in the embodiment of the steps A of scheme 2.In the steps A of scheme 5 and the embodiment of B, and the embodiment of the step F of scheme 5 and G provides the extra example of compiling process.
The embodiment of the inventive method is particularly suitable for synthesizing compound described herein and related compound thereof on a large scale, and described related compound can obtain on instruction provided herein and those of ordinary skills' basis.These related compounds comprise the acceptable salt of the medicine of The compounds of this invention, ester and acid amides.
Ordinary method is used for nucleophilic substitution, will obtain the target substitution product of unpractical low yield, and the yield of described product is about 50%, and all the other by products are mainly corresponding elimination product.A title compound that example is embodiment 16 of target substitution product.An example eliminating by product is following compound:
Figure A0382589700711
Can generate this elimination by product according to a conventional method, its yield equals 50%.Provide the background material of relevant ordinary method below with reference to document: Abdel-Magid, A.F. etc., J.Org.Chem.1996,61:3849-3862; Furst, A., Helvetica Chemica Acta 1947,30:1454; And Kawai, S.H. etc., J. Org.Chem.1994,59:2620-2622.By contrast, method of the present invention reduces the generation of described elimination by product, makes its yield be no more than 20%, and is low to moderate 15% in some embodiments.
Use consumption that the relevant ordinary method of palladium-containing catalyst and/or mantoquita uses palladium-containing catalyst usually about 1% to the scope of about 5% (percentage all provides in molar ratio).The background material of relevant ordinary method: Sonogashera is provided below with reference to document, K. etc., TetrahedronLetters 1975,50:4467-4470.By contrast, method of the present invention allows to reduce the consumption of palladium catalyst, makes that its effective use is low to moderate 0.1% (also being mol ratio) in some embodiments.Will cause the reduction of production cost in the minimizing of catalyst levels, this is the major issue of large-scale production just.In addition, few more use catalyzer, the possibility that catalyst contamination increases substantially along synthesis process will be few more.When such pollution is obvious, just must carry out the purifying of technological process and/or the purifying of final product.
Relevant ordinary method depends on the chromatogram purification of final product.By contrast, method of the present invention when no matter carrying out, is all carried out the final product purifying by selective precipitation and/or crystallization under linearity is still compiled the form of embodiment.The final product purity that these technology cause obtaining is in 95% to 99% scope, and they are more suitable for the mass-producing building-up process than chromatogram purifying.According to crystallization general knowledge, when lacking open text provided herein, think that the crystallization behavior of embodiment of The compounds of this invention is uncertain.As described herein, have been found that in text of the present invention compound of the present invention can crystallization, and this technology can be at it be carried out in the synthetic and purifying.
The present invention compiles the elimination product that the implementation of processes scheme can be removed generation.Under the synthesis step that reduces, obtain the final product of high yield.The method of compiling of 3 linear steps is that example illustrates to embodiment of the present invention to have at the most.The minimizing of such synthesis step causes the raising of efficient.
Depend on the ordinary method of the Sonogashira linked reaction that relates to ynamine, obtain medium yield usually, be about 50%.In conventional practice, the dimerisation of acetylenic compound produces by product, thereby causes so low yield.Provide the background material of relevant ordinary method below with reference to document: Kano, H. etc., J.Med.Chem.1967,10 (3): 411-418; Vaillancourt, V.A. etc., WO 0202558 A1; Guzikowski, A.P. etc., J.Med.Chem.2000,43:984-994; Wright, J.L. etc., J.Med.Chem.2000,43:3408-3419.By contrast, method of the present invention makes the yield of reaction bring up at least 80%, and its actual recovery is in about 86% (position replaces, and by contrast, the conventional yield of identical replacement but be 25%-30%) extremely in the scope of about 92% (ortho position or para-orientation).Adopt highly basic for example tetramethyleneimine and temperature condition temperature condition for example described herein, from the inventive method, be easy to obtain high yield.Preferred temperature condition comprises be about room temperature (RT) when ortho position or para-orientation, and when between be about 50 ℃ during replacement.
D. preparation, administration and treatment
Compound list usefulness disclosed by the invention or coupling are (with for example histamine H 1The receptor antagonist coupling), be used for the treatment of or prevent the patient's of this needs neurology department's disease and other histamine H 3Receptor-mediated disease, described neurology department disease comprise sleep/Arousal disorders and wake/wake up with a start obstacle (for example insomnia and trouble with jet lag), scatterbrained hyperactivity disorder (ADHD), learning and memory obstacle, cognition dysfunction, migraine, neurogenic inflammation, dementia, mild cognitive go down (forerunner's dementia), alzheimer's disease, epilepsy, narcolepsy, eating disorder, obesity, motion sickness, dizzy, schizophrenia, substance abuse, two-phase obstacle, mania and dysthymia disorders up; Described histamine H 3Receptor-mediated disease is upper respiratory tract hypersensitivity reaction, asthma, itch, nasal congestion and allergic rhinitis for example.
1. preparation and administration
Compound of the present invention or composition can be prepared and give the patient by any conventional route of administration, and described route of administration includes but not limited to intravenously, oral, subcutaneous, intramuscular, intracutaneous and parenteral admin.The compound significant quantity for the treatment of every kind of illness can change, and can be determined by those of ordinary skills.
With regard to pharmaceutical way, the salt of The compounds of this invention is meant nontoxic " the acceptable salt of medicine ".But, other salt also can be used for preparing compound of the present invention or the acceptable salt of its medicine.The acceptable salt of the medicine of suitable compound comprises acid salt, it can prepare by the acceptable acid solution of compound solution and medicine is mixed, and the acceptable acid of described medicine is hydrochloric acid, sulfuric acid, fumaric acid, toxilic acid, succsinic acid, acetate, phenylformic acid, citric acid, tartrate, carbonic acid or phosphoric acid etc. for example.And, having at The compounds of this invention under the situation of acidic moiety, the acceptable salt of its suitable medicine can comprise an alkali metal salt, for example sodium salt or sylvite; Alkaline earth salt, for example calcium salt or magnesium salts; And the salt that forms with suitable organic aglucon, for example quaternary ammonium salt.
Therefore, the acceptable salt of representational medicine comprises: acetate, benzene sulfonate, benzoate, supercarbonate, hydrosulfate, bitartrate, borate, bromide, Ca-EDTA, camsilate, carbonate, muriate, Clavulanate, Citrate trianion, dihydrochloride, edetate, ethanedisulphonate, estolate, esilate, fumarate, gluceptate, gluconate, glutaminate, the glycolyl arsanilate, Sucrets salt, sea crust amine salt, hydrobromate, hydrochloride, Hydroxynaphthoate, iodide, different thiosulphate, lactic acid salt, Lactobionate, lauroleate, malate, maleate, mandelate, mesylate, MB, methyl nitrate, Methylsulfate, mucate, naphthalenesulfonate, nitrate, N-methyl glucose ammonium salt, oleate, embonate (embonate), palmitate, pantothenate, phosphoric acid salt/diphosphate, Polygalacturonate, salicylate, stearate, vitriol, inferior acetate, succinate, tannate, tartrate, the teoclate, tosylate, triethyl iodate thing and valerate.
The present invention includes the prodrug in the The compounds of this invention scope.Generally speaking, this prodrug can be its functional derivatives that easily changes into required compound in vivo.Therefore, in the methods of treatment of the present invention, term " administration " should comprise with the described various diseases of concrete disclosed compounds for treating, perhaps with not have specifically to disclose but give to change into behind the patient the described various diseases of compounds for treating of described particular compound in its body.Select and the ordinary method of preparation appropriate precursors medicaments derivative for example is described in " Design ofProdrugs ", H.Bundgaard edits, and Elsevier is in 1985.Outside the desalination, the present invention also provides ester, acid amides and other protection or the derivatize form of described compound.
When The compounds of this invention had at least one chiral centre, they can exist with enantiomer.When described compound had two or more chiral centres, they also can exist with diastereomer.Should be appreciated that isomer that all are such and composition thereof all comprises within the scope of the present invention.In addition, some crystal formation of described compound can exist by polymorphic form, the present invention includes such polymorphic form.In addition, some compounds can form solvate with water (being hydrate) or ordinary organic solvents, and this solvate comprises within the scope of the present invention.
The present invention also provides and comprises one or more The compounds of this invention and medicine acceptable carrier and optional H 1The pharmaceutical composition of extra medicine such as antagonist or SSRI.These compositions are unit dosage preferably, for example pill, tablet, Caplet, capsule (comprising quick releasing formulation, time release formulation and sustained release preparation respectively), powder, granule, aseptic parenteral solution or suspensoid (comprising syrup and emulsion), quantitative aerosol or liquid spray, drops, ampulla, automated injection device or suppository; Be used in oral, parenteral, the nose, hypogloeeis or rectal administration, or be used for by sucking or the insufflation administration.Perhaps, described composition also can provide to be suitable for form weekly or every month single administration; Can adopt for example insoluble salt such as the caprate of described active compound, to be provided for the depot formulation of intramuscularly.In order to prepare for example tablet of solids composition, with described main active ingredient with such as following pharmaceutical carrier and other medicinal diluent for example water mixes with formation solid pre-formed composition: conventional tablet compositions such as W-Gum, lactose, sucrose, sorbyl alcohol, talcum powder, stearic acid, Magnesium Stearate, secondary calcium phosphate or natural gum, described solid pre-formed composition contains the homogenizing mixture of The compounds of this invention or the acceptable salt of its medicine.When these pre-formed composition are called homogeneous, mean described activeconstituents homodisperse in whole described composition, make easily described composition to be further divided into equal effectively formulation for example tablet, pill and capsule.Then this solid pre-formed composition is divided again at the above-mentioned 5mg of containing to the unit dosage of about 1000mg activeconstituents of the present invention.Example comprises 5mg, 7mg, 10mg, 15mg, 20mg, 35mg, 50mg, 75mg, 100mg, 120mg, 150mg or the like.Can or do other and handle the tablet or the pill sugar coating of disclosed composition, to provide the formulation that prolongs the onset advantage.For example, described tablet or pill can comprise a kind of interior administration component and a kind of external administration component, and the latter is the former capsule form.These two kinds of components can be separated by one deck enteric coating, the effect that described enteric coating has opposing to decompose under one's belt, make described in component complete by duodenum or be delayed release.Various materials can be used as such enteric coating or dressing, and such material comprises various polymeric acid, for example shellac, hexadecanol and cellulose acetate.
Can be for oral administration or drug administration by injection with, the liquid form that wherein can mix compound of the present invention and composition comprise the aqueous solution agent, suitably flavoring syrup, water-based or oiliness suspensoid with edible oil for example emulsion and the elixir and similar medicinal solvent of Oleum Gossypii semen, sesame oil, Oleum Cocois or peanut oil flavoring.But suitable dispersant that the water supplying capability suspensoid is used or suspension agent comprise synthetic and natural natural gum for example tragakanta, gum arabic, alginate, dextran, Xylo-Mucine, methylcellulose gum, polyvinylpyrrolidone or gelatin.
If obtain the mixture of steric isomer among the preparation technology of The compounds of this invention, then these isomer can separate with routine techniquess such as preparative scale chromatographies.Described compound can be prepared into racemic form, and is perhaps synthetic or by splitting preparation enantiomer separately by the enantiomorph specificity.Described compound can be by forming salt with optically-active acid (for example (-)-two pair toluyl-d-tartrate and/or (+)-two pair toluyl-1-tartrate); fractional crystallization and regenerate free alkali and form diastereomer equity standard technique resolves to the enantiomorph of its each component then.Described compound also can be resolved by the following method: form the ester or the acid amides of diastereomer, then chromatographic separation is removed chiral auxiliary(reagent) at last.Perhaps, described compound can be resolved with chirality HPLC post.
Advantageously, compound of the present invention can give with the single per daily dose, and perhaps total per daily dose can give with the fractionated dose of every day 2 times, 3 times or 4 times.In addition, can give compound of the present invention by form in the nose of carrier in the suitable nose of topical application or by the transdermal patch form that those of ordinary skills know.For the form administration with transdermal delivery system, in the whole dosage regimen, administration will be successive rather than intermittent certainly.
For example, for oral administration with tablet or Capsule form, can for example ethanol, glycerine, water etc. mix with the acceptable inert support of oral nontoxic medicine with described active medicine component.In addition, when necessary or essential, also suitable binder, lubricant, disintegrating agent and tinting material can be incorporated in the described mixture.Suitable binder includes but not limited to for example for example gum arabic, tragakanta or sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium acetate, sodium-chlor etc. of glucose or beta lactose, corn sweetener, natural and synthetic gum of starch, gelatin, natural sugar.Disintegrating agent includes but not limited to starch, methylcellulose gum, agar, bentonite, xanthan gum etc.
Compound of the present invention also can give with the form of liposome delivery system, and described liposome delivery system is small unilamellar vesicle, big unilamellar liposome and multilamellar liposome for example.Liposome can be formed by various phosphatide, for example cholesterol, hard esteramides or phosphatidylcholine.
The compounds of this invention also can be by using monoclonal antibody as passing medicine with the various carriers of compound molecule coupling.The compounds of this invention also can with the soluble polymer coupling as target medicine carrier.This polymkeric substance can comprise polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropylmethyl acrylamide phenol, poly-hydroxyethyl amino-succinamic acid phenol or the polyethylene oxide polylysin that is replaced by the palmityl residue.In addition, but the The compounds of this invention coupling is applicable to the biodegradable polymer that produces medicine controlled releasing, for example crosslinked the or amphiphilic inlay and break copolymer of poly(lactic acid), poly epsilon caprolactone acid lactone, multi-hydroxybutyrate, polyester, polyacetal resin, poly-dihydropyrane, polybutylcyanoacrylate and hydrogel.
The compounds of this invention can give in any foregoing, and can give at any time when needs are treated ADHD according to the dosage regimen that this area is set up.
The per daily dose variation range of this product is very big, and scope is every per day for adults 1-1,000mg.With regard to oral administration, described composition preferably offers the patient that will treat with tablet form, and described tablet contains the activeconstituents that 1.0,5.0,10.0,15.0,25.0,50.0,100,250 and 500 milligrams of dosage are suited the medicine to the illness and regulated.The common dosage level scope of effective amount of drug be every day about 0.01mg/kg to about 20mg/kg body weight.Preferably, described scope every day about 0.02mg/kg to about 10mg/kg body weight, about 0.05mg/kg every day about 10mg/kg body weight extremely more preferably.Described compound can be by 1-4 time scheme administration every day.
Best dosage can easily be determined by those skilled in the art, and will change with the development of used particular compound, administering mode, preparation specification and illness.In addition, relevant with concrete patient to be treated factor comprises that patient age, body weight, diet situation and administration time all will cause needs to regulate dosage.
2. combination therapy
Disclosed compound is applicable to other therapeutical agent unites use, comprises H 1Receptor antagonist, H 2Receptor antagonist and neurotransmitter are regulated medicine for example SSRI and non-selective serotonin reuptake inhibitor (NSSRI).
The method of the effective dose of the treatment of disclosed pharmaceutical composition of multiple mensuration known in the art or disclosed drug regimen (no matter whether being formulated in the same composition) and prevention purpose.For therapeutic purpose, term used herein " associating significant quantity " be meant by the determined every kind of active compound of researchist, animal doctor, the doctor of medicine or other clinicist or medicine list with or in tissue system, animal or human, cause the amount of biological respinse or drug reaction (comprising the symptom of alleviating institute's disease for the treatment of or disorder) during coupling.For prevention purpose (generation or the process that promptly suppress disease), term " associating significant quantity " be meant by the determined every kind of active compound of researchist, animal doctor, the doctor of medicine or other clinicist or medicine list with or suppress the generation of disease of patient or the amount of process during coupling, patient disease takes place or process to postpone be because the disease of regulating mediation by one or more Histamine Receptorss to small part is adjusted.Therefore, the invention provides the applied in any combination of two or more medicine, wherein for example (a) every kind of medicine is so that independently treatment or prevention significant quantity give; (b) separately during medication, in the described applied in any combination at least a medicine for inferior treatment or inferior preventive dose medication, but when giving in conjunction with second kind or other medicine according to the present invention for treating or the preventive dose medication; Or (c) be inferior treatment or inferior prophylactic amount during the independent medication of two kinds of medicines, but when drug combination for treating or the preventive dose medication.Drug combination is feasible equally more than three kinds.The method of combination therapy comprises the unitary agent that contains all promoting agents jointly; Basically give more than a kind of preparation simultaneously; With the promoting agent that gives two or more independent allotments.
In order more to be briefly described, some quantitative statements term " about " of no use that this paper provides limits.Be appreciated that, no matter whether clearly use " pact ", the amount that this paper provides at every turn is meant the actual value that provides, and also be meant the approximation of the described value of providing, this approximation will reasonably be inferred by those of ordinary skills, comprise because the experiment condition of the described value of providing and/or the approximation of condition determination.When representing yield with percentage, this yield is meant the total amount of yield given with regard to following getable maximum of particular chemical metering condition.
E. embodiment
Embodiment 1
Figure A0382589700781
1-(4-bromo-benzyl)-piperidines
DCE (65mL) solution of 4-bromobenzaldehyde (5g), piperidines (2.9mL) and acetate (1.5mL) is handled with sodium triacetoxy borohydride (6.9g).After 27 hours, the gained mixture is handled with saturated sodium bicarbonate aqueous solution (50mL), uses DCM (2 * 50mL) extractions then.The organic phase that dry (sal epsom) and evaporation merge.Resistates carries out Kugelrohr distillation (160 ℃ 5mmHg), obtain light yellow oily title compound (5.9g).
Embodiment 2
Figure A0382589700791
1-fourth-3-alkynyl-piperidines
Ethanol (70mL) solution of toluene-4-sulfonic acid-Ding-3-alkynyl ester (45.0g) and piperidines (40mL) is handled with water (70mL) solution of salt of wormwood (27.8g).Mixture heating up to 80 ℃ is reached 2 hours, be cooled to room temperature, use DCM (3 * 100mL) extractions then.The organic phase that dry (sal epsom) and evaporation merge.Distillation residue (110 ℃ 30mmHg), obtain colorless oil title compound (17.3g).
Embodiment 3
4-fourth-3-alkynyl-morpholine
Can prepare with morpholine according to the method that is similar to embodiment 2.
Embodiment 4
Figure A0382589700793
4-fourth-3-alkynyl-thiomorpholine
Can prepare with thiomorpholine according to the method that is similar to embodiment 2.
Embodiment 5
Figure A0382589700801
3-(4-hydroxyl-Ding-1-alkynyl)-phenyl aldehyde
This is one and generates for example embodiment of the linked reaction of title compound of compound, promptly passes through coupling compound for example bromobenzaldehyde and 3-butine-1-alcohol.1L three neck round-bottomed flask are equipped with magnetic stirring bar, have condenser and two stoppers of nitrogen inlet.Be equipped with in this container the 3-bromobenzaldehyde (18.5g, 0.1mol), 3-butine-1-alcohol (10.5g, 0.15mol), triethylamine (100mL) and THF (100mL).In this mixture, add PdCl 2(PPh 3) 2(1.4g, 2mmol) and CuBrMe 2S (0.405g, 4mmol).In other embodiments, by using CuI and containing the palladium entity, also can obtain title compound.With heating mantles reaction mixture is heated to backflow.After 4 hours, after TLC (tlc) shows the bromide completely consumed, allow this mixture be cooled to room temperature, transfer in the 1L round-bottomed flask, then concentrating under reduced pressure.Resistates is dissolved in the 250mL ethyl acetate.Gained solution with water and salt water washing are through MgSO 4Drying, and filter.After the filtration,, remove the solvent in the filtrate, obtain light yellow oily title compound (16.8g, yield 97%) through reduction vaporization.Thus obtained compound purity is measured greater than 95% through HPLC.TLC (R f=0.32, SiO 2, ethyl acetate/hexane, 1: 1).MS (electron spray(ES), holotype), M +174.
1H?NMR(400MHz，CDCl 3)δ：2.72(t，2H，J＝6.3)，3.84(t，2H，J＝6.2)，7.47(t，1H，J＝7.7)，7.66(dt，1H，J＝7.7，1.4)，7.81(dt，1H，J＝7.7，1.4)，7.91(t，1H，J＝1.4)，9.98(s，1H).
With the embodiment that provides among this embodiment is example, finds in content of the present invention, and the consumption of palladium catalyst can be reduced to catalyst consumption and be about 0.1% (mol/mol).By contrast, ordinary method depends on the scope of Pd catalyst consumption at 1%-5%, and its percentage is to use same unit.So reduce the consumption of palladium catalyst, cause cost obviously to reduce.In addition, so reduce the consumption of palladium catalyst, make the reduction that palladium pollutes in the final product.
Embodiment 6
4-(3-morpholine-4-ylmethyl-phenyl)-Ding-3-alkynes-1-alcohol
This is one and generates for example embodiment of the reductive amination of title compound of compound, promptly by making compound for example aldehyde and morpholine reaction.In 1L three neck round-bottomed flasks mechanical stirrer is housed, has rubber septum and a stopper of nitrogen inlet.Be equipped with in this bottle embodiment 5 product (14.6g, 0.0838mol) and methylene dichloride (250mL).(8.85mL 0.1mol), adds sodium triacetoxy borohydride (32g, 4 aliquots 0.15mol) then in this well-beaten reaction mixture to add morpholine.After the adding, reaction mixture at room temperature stirs and spends the night.(10%w/v 75mL), is transferred to reaction mixture in the 1L separating funnel, then to wherein adding entry (100mL) to add the NaOH aqueous solution.After the layering, water with methylene dichloride (100mL) extraction once.The organic extract liquid that merges is with salt solution (30mL) washing, through MgSO 4Drying is filtered then.After the filtration,, remove the solvent in the filtrate, obtain yellow oil product (19g, yield 90%) through reduction vaporization.Measure through HPLC, the purity of this step is no more than 90%.Crude product filters purifying (ethyl acetate/hexane with silicagel pad; 7: 3), obtain light yellow oily title compound (13.7g).Thus obtained compound purity is measured greater than 98% (this purity is considered to " pure " usually) through HPLC.TLC (R f=0.22, SiO 2, ethyl acetate/hexane, 3: 1).MS (electron spray(ES), holotype), (M ++ H) 246.
1H?NMR(400MHz，CDCl 3)δ：2.43(bt，2H，J＝4.4)，2.70(t，2H，J＝6.2)，3.46(s，2H)，3.71(t，4H，J＝4.6)，3.82(t，2H，J＝6.2)，7.24-7.39(m，4H).
Embodiment 7
Figure A0382589700812
Methylsulfonic acid 4-(3-morpholine-4-ylmethyl-phenyl)-Ding-3-alkynyl ester
This is one, and for example embodiment 6 is described that compound is changed into the embodiment of its methanesulfonates, is example with title compound.The single neck round-bottomed flask of 500mL is equipped with magnetic stirring bar and the rubber septum that has nitrogen inlet.Be equipped with in this container embodiment 6 product (13.6g, 0.055mol), methylene dichloride (100mL) and triethylamine (8.43mL, 0.060mol).Reaction mixture is cooled to 0 ℃ in ice bath, dripped methylene dichloride (10mL) solution of methylsulfonyl chloride (6.93g) in 30 minutes.Remove ice bath, allow reaction mixture rise to room temperature then.After 1 hour, after TLC shows conversion fully, add the 50mL frozen water, then reaction mixture is transferred in the 500mL separating funnel.Separate organic extract liquid, use NaHCO 3The aqueous solution, salt water washing are through MgSO 4Dry.After the filtration, solvent obtains light yellow gluey title compound (17.5g through reduction vaporization (rotatory evaporator, 30 ℃); Yield 98%).Measure through HPLC, thus obtained product purity is greater than 95%.TLC (R f=0.27, SiO 2, ethyl acetate/hexane, 3: 1), MS (electron spray(ES), holotype), M +323.
1H?NMR(400MHz，CDCl 3)δ：2.3(bt，2H，J＝4.4)，2.62(t，2H，J＝6.2)，3.38(s，2H)，3.63(t，4H，J＝4.6)，3.75(t，2H，J＝6.2)，7.12-7.32(m，4H).
Embodiment 8
Toluene-4-sulfonic acid-4-(4-formyl radical-phenyl)-Ding-3-alkynyl ester
With 4-bromobenzaldehyde (25.0g), salt of wormwood (46.6h), cupric iodide (I) (1.0g), triphenyl phosphine (2.8g), the water (250mL) of 10% palladium on carbon (288mg) and the mixture of DME (250mL) at room temperature stirred 30 minutes, adds 3-butine-1-alcohol (25mL) then.The gained mixture is cooled to room temperature 90 ℃ of heating 16 hours, filters by Celite pad then.(3 * 50mL) washings, filtrate water (100mL) dilutes this pad then with DCM.(2 * 400mL) extractions, the organic phase water (100mL) of merging and salt solution (100mL) wash water, dry (MgSO with ethyl acetate 4), concentrating under reduced pressure.(2 * 100mL) azeotropic obtain brown solid (2.1g) for resistates and toluene.At 0 ℃, in the DCM (100mL) of this solid and triethylamine (7.1mL) solution, add Tosyl chloride.Make the gained mixture rise to room temperature in 2.5 hours time, water (10mL) dilution is with DCM (2 * 300mL) extractions.The organic phase water that merges (2 * 40mL), salt solution (40mL) washing, dry then (MgSO 4) and concentrating under reduced pressure.Resistates carries out purifying (10-20% ethyl acetate/hexane) with chromatography, obtains yellow oily title compound (6.7g).
Embodiment 9
Figure A0382589700831
3-(4-piperidines-1 Ji-Ding-1-alkynyl)-phenyl aldehyde
With 3-bromobenzaldehyde (0.58mL), salt of wormwood (1.73g), cupric iodide (I) (38mg), triphenyl phosphine (105mg), the water (10mL) of 10% palladium on carbon (220mg) and the mixture of DME (5mL) at room temperature stirred 20 minutes, uses DME (5mL) solution-treated of the product (1.7g) of embodiment 2 then.The gained mixture is cooled to room temperature 80 ℃ of heating 16 hours, filters by Celite pad then.(5 * 20mL) washings, filtrate water (30mL) dilutes this pad then with DCM.(2 * 30mL) extract the organic phase drying (sal epsom) and the concentrating under reduced pressure of merging to water with DCM.Resistates carries out purifying (0-3%2M methanol ammonium hydroxide/DCM), obtain light yellow oily title compound (734mg) with chromatography.
Embodiment 10
Figure A0382589700832
3-(4-morpholine-4-Ji-Ding-1-alkynyl)-phenyl aldehyde
Can be according to the method that is similar to embodiment 9, prepare with the product of embodiment 3.
Embodiment 11
3-(4-thiomorpholine-4-Ji-Ding-1-alkynyl)-phenyl aldehyde
Can be according to the method that is similar to embodiment 9, prepare with the product of embodiment 4.
Embodiment 12
4-(4-piperidines-1-Ji-Ding-1-alkynyl)-phenyl aldehyde
Method A: in 1-butanols (20mL) solution of the product (8.0g) of embodiment 8, add piperidines (2.4mL), then add yellow soda ash (1.3g) and potassiumiodide (81mg).The gained mixture is cooled to room temperature 80 ℃ of heating 16 hours, and dilute with water (200mL) is used DCM (2 * 400mL) extractions then.Organic phase water (100mL) that merges and salt solution (100mL) washing, dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying with chromatography, and (6-8%2M methanol ammonium hydroxide/DCM) obtains brown oily title compound (4.6g, title compound and 1-[4-(4-dibutoxy methyl-phenyl)-Ding-3-alkynyl]-1: 1 mixture of piperidines).
Method B: at N 2Down, to Pd (PPh 3) 2Cl 2Add THF (180mL) and Et in the mixture of (0.57g, 0.81mmol, 0.01 equivalent) and CuI (0.31g, 1.6mmol, 0.02 equivalent) 3N (90mL, 0.64mol, 8.0 equivalents).In this solution, feed N 2Air-flow 15 minutes adds 1-fourth-3-alkynyl-piperidines (11.7g, 85mmol, 1.05 equivalents) then.Reaction mixture at room temperature stirred 16 hours.Filter and collect white precipitate (Et 3NHBr), and with EtOAc wash.Concentrating under reduced pressure filtrate, the gained resistates is dissolved among the EtOAc again.This EtOAc solution is with 1M NaOH (aqueous solution) washing 2 times, through MgSO 4Drying directly is poured on the short silicagel pad then and (uses 5%Et 3The hexane solution neutralization of N), wash with EtOAc then.Concentrating under reduced pressure filtrate obtains Vandyke brown oily product (18.1g, 75mmol, 92%), and this product need not to be further purified and can use (measuring purity＞95% through HPLC).MS (electron spray(ES)): calculate C 16H 19The quality of ON, 241.1; The m/z measured value, 242.2[M+H] +
Embodiment 12a
3-(4-piperidines-1-Ji-Ding-1-alkynyl)-phenyl aldehyde
At N 2Down, to Pd (PPh 3) in the mixture of Cl (24mg, 0.034mmol, 0.02 equivalent), CuI (13mg, 0.068mmol, 0.04 equivalent) and 3-bromobenzaldehyde (0.316g, 1.7mmol, 1 equivalent), add tetramethyleneimine (10mL).The preferred tetramethyleneimine that uses in this synthesis step.In this solution, feed N 2Air-flow 5 minutes adds 1-fourth-3-alkynyl-piperidines (0.46g, 3.3mmol, 2 equivalents) then.Reaction mixture stirred 40 hours at 50 ℃.Preferred this temperature that adopts in this synthesis step.On TLC and HPLC, show to react and finish.Filter white precipitate (Et 3NHBr) and with EtOAc wash.Evaporating solvent, resistates is dissolved among the EtOAc again.(1N washing 2 times is through MgSO with the NaOH aqueous solution for organic layer 4Dry.After the filtration, EtOAc solution directly is poured on the short silicagel pad (uses 5%Et 3The hexane neutralization of N), wash with EtOAc then.Evaporating solvent obtains brown oily product (0.35g, 1.45mmol, 86%); Purity＞95% (HPLC); MS M+H +242.This product need not to be further purified and promptly can be used for subsequent step of the present invention.86% yield is compared significantly different with ordinary method, the yield that the latter generates title compound is no more than 30% usually.
Embodiment 13
Toluene-4-sulfonic acid 4-(4-piperidines-1-ylmethyl-phenyl)-Ding-3-alkynyl ester
At room temperature, with DCM (100mL) solution of product (2.0g), piperidines (0.91mL) and the acetate (0.42mL) of embodiment 8, handle with sodium triacetoxy borohydride (1.95g).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (30mL).(2 * 300mL) extract water with DCM.The organic phase drying (sal epsom) and the concentrating under reduced pressure that merge.Resistates passes through silicagel pad then with DCM (100mL) dilution.DCM (3 * 200mL) washings of this pad back.The filtrate that merges obtains brown oily title compound (2.3g) through concentrating under reduced pressure.
Embodiment 14
Figure A0382589700861
1-[4-(4-piperidines-1-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines
K i＝1.6nM
The product of embodiment 1 (254mg), salt of wormwood (346mg), cupric iodide (I) are (7.6mg), triphenyl phosphine (21mg), the water (2mL) of 10% palladium on carbon (43mg) and the mixture of DME (1mL) at room temperature stirred 30 minutes, use the product (DME of 343mg0 (1mL) solution-treated of embodiment 2 then.The gained mixture is cooled to room temperature 80 ℃ of heating 16 hours, filters by Celite pad then.(3 * 3mL) washings, filtrate water (3mL) dilutes this pad then with DCM.(2 * 3mL) extract the organic phase drying (sal epsom) and the concentrating under reduced pressure of merging to water with DCM.Resistates carries out purifying (2.5%-5%2M methanol ammonium hydroxide/DCM), obtain colorless oil title compound (88mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.33(d，J＝7.4Hz，2H)，7.22(d，J＝7.8Hz，2H)，3.44(s，2H)，2.68-2.56(m，4H)，2.50-2.43(m，4H)，2.39-2.30(m，4H)，1.64-1.52(m，8H)，1.48-1.38(m，4H).
Embodiment 15
1-[3-(4-piperidines 4-Ji-Ding-1-alkynyl)-benzyl]-piperidines
K i＝0.8nM
DCE (2mL) solution of the product of embodiment 9 (193mg) and piperidines (0.09mL) is handled with sodium triacetoxy borohydride (254mg).After 16 hours, the gained mixture is handled with 10% potassium hydroxide aqueous solution (2mL), then with DCM extraction (2 * 3mL).The organic phase drying (sal epsom) and the concentrating under reduced pressure that merge.Resistates carries out purifying (0-8%2M methanol ammonium hydroxide/DCM), obtain light yellow oily title compound (65mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.35(br?s，1H)，7.28-7.21(m，3H)，3.42(s，2H)，2.67-2.57(m，4H)，2.50-2.43(m，4H)，2.39-2.31(m，4H)，1.63-1.53(m，8H)，1.48-1.38(m，4H).
Embodiment 16
Figure A0382589700872
4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine
K i＝0.8nM
Method A: the product (193mg) of embodiment 9 and DCE (2mL) solution of morpholine (0.08mL) are handled with sodium triacetoxy borohydride (254mg).After 16 hours, the gained mixture is handled with 10% potassium hydroxide aqueous solution (2mL), then with DCM extraction (2 * 3mL).The organic phase drying (sal epsom) and the concentrating under reduced pressure that merge.Resistates carries out purifying (0-8%2M methanol ammonium hydroxide/DCM), obtain light yellow oily title compound (188mg) with chromatography.
1HNMR(400MHz，CDCl 3)：7.36(br?s，1H)，7.30-7.22(m，3H)，3.70(t，J＝4.6Hz，4H).3.45(s，2H)，2.68-2.57(m，4H)，2.51-2.40(m，8H)，1.64-1.57(m，4H)，1.48-1.41(m，2H).
Method B: 500mL three neck round-bottomed flask are equipped with magnetic stirring bar, addition funnel, a thermometer and have the rubber septum of nitrogen inlet.Be equipped with in this container piperidines (54mL, 46g, 0.54mol) and dehydrated alcohol (25mL).Solution is cooled to 0 ℃ in ice bath, adds product (17.5g, dehydrated alcohol 0.054mol) (30mL) solution of embodiment 7 then.Remove ice bath, allow reaction mixture rise to room temperature.Room temperature is preferred temperature condition.The consumption of ethanol of the 10mol equivalent piperidines that herein provides is a preferable amount.After 14 hours, after judging that with HPLC reaction is finished, reaction mixture is transferred in the 500mL round-bottomed flask, is evaporated to dried then.Resistates is dissolved in CH 2Cl 2(300mL), with the 5%NaOH aqueous solution (75mL) washing, through MgSO 4Dry also filtration.After the filtration,, obtain oily matter (20g) by the solvent evaporated under reduced pressure concentrated filtrate, this oily matter through HPLC and 1H NMR measures, and contains 85: 15 mixtures of title compound and 4-(3-penta-4-alkene-1-alkynyl-benzyl)-morpholine (a kind of compound in back is the elimination compound in this reaction).This mixture need not to be further purified and promptly can be used for subsequent step of the present invention.TLC: title compound, (R f=0.58, SiO 2, methylene dichloride/0.02M methanol ammonium hydroxide, 9: 1); 4-(3-penta-4-alkene-1-alkynyl-benzyl)-morpholine, (R f=0.38, SiO 2, ethyl acetate/hexane, 3/1).MS (electron spray(ES), holotype), (M ++ H) 313.
1H?NMR(400MHz，CDCl 3)δ：1.45(bm，2H)，1.62(m，4H)，2.41-2.48(m，8H)，2.62(m，4H)，3.44(s，2H)，3.71(t，4H，J＝4.6)，7.22-7.36(m，4H).
Method C:4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine: to 3-(4-piperidines-1-Ji-Ding-1-alkynyl)-phenyl aldehyde (0.3g, 1.24mmol, 1 equivalent) the 20mL dichloroethane solution in, add morpholine (0.13g, 1.5mmol, 1.2 equivalents).At 0 ℃, at N 2In well-beaten reaction mixture, add NaHB (OAc) down, 3(0.4g, 1.8mmol, 1.5 equivalents).After the adding, remove ice bath, reaction mixture at room temperature stirred 1.5 hours then, judged to react through HPLC this moment and finished.The slow adding NaOH aqueous solution (1N, 10mL), the unreacted reagent of quencher.Organic layer is with the NaOH aqueous solution (1mol/L) washing, through MgSO 4Dry.After the filtration, solvent evaporated under reduced pressure.The oily resistates that obtains thus is dissolved among the EtOAc again, (uses 5%Et by silicagel pad then 3The hexane neutralization of N), wash with EtOAc then.Evaporating solvent obtains light yellow oily product (0.36g, 1.16mmol, 93%).Purity＞95% (HPLC).MS?M+H +?313。
Embodiment 17
Figure A0382589700891
4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-the morpholine dihydrochloride
The selective precipitation compound is the embodiment of title compound for example.Be equipped with in 3L three neck round-bottomed flask embodiment 16 method B product (77.0g, 0.25mol).In this bottle, add anhydrous EtOH (385mL).Stirred reaction mixture also is cooled to about 0 ℃ in ice bath.In 0.5 hour, and dropping HCl De dioxane solution (4N, 126.5mL).Remove ice bath, reaction mixture was at room temperature stirred 2 hours.The thickness reaction mixture is transferred in the 500mL addition funnel, slowly and continuously joins then in the 3L three neck round-bottomed flasks that ether (500mL) is housed, simultaneously content in the blender jar.Clean addition funnel with anhydrous EtOH (115mL), this liquid joins in the diethyl ether solution subsequently.By an addition funnel, slowly and continuously add ether (500mL).Generate light brown precipitation thus.This suspension at room temperature stirred 12 hours.Add more ether (500mL), suspension is cooled to 0 ℃ and stirred 3 hours under this temperature.With the glass core suction filtration of intermediate pore size, collect product (slowly filtering).Smash filter cake to pieces and use anhydrous EtOH/Et 2O (1: 3,2 * 75mL) washings.Product is in indoor vacuum-drying, then in vacuum drying oven 35 ℃ of dryings 24 hours.Obtaining its dihydrochloride is pale powder (80.7g).HPLC and 1H-NMR shows product purity＞95%.Only there is the elimination product of trace to exist at the most.In the 2L three neck round-bottomed flasks that has been equipped with addition funnel, reflux exchanger and mechanical stirrer rough dihydrochloride (80.0g) is housed.Add anhydrous EtOH (160mL), gained suspension is warming up to about 50 ℃.Slowly add ether (320mL) by addition funnel.Stop heating, allow suspension slowly cool to room temperature, stir about is 4 hours simultaneously.Should in ice bath, cool off by bottle, stir, and about 3 hours of 0-5 ℃ of insulation.With the glass core suction filtration of intermediate pore size, collecting precipitation (slowly filtering).Smash filter cake to pieces and use cold EtOH/Et 2O (1: 2,2 * 75mL) washings.Product is 35 ℃ of vacuum-dryings.Obtain the pale powder (76.2g, yield 95%) of title compound.239 ℃ of MP (decomposition).MS (electron spray(ES), holotype), (M ++ H) 313.
1H?NMR(400MHz，MeOH)：1.56(bm，1H)，1.82-1.85(m，3H)，1.96-1.99(m，2H)，2.99-3.07(m，4H)，3.17-3.24(m，2H)，3.30-3.41(m，6H)，3.62(bd，J＝12.7Hz，2H)，3.79(bt，J＝12.6Hz，2H)，4.01(bd，J＝12.5Hz，2H)，4.37(s，2H)，7.46-7.69(m，1H)，7.53-7.56(m，2H)，7.25(m，1H).
C 20H 30N 2OCl 2The analytical calculation value: C, 62.33%; H, 7.85%; N, 7.27%; Measured value: C, 62.13%; H, 7.52%; N, 7.23%.Compare with ordinary method, title compound is to obtain with high yield.In addition, compare with ordinary method, the gained title compound need not to carry out purifying with chromatography.
Embodiment 18
Figure A0382589700901
1-[4-(4-tetramethyleneimine-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines
K i＝2.0nM
With the mixture of 1: 1 ethanol/water (6mL) of product (199mg), tetramethyleneimine (0.084mL) and the salt of wormwood (69mg) of embodiment 13 80 ℃ of heating 16 hours.Make the gained mixture be cooled to room temperature, DCM (2 * 100mL) extractions are used in water (10mL) dilution then.The organic phase that merges is washed with (20mL) and salt solution (20mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0-5%2M methanol ammonium hydroxide/DCM), obtain light yellow oily title compound (60mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.33(d，J＝8.1Hz，2H)，7.23(d，J＝8.1Hz，2H)，3.44(s，2H)，2.78-2.73(m，2H)，2.64-2.57(m，6H)，2.35(br?s，4H)，1.82-1.78(m，4H)，1.59-1.53(m，4H)，1.45-1.40(m，2H).
Embodiment 19
Figure A0382589700911
Diethyl-[4-(4-piperidines-1-ylmethyl-phenyl)-Ding-3-alkynyl]-amine
K i＝2.4nM
With the mixture of 1: 1 ethanol/water (6mL) of product (199mg), diethylamine (0.104mL) and the salt of wormwood (69mg) of embodiment 13 80 ℃ of heating 16 hours.Make the gained mixture be cooled to room temperature, DCM (2 * 100mL) extractions are used in water (10mL) dilution then.Organic phase water (20mL) that merges and salt solution (20mL) washing, dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0-5%2M methanol ammonium hydroxide/DCM), obtain light yellow oily title compound (21mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.33(d，J＝8.0Hz，2H)，7.23(d，J＝8.0Hz，2H)，3.44(s，2H)，2.81-2.73(m，2H)，2.64-2.51(m，6H)，2.35(bs，4H)，1.82-1.78(m，3H)，1.59-1.53(m，4H)，1.44-1.39(m，2H)，1.07(t，J＝7.2Hz，3H).
Embodiment 20
Figure A0382589700912
4-[4-(4-piperidines-1-ylmethyl-phenyl)-Ding-3-alkynyl]-thiomorpholine
K i＝6.0nM
The mixture of 1: 1 ethanol/water (6mL) of the product of embodiment 13 (199mg), thiomorpholine (0.062mL) and salt of wormwood (69mg) was 80 ℃ of heating 16 hours.Make the gained mixture be cooled to room temperature, DCM (2 * 100mL) extractions are used in water (10mL) dilution then.Organic phase water (20mL) that merges and salt solution (20mL) washing, dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0-5%2M methanol ammonium hydroxide/DCM), obtain light yellow oily title compound (27mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.32(d，J＝8.0Hz，2H)，7.23(d，J＝8.1Hz，2H)，3.44(s，2H)，2.83-2.80(m，4H)，2.74-2.68(m，6H)，2.59-2.55(m，2H)，2.35(br?s，4H)，1.59-1.53(m，4H)，1.44-1.39(m，2H).
Embodiment 21
Figure A0382589700921
4-[4-(4-piperidines-1-ylmethyl-phenyl)-Ding-3-alkynyl]-morpholine
K i＝15nM
With the mixture of 1: 1 ethanol/water (6mL) of product (199mg), morpholine (0.052mL) and the salt of wormwood (69mg) of embodiment 13 80 ℃ of heating 16 hours.Make the gained mixture be cooled to room temperature, water (10mL) dilutes and (2 * 100mL) extract with DCM.Organic phase water (20mL) that merges and salt solution (20mL) washing, dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0-5%2M methanol ammonium hydroxide/DCM), obtain light yellow oily title compound (40mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.32(d，J＝8.1Hz，2H)，7.23(d，J＝8.0Hz，2H)，3.73(t，J＝4.6Hz，4H)，3.44(s，2H)，2.72-2.58(m，4H)，2.54(t，J＝4.5Hz，4H)，2.35(br?s，4H)，1.59-1.53(m，4H)，1.44-1.40(m，2H).
Embodiment 22
1-methyl-4-[4-(4-piperidines-1-ylmethyl-phenyl)-Ding-3-alkynyl]-piperazine
K i＝21nM
With the mixture of 1: 1 ethanol/water (6mL) of product (199mg), 1-methylpiperazine (0.067mL) and the salt of wormwood (69mg) of embodiment 13 80 ℃ of heating 16 hours.Reaction mixture is cooled to room temperature.Add entry (10mL), (2 * 100mL) extract this mixture with DCM then.Organic phase water (20mL) that merges and salt solution (20mL) washing, dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0-5%2M methanol ammonium hydroxide/DCM), obtain the white solid (13mg) of title compound with chromatography.
1H?NMR(400MHz，CDCl 3)：7.32(d，J＝8.1Hz，2H)，7.23(d，J＝8.1Hz，2H)，3.44(s，2H)，2.71-2.46(m，12H)，2.35(br?s，4H)，2.30(s，3H)，1.59-1.53(m，4H)，1.45-1.38(m，2H).
Embodiment 23
1-[4-(4-tetramethyleneimine-1-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines
K i＝1.4nM
At room temperature, DCM (2mL) solution of product (241mg), tetramethyleneimine (0.125mL) and the acetate (0.067mL) of embodiment 12 is handled with sodium triacetoxy borohydride (318mg).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).(2 * 100mL) extract water with DCM.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0.5-5.5%2M methanol ammonium hydroxide/DCM), obtain colorless oil title compound (73mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.34(d，J＝8.0Hz，2H)，7.24(d，J＝8.0Hz，2H)，3.58(s，2H)，2.68-2.57(m，4H)，2.50-2.45(m，8H)，1.79-1.76(m，4H)，1.63-1.57(m，4H)，1.47-1.41(m，2H).
Embodiment 24
Figure A0382589700941
4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine
K i＝5.5nM
At room temperature, DCM (2mL) solution of product (241mg), morpholine (0.131mL) and the acetate (0.067mL) of embodiment 12 is handled with sodium triacetoxy borohydride (318mg).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).(2 * 100mL) extract water with DCM.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0.5-5.5%2M methanol ammonium hydroxide/DCM), obtain yellow oily title compound (53mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.34(d，J＝8.2Hz，2H)，7.24(d，J＝8.2Hz，2H)，3.70(t，J＝4.6Hz，4H)，3.47(s，2H)，2.68-2.57(m，4H)，2.50-2.41(m，8H)，1.63-1.57(m，4H)，1.48-1.42(m，2H).
Embodiment 25
Diethyl-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine
K i＝1.1nM
At room temperature, DCM (2mL) solution of product (241mg), diethylamine (0.155mL) and the acetate (0.067mL) of embodiment 12 is handled with sodium triacetoxy borohydride (318mg).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).(2 * 100mL) extract water with DCM.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0.5-5.5%2M methanol ammonium hydroxide/DCM), obtain colorless oil title compound (61mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.33(d，J＝8.1Hz，2H)，7.24(d，J＝8.0Hz，2H)，3.53(s，2H)，2.68-2.57(m，4H)，2.52-2.45(m，8H)，1.63-1.57(m，4H)，1.47-1.41(m，2H)，1.02(t，J＝7.1Hz，6H).
Embodiment 26
Figure A0382589700951
1-{4-[4-(4-benzyl-piperidines-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-piperidines
K i＝2.9nM
At room temperature, DCM (2mL) solution of product (241mg), 4-benzyl piepridine (0.264mL) and the acetate (0.067mL) of embodiment 12 is handled with sodium triacetoxy borohydride (318mg).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).(2 * 100mL) extract water with DCM.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0.5-5.5%2M methanol ammonium hydroxide/DCM), obtain the white solid (80mg) of title compound with chromatography.
1H?NMR(400MHz，CDCl 3)：7.32(d，J＝8.0Hz，2H)，7.28-7.15(m，5H)，7.12(d，J＝7.1Hz，2H)，3.43(s，2H)，2.83-2.80(d，J＝11.5Hz，2H)，2.68-2.56(m，4H)，2.52(d，7.0Hz，2H)，2.46(br?s，4H)，1.87(t，J＝9.9Hz，2H)，1.62-1.57(m，6H)，1.53-1.41(m，3H)，1.34-1.24(m，2H)
Embodiment 27
1-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-alcohol
K i＝1.7nM
At room temperature, DCM (2mL) solution of product (241mg), 4-hydroxy piperidine (152mg) and the acetate (0.067mL) of embodiment 12 is handled with sodium triacetoxy borohydride (318mg).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).(2 * 100mL) extract water with DCM.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0.5-5.5%2M methanol ammonium hydroxide/DCM), obtain colorless oil title compound (60mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.34(d，J＝8.0Hz，2H)，7.22(d，J＝8.0Hz，2H)，3.72-3.65(m，1H)，3.47(s，2H)，2.75-2.57(m，6H)，2.47(br?s，4H)，2.13(t，J＝9.6Hz，2H)，1.90-1.84(m，2H)，1.63-1.53(m，5H)，1.47-1.41(m，3H).
Embodiment 28
Figure A0382589700962
2-{1-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-2-yl }-ethanol
K i＝0.4nM
At room temperature, DCM (2mL) solution of product (241mg), 2-piperidines ethanol (194mg) and the acetate (0.067mL) of embodiment 12 is handled with sodium triacetoxy borohydride (318mg).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).(2 * 100mL) extract water with DCM.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0.5-5.5%2M methanol ammonium hydroxide/DCM), obtain colorless oil title compound (9mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.34(d，J＝8.1Hz，2H)，7.22(d，J＝8.0Hz，2H)，4.15(d，J＝13.1Hz，1H)，3.95-3.90(m，1H)，3.77-3.71(m，1H)，3.43(d，J＝13.0Hz，1H)，2.96-2.90(m，1H)，2.74-2.57(m，7H)，2.47(br?s，5H)，2.20-2.12(m，1H)，1.97-1.25(m，11H)
Embodiment 29
Figure A0382589700971
1-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-decahydro-quinoline
K i＝0.8nM
At room temperature, DCM (2mL) solution of product (241mg), decahydroquinoline (0.224mL) and the acetate (0.067mL) of embodiment 12 is handled with sodium triacetoxy borohydride (318mg).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).(2 * 100mL) extract water with DCM.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0.5-5.5%2M methanol ammonium hydroxide/DCM), obtain colorless oil title compound (29mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.32(d，J＝8.0Hz，2H)，7.21(d，J＝8.0Hz，2H)，4.03(d，J＝13.7Hz，1H)，3.19(d，J＝13.7Hz，1H)，2.77(d，J＝11.1Hz，1H)，2.68-2.57(m，5H)，2.47(br?s，5H)，2.23-2.18(m，1H)，1.95-0.83(m，18H).
Embodiment 30
Figure A0382589700981
1-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-methane amide
K i＝1.6nM
At room temperature, DCM (2mL) solution of product (241mg), 4-piperidyl urea (192mg) and the acetate (0.067mL) of embodiment 12 is handled with sodium triacetoxy borohydride (318mg).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).(2 * 100mL) extract water with DCM.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0.5-5.5%2M methanol ammonium hydroxide/DCM), obtain the white solid (87mg) of title compound with chromatography.
1H?NMR(400MHz，CDCl 3)：7.33(d，J＝8.0Hz，2H)，7.23(d，J＝8.0Hz，2H)，3.94(s，2H)，3.49(s，2H)，2.67-2.57(m，4H)，2.51-2.45(m，8H)，1.77-1.71(m，5H)，1.63-1.57(m，4H)，1.47-1.42(m，2H).
Embodiment 31
8-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-1,4-two oxa-s-8-azepine-spiral shell [4.5] decane
K i＝1.8nM
At room temperature, with the product (241mg), 1 of embodiment 12, DCM (2mL) solution of 4-two oxa-s-8-azepine-spiral shell [4.5] decane (0.192mL) and acetate (0.067mL) is handled with sodium triacetoxy borohydride (318mg).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).(2 * 100mL) extract water with DCM.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0.5-5.5%2M methanol ammonium hydroxide/DCM), obtain colorless oil title compound (108mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.33(d，J＝8.1Hz，2H)，7.22(d，J＝8.1Hz，2H)，5.45(br?s，1H)，5.31(br?s，1H)，3.46(s，2H)，2.92-2.87(m，2H)，2.68-2.57(m，4H)，2.47(br?s，4H)，2.19-2.11(m，1H)，2.02-1.95(m，2H)，1.87-1.83(m，2H)，1.79-1.57(m，7H)，1.47-1.41(m，2H).
Embodiment 32
Figure A0382589700991
1-methyl-4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine
K i＝0.7nM
At room temperature, DCM (2mL) solution of product (241mg), 1-methylpiperazine (0.166mL) and the acetate (0.067mL) of embodiment 12 is handled with sodium triacetoxy borohydride (318mg).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).(2 * 100mL) extract water with DCM.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0.5-5.5%2M methanol ammonium hydroxide/DCM), obtain colorless oil title compound (65mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.33(d，J＝8.2Hz，2H)，7.23(d，J＝8.2Hz，2H)，3.47(s，2H)，2.68-2.57(m，4H)，2.47(br?s，12H)，2.28(s，3H)，1.62-1.57(m，4H)，1.47-1.41(m，2H).
Embodiment 33
Figure A0382589701001
Cyclohexyl-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine
K i＝0.5nM
At room temperature, DCM (2mL) solution of product (241mg), hexahydroaniline (0.172mL) and the acetate (0.067mL) of embodiment 12 is handled with sodium triacetoxy borohydride (318mg).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).(2 * 100mL) extract water with DCM.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0.5-5.5%2M methanol ammonium hydroxide/DCM), obtain colorless oil title compound (95mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.34(d，J＝8.0Hz，2H)，7.23(d，J＝8.0Hz，2H)，3.79(s，2H)，2.68-2.57(m，4H)，2.49-2.40(m，5H)，1.92-1.86(m，2H)，1.76-1.69(m，2H)，1.62-1.54(m，4H)，1.47-1.41(m，2H)，1.29-1.05(m，6H).
Embodiment 34
Indane-1-base-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine
K i＝1.3nM
At room temperature, DCM (2mL) solution of product (241mg), 1-aminoidan (0.192mL) and the acetate (0.067mL) of embodiment 12 is handled with sodium triacetoxy borohydride (318mg).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).(2 * 100mL) extract water with DCM.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0.5-5.5%2M methanol ammonium hydroxide/DCM), obtain colorless oil title compound (118mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.37-7.28(m，8H)，4.27(t，6.6Hz，1H)，3.88(d，5.6Hz，2H)，3.05-2.97(m，1H)，2.85-2.77(m，1H)，2.68-2.57(m，4H)，2.49-2.57(m，5H)，1.90-1.82(m，1H)，1.63-1.57(m，4H)，1.47-1.41(m，2H).
Embodiment 35
1-phenyl-4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine
K i＝7.0nM
At room temperature, DCM (2mL) solution of product (241mg), 1-phenylpiperazine (0.229mL) and the acetate (0.067mL) of embodiment 12 is handled with sodium triacetoxy borohydride (318mg).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).(2 * 100mL) extract water with DCM.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0.5-5.5%2M methanol ammonium hydroxide/DCM), obtain colorless oil title compound (38mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.17(d，J＝8.0Hz，2H)，7.09-7.05(m，4H)，6.74(d，J＝8.2Hz，2H)，6.67(t，J＝7.4Hz，1H)，3.36(s，2H)，3.01(t，4.9Hz，4H)，2.50-2.39(m，8H)，2.29(br?s，4H)，1.45-1.37(m，4H)，1.30-1.23(m，2H).
Embodiment 36
Figure A0382589701021
1-benzyl-4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine
K i＝9.0nM
At room temperature, DCM (2mL) solution of product (241mg), 1-benzyl diethylenediamine (0.261mL) and the acetate (0.067mL) of embodiment 12 is handled with sodium triacetoxy borohydride (318mg).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).(2 * 100mL) extract water with DCM.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0.5-5.5%2M methanol ammonium hydroxide/DCM), obtain colorless oil title compound (136mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.38-7.21(m，9H)，3.51(s，2H)，3.48(s，2H)，2.68-2.56(m，4H)，2.46(br?s，10H)，1.62-1.56(m，6H)，1.47-1.42(m，2H).
Embodiment 37
4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine-1-t-butyl formate
K i＝15nM
At room temperature, DCM (2mL) solution of product (241mg), the 1-piperazinecarboxylic acid tert-butyl ester (559mg) and the acetate (0.067mL) of embodiment 12 is handled with sodium triacetoxy borohydride (318mg).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).(2 * 100mL) extract water with DCM.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0.5-5.5%2M methanol ammonium hydroxide/DCM), obtain the white solid (218mg) of title compound with chromatography.
1H?NMR(400MHz，CDCl 3)：7.34(d，J＝8.1Hz，2H)，7.23(d，J＝8.0Hz，2H)，3.48(s，2H)，3.43-3.40(m，4H)，2.68-2.57(m，4H)，2.47(br?s，4H)，2.36(br?s，4H)，1.64-1.57(m，6H)，1.45(s，9H).
Embodiment 38
1-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine
K i＝1.3nM
At room temperature, with 1 of the product (184mg) of embodiment 37,4-diox (7mL) solution is with 1 of 4N HCl, and the 4-diox was handled 16 hours.Evaporating solvent, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).Water is with the DCM of 10% methyl alcohol (2 * 100mL) extractions.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (1-6%2M methanol ammonium hydroxide/DCM), obtain the white solid (97mg) of title compound with chromatography.
1H?NMR(400MHz，CDCl 3)：7.34(d，J＝8.0Hz，2H)，7.23(d，J＝8.0Hz，2H)，3.47(s，2H)，2.91(t，J＝4.8Hz，4H)，2.69-2.58(m，4H)，2.48-2.43(m，8H)，1.64-1.58(m，4H)，1.47-1.41(m，2H).
Embodiment 39
Figure A0382589701041
1-sec.-propyl-4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine
K i＝1.3nM
At room temperature, DCM (3mL) solution of product (74mg), acetone (5mL) and the acetate (0.014mL) of embodiment 38 is handled with sodium triacetoxy borohydride (67mg).After 16 hours, the gained mixture is handled with 10% aqueous sodium hydroxide solution (10mL).(2 * 100mL) extract water with DCM.The organic phase that merges is washed with salt solution (50mL), dry (sal epsom) and concentrating under reduced pressure.Resistates carries out purifying (0.5-5.5%2M methanol ammonium hydroxide/DCM), obtain colorless oil title compound (65mg) with chromatography.
1H?NMR(400MHz，CDCl 3)：7.33(d，J＝8.0Hz，2H)，7.23(d，J＝8.1Hz，2H)，3.48(s，2H)，2.68-2.47(m，16H)，1.66(br?s，1H)，1.63-1.57(m，4H)，1.48-1.41(m，2H)，1.04(d，J＝6.5Hz，2H).
Embodiment 40
Figure A0382589701042
1-phenyl-8-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone
K i＝2.0nM
According to the method that is similar to embodiment 15, with 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone prepares.
1H?NMR(400MHz，CDCl 3)：7.41(s，1H)，7.32-7.21(m，5H)，6.94-6.85(m，2H)，4.73(s，2H)，3.54(s，2H)，2.84-2.58(m，10H)，2.47(bs，4H)，1.65(d，23.2Hz，2H)，1.62-1.58(m，4H)，1.47-1.43(m，2H).
Embodiment 41
1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-3-formic acid diethylamide
K i＝3.0nM
According to the method that is similar to embodiment 15, prepare with piperidines-3-formic acid diethylamide.
1H?NMR(400MHz，CDCl 3)：7.36(s，1H)，7.28-7.21(m，3H)，3.46(s，2H)，3.38-3.25(m，4H)，2.87-2.81(m，2H)，2.75-2.57(m，5H)，2.46-2.42(m，4H)，2.19(t，J＝11.1Hz，1H)，1.99-1.94(m，1H)，1.77-1.42(m，10H)，3.94(t，J＝7.1Hz，3H)，1.07(t，J＝7.1Hz，3H).
Embodiment 42
Figure A0382589701052
1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-1,2,3,4,5,6-six hydrogen-[2,3 '] dipyridyl
K i＝11nM
According to the method that is similar to embodiment 15, with 1,2,3,4,5,6-six hydrogen-[2,3 '] dipyridyl prepares.
1H?NMR(400MHz，CDCl 3)：8.64(d，J＝2.6Hz，1H)，8.50-8.48(m，1H)，7.80(d，J＝7.9Hz，1H)，7.81-7.12(m，5H)，3.64(d，J＝13.5Hz，1H)，3.17-3.13(m，1H)，2.94(d，J＝11.4Hz，1H)，2.79(d，J＝13.6Hz，1H)，2.60-2.58(m，4H)，2.47(bs，4H)，1.96-1.90(m，1H)，1.82-1.75(m，2H)，1.66-1.39(m，10H).
Embodiment 43
Figure A0382589701061
1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-4-(3-trifluoromethyl-phenyl)-piperazine
K i＝91nM
According to the method that is similar to embodiment 15, prepare with 1-(3-trifluoromethyl-phenyl)-piperazine.
1H?NMR(400MHz，CDCl 3)：7.39(s，1H)，7.35-7.22(m，4H)，7.10-7.03(m，3H)，3.52(s，2H)，3.24(t，J＝5.0Hz，4H)，2.69-2.58(m，8H)，2.47(bs，4H)，1.63-1.58(m，4H)，1.47-1.42(m，2H).
Embodiment 44
Figure A0382589701062
2-{4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine-1-yl }-pyrimidine
K i＝9.0nM
According to the method that is similar to embodiment 15, prepare with 2-piperazine-1-base-pyrimidine.
1HNMR(400MHz，CDCl 3)：8.29(d，J＝4.7Hz，2H)，7.39(s，1H)，7.31-7.22(m，3H)，6.48(t，J＝4.8Hz，1H)，3.82(t，J＝5.1Hz，4H)，3.50(s，2H)，2.68-2.58(m，4H)，2.50-2.47(m，8H)，1.72-1.57(m，4H)，1.47-1.41(m，2H).
Embodiment 45
Figure A0382589701071
1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-methane amide
K i＝2.0nM
According to the method that is similar to embodiment 15, prepare with piperidines-4-methane amide.
1H?NMR(400MHz，CDCl 3)：8.29(s，1H)，7.40(s，1H)，7.31-7.23(m，3H)，4.38-4.31(m，1H)，3.52(S，2H)，3.02(d，2H)，2.70-2.55(m，4H)，2.48-2.42(m，8H)，2.19-2.13(m，2H)，1.81-1.78(m，2H)1.63-1.60(m，2H)，1.46-1.45(m，2H).
Embodiment 46
Figure A0382589701072
Methyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-(2-pyridine-2-base-ethyl)-amine
K i＝4.0nM
According to the method that is similar to embodiment 15, prepare with methyl-(2-pyridine-2-base-ethyl)-amine.
1H?NMR(400MHz，CDCl 3)：8.53-8.51(m，1H)，7.61-7.56(m，1H)，7.30-7.09(m，6H)，3.51(s，2H)，3.02-2.98(m，2H)，2.82-2.78(m，2H)，2.88-2.57(m，4H)，2.47(bs，4H)，2.26(s，3H)，1.63-1.57(m，4H)，1.47-1.42(m，2H).
Embodiment 47
Figure A0382589701081
[2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine
K i＝3.0nM
According to the method that is similar to embodiment 15, prepare with [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine.
1H?NMR(400MHz，CDCl 3)：7.36(s，1H)，7.29-7.20(m，3H)，6.80-6.71(m，3H)，3.86(s，6H)，3.51(s，2H)，2.78-2.75(m，2H)，2.68-2.57(m，6H)，2.46(bs，4H)，2.26(s，3H)，1.63-1.59(m，4H)，1.47-1.44(m，2H).
Embodiment 48
Figure A0382589701082
4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-thiomorpholine
K i＝1.0nM
Method according to being similar to embodiment 15 prepares with thiomorpholine.
1H?NMR(400MHz，CDCl 3)：7.34(s，1H)，7.29-7.20(m，3H)，3.46(s，2H)，2.69-2.57(m，12H)，2.47(s，4H)，1.63-1.57(m，4H)，1.47-1.42(m，2H).
Embodiment 49
Figure A0382589701091
Allyl group-cyclopentyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine
K i＝2.0nM
According to the method that is similar to embodiment 15, prepare with allyl group-cyclopentyl-amine.
1H?NMR(400MHz，CDCl 3)：7.37(s，1H)，7.26-7.18(m，3H)，5.94-5.84(m，1H)，5.16-5.09(m，2H)，3.57(s，2H)，3.13-3.07(m，3H)，2.69-2.57(m，4H)，2.47(bs，4H)，1.81-1.75(m，2H)，1.67-1.43(m，12H).
Embodiment 50
Figure A0382589701092
10-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-1,4,7-trioxa-10-azepine-cyclododecane
K i＝2.0nM
According to the method that is similar to embodiment 15, with 1,4,7-trioxa-10-azepine-cyclododecane prepares.
1H?NMR(400MHz，CDCl 3)：7.38(s，1H)，7.30-7.19(m，3H)，3.72-2.69(m，8H)，3.64-3.62(m，6H)，2.74(t，J＝4.9Hz，4H)，2.68-2.58(m，4H)，2.47(bs，4H)，1.63-1.57(m，4H)，1.47-1.43(m，2H).
Embodiment 51
Figure A0382589701101
1-[4-(3-thiazolidine-3-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines
K i＝1.0nM
Method according to being similar to embodiment 15 prepares with thiazolidine.
1H?NMR(400MHz，CDCl 3)：7.41(s，1H)，7.32-7.23(m，3H)，4.05(s，2H)，3.51(s，2H)，3.09(t，J＝6.3Hz，2H)，2.95(t，J＝6.4Hz，2H)，2.68-2.58(m，4H)，2.47(bs，4H)，1.63-1.58(m，4H)，1.47-1.43(m，2H).
Embodiment 52
[2-(1H-indol-3-yl)-ethyl]-methyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine
K i＝2.0nM
According to the method that is similar to embodiment 15, prepare with [2-(1H-indol-3-yl)-ethyl]-methyl-amine.
1H?NMR(400MHz，CDCl 3)：8.11(s，1H)，7.55(d，1H)，7.36-7.01(m，8H)，3.54(s，2H)，3.00-2.96(m，2H)，2.75-2.58(m，6H)，2.48(bs，4H)，2.32(s，3H)，1.63-1.59(m，4H)，1.47-1.43(m，2H).
Embodiment 53
1-{1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidin-4-yl }-1,3-dihydro-benzimidazolyl-2 radicals-ketone
K i＝1.0nM
According to the method that is similar to embodiment 15, with 1-piperidin-4-yl-1,3-dihydro-benzimidazolyl-2 radicals-ketone prepares.
1H?NMR(400MHz，CDCl 3)：7.35(s，1H)，7.29-7.21(m，3H)，5.41(d，30.1Hz，2H)，3.45(s，2H)，2.90(d，J＝11.7Hz，2H)，2.68-2.57(m，4H)，2.68-2.57(m，4H)，2.47(bs，4H)，2.19-2.11(m，1H)，2.02-1.96(m，2H)，1.88-1.63(m，4H)，1.62-1.57(m，4H)，1.47-1.42(m，2H).
Embodiment 54
Figure A0382589701112
Phenyl-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine
K i＝110nM
Method according to being similar to embodiment 15 prepares with aniline.
1H?NMR(400MHz，CDCl 3)：7.41(s，1H)，7.40-7.24(m，3H)，7.19-7.15(m，2H)，6.72(t，J＝7.3Hz，1H)，6.63-6.81(m，2H)，4.29(d，J＝5.2Hz，2H)，4.03(bs，1H)，2.68-2.57(m，4H)，2.46(bs，4H)，2.18(s，1H)，1.62-1.57(m，4H)，1.47-1.44(m，2H).
Embodiment 55
Figure A0382589701121
1-[4-(3-tetramethyleneimine-1-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines
K i＝1.0nM
Method according to being similar to embodiment 15 prepares with tetramethyleneimine.
1H?NMR(400MHz，CDCl 3)：7.37(s，1H)，7.28-7.22(m，3H)，3.56(s，2H)，2.68-2.57(m，4H)，2.51-2.46(m，8H)，1.79-1.76(m，4H)，1.70-1.57(m，4H)，1.47-1.43(m，2H).
Embodiment 56
1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-the nitrogen heterocyclic tridecane
K i＝13nM
According to the method that is similar to embodiment 15, prepare with the nitrogen heterocyclic tridecane.
1H?NMR(400MHz，CDCl 3)：7.37(s，1H)，7.28-7.19(m，3H)，3.43(s，2H)，2.50(bs，4H)，2.36-2.33(m，8H)，1.65-1.38(m，26H).
Embodiment 57
Figure A0382589701131
Dimethyl-[4-(4-piperidines-1-ylmethyl-phenyl)-Ding-3-alkynyl]-amine
Can prepare with dimethylamine hydrochloride according to the method that is similar to embodiment 19.
Embodiment 58
Figure A0382589701132
Dimethyl-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine
Can prepare with dimethylamine hydrochloride according to the method that is similar to embodiment 23.
Embodiment 59
Figure A0382589701133
Phenyl-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-amine
Can prepare with aniline according to the method that is similar to embodiment 23.
Embodiment 60
Figure A0382589701134
1-[4-(3-aziridine-1-ylmethyl-phenyl)-Ding-3-alkynyl]-piperidines
Can prepare with the aziridine hydrochloride according to the method that is similar to embodiment 15.
Embodiment 61
Figure A0382589701141
2-{1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidin-4-yl oxygen base }-pyrimidine
Can prepare with 2-(piperidin-4-yl oxygen base)-pyrimidine according to the method that is similar to embodiment 15.
Embodiment 62
Figure A0382589701142
1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidin-4-yl }-pyridine-2-base-amine
Can prepare with piperidin-4-yl-pyridine-2-base amine according to the method that is similar to embodiment 15.
Embodiment 63
Figure A0382589701143
4-[4-(3-morpholine-4-ylmethyl-phenyl)-Ding-3-alkynyl]-morpholine
Can be according to the method that is similar to embodiment 15, prepare with product and the morpholine of embodiment 10.
Embodiment 64
4-[3-(4-thiomorpholine-4-Ji-Ding-1-alkynyl)-benzyl]-morpholine
Can be according to the method that is similar to embodiment 15, prepare with product and the morpholine of embodiment 11.
Embodiment 65
Figure A0382589701152
4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-thiomorpholine
Can prepare with thiomorpholine according to the method that is similar to embodiment 15.
Embodiment 66
Figure A0382589701153
4-[4-(3-thiomorpholine-4-ylmethyl-phenyl)-Ding-3-alkynyl]-morpholine
Can be according to the method that is similar to embodiment 15, prepare with product and the thiomorpholine of embodiment 10.
Embodiment 67
Figure A0382589701161
4-[3-(4-thiomorpholine-4-Ji-Ding-1-alkynyl)-benzyl]-thiomorpholine
Can be according to the method that is similar to embodiment 15, prepare with product and the thiomorpholine of embodiment 11.
Embodiment 68
Figure A0382589701162
4-{4-[3-(4-methyl-piperazine-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-morpholine
Can be according to the method that is similar to embodiment 15, prepare with product and the 1-methylpiperazine of embodiment 10.
Embodiment 69
Figure A0382589701163
4-{4-[3-(4-methyl-piperazine-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-thiomorpholine
Can be according to the method that is similar to embodiment 15, prepare with product and the 1-methylpiperazine of embodiment 11.
Embodiment 70
Figure A0382589701171
1-methyl-4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperazine
Can prepare with the 1-methylpiperazine according to the method that is similar to embodiment 15.
Embodiment 71
Figure A0382589701172
1-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-alcohol
Can prepare with piperidines-4-alcohol according to the method that is similar to embodiment 15.
Embodiment 72
Figure A0382589701173
1-[3-(4-morpholine-4-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-alcohol
Can be according to the method that is similar to embodiment 15, prepare with product and the piperidines-4-alcohol of embodiment 10.
Embodiment 73
1-[3-(4-thiomorpholine-4-Ji-Ding-1-alkynyl)-benzyl]-piperidines-4-alcohol
Can be according to the method that is similar to embodiment 15, prepare with product and the piperidines-4-alcohol of embodiment 11.
Embodiment 74
Figure A0382589701182
1-{4-[3-(4-methoxyl group-piperidines-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-piperidines
Can prepare with 4-methoxyl group piperidines according to the method that is similar to embodiment 15.
Embodiment 75
Figure A0382589701183
4-{4-[3-(4-methoxyl group-piperidines-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-morpholine
Can be according to the method that is similar to embodiment 15, prepare with product and the 4-methoxyl group piperidines of embodiment 10.
Embodiment 76
Figure A0382589701191
4-{4-[3-(4-methoxyl group-piperidines-1-ylmethyl)-phenyl]-Ding-3-alkynyl }-thiomorpholine
Can be according to the method that is similar to embodiment 15, prepare with product and the 4-methoxyl group piperidines of embodiment 11.
Embodiment 77
Biological method
In vitro method
Personnel selection Histamine Receptors transfectional cell
In transfection preceding 2 days, the 10cm tissue culture ware that covers with individual layer SK-N-MC cell is carried out the branch kind.Remove substratum with Aseptic technique, cell is separated from culture dish by adding trypsinase.Then with on 1/5 cell inoculation to the new 10cm culture dish.Cell is at 5%CO 2In 37 ℃ of incubators, in the MEM Eagle that adds 10% foetal calf serum, grow.After 2 days, cell covers with 80% approximately.With trypsinase it is separated from culture dish, centrifugal on clinical centrifuge.Then with pellet resuspended in 400 μ L perfect mediums, be transferred in the electroporation sulculus, the 0.4cm spacing is arranged between electrode wherein.In cell, add 1 microgram superhelix H 3Receptor cdna also mixes.The voltage of electroporation is arranged on 0.25kV, and electric capacity is arranged on 960 μ F.Behind the electroporation, cell dilution in the 10mL perfect medium, is inoculated in 4 10cm culture dish then.Because the difference of electroporation efficiency, so inoculate the cell of 4 kinds of different concns.Used ratio is 1: 20,1: 10,1: 5, and all the other cells join in the 4th culture dish.Allow cellular-restoring 24 hours, the substratum that brings Selection In then (perfect medium that contains 600 μ g/mL G418).After 10 days, analyze survivaling cell colony in the culture dish.Adopt band foraminous culture dish to separate colony.Separation detects then from the cell of single colony.Adopt the SK-N-MC cell, effective coupling of adenylate cyclase because they can be inhibited.In the response histamine, clone that can strongly inhibited adenylate cyclase is used for further research.
[ 3H]-combination of N-methylhistamine
To express histamine H 3Cell precipitation homogenate in 20mMTrisHCl/0.5mM EDTA of the SK-N-MC cell of acceptor.Collection is with 800g centrifugal supernatant liquor, again with 30, and centrifugal 30 minutes of 000g.Be deposited in homogenate again among the 50mM Tris/5mM EDTA (pH7.4).With film and 0.8nM[ 3H]-the N-methylhistamine+/-test compound hatched 45 minutes at 25 ℃, gathered in the crops by going up to filter fast at GF/C glass fibre filter (with 0.3% polymine pre-treatment) then, then wash 4 times with ice-cold damping fluid.With the filter membrane drying, join in the 4mL scintillation mixed solution, on liquid scintillation counter, count then.Determine non-specific binding with 10 μ M histamine.K according to 800pM dLigand concentration ([L]) with 800pM according to following formula, calculates pK iValue:
K i＝(IC 50)/(1+([L]/(K d))
Method in the body
Set forth rat H 3The oral absorption of receptor antagonist and hemato encephalic barrier Penetration Signature.
Behind the heavy dose of oral administration of single, detect hemato encephalic barrier Penetration Signature and various H with system in the rat body 3The kinetics of receptor antagonist.
According to the female Sprague Dawley of established feeding standard rat (the about 300g of body weight), and before test, allow it adapt at least 7 days.Every kind of H 3Antagonist all is formulated in 0.5% Vltra tears, and concentration is 1mg/mL, is used for oral administration.Press the single oral dose of 10mL/kg (10mg/kg), with test compound give in 8 animals each only.Keeping the residue soup is used for analyzing.At t=1 hour, 6 hours, 24 hours and 48 hours, 2 in every group of initial 8 animals were passed through CO 2Anesthesia suffocates.After every Animal Anesthesia, gather the 0.1mL blood sample, and take out its cerebral tissue, be placed on the preweighted 50mL tapered tube that places dry ice by opening cranium by cardiac puncture.
Blood is joined in 0.3mL 6% trichoroacetic acid(TCA), with the acidified sample vortex mixed, centrifugal then (in Eppendorf centrifuge with 14, centrifugal 5 minutes of 000rpm).Keeping clarifying supernatant liquor uses for analyzing.The refrigerated cerebral tissue is weighed, homogenate in 6% trichoroacetic acid(TCA) (3mL/g organizes (weight in wet base)), centrifugal then.Keeping clarifying supernatant liquor uses for analyzing.By the liquid chromatography and the use selective reaction monitoring (LC-MS/MS) of band mass detector, analyze supernatant liquor from blood sample and brain tissue sample.This LC method adopts Phenomonex Polar RP post (2 * 50mm) and the water and the acetonitrile (being 1% acetic acid solution) of linear solvent gradient.
According to the result of LC-MS/MS, draw the H of blood and brain 3The graphic representation of receptor antagonist agent concentration and time.Ratio according to area (AUC) under the first factor area under curve (AUMC) and the Cot curve is AUMC/AUC, calculates H 3The average retention time (MRT) of receptor antagonist in blood or brain.According to AUC Brain/ AUC BloodLogarithmic value, calculate the hemato encephalic barrier index.
F. other embodiment
Relevant discussion, embodiment, embodiment and claims according to the present invention, concerning those of ordinary skill, feature of the present invention and advantage will be conspicuous.The present invention also comprises variation and the modification based on key feature of the present invention that relates in the disclosure text and advantage, and all in the limit of power of those of ordinary skill.

Claims (109)

1. method for preparing following formula (I) compound and the acceptable salt of medicine, ester or acid amides:
Figure A038258970002C1
Wherein n is the integer of 0-1;
R 1And R 2Independently be selected from C 1-3Alkyl, allyl group and C 3-8Cycloalkyl, perhaps the nitrogen that is connected with them combines, and they form optional 2 the first heterocyclic radicals of extra heteroatomic non-aromatics 4-7 that independently are selected from O, S and N at the most that comprise;
R 3, R 4And R 5One of be G, one in all the other two is hydrogen, and another is selected from hydrogen, fluorine and chlorine;
G is L 2Q;
L 2Be methylene radical;
Q is NR 8R 9, R wherein 8Independently be selected from hydrogen, C 1-6Alkyl, C 3-6Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 1-6Alkylidene group and (phenyl) C 1-6Alkylidene group; R 9Independently be selected from C 1-6Alkyl, C 3-6Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 1-6Alkylidene group and (phenyl) C 1-6Alkylidene group;
Or
Q is the heterocyclic radical that the saturated N of 3-13 unit connects, and wherein, except that N connected nitrogen, 3-13 unit heterocyclic radical also can be chosen wantonly and contain 1-3 extra heteroatoms that independently is selected from O, S and N;
Each abovementioned alkyl, alkylidene group, thiazolinyl, heterocyclic radical, cycloalkyl, carbocylic radical and aryl can independently separately and optional independently be selected from following substituting group replacement by 1-3 in its Chinese style (I): methoxyl group, halogen, amino, nitro, hydroxyl and C 1-3Alkyl;
Wherein the 1-3 of a Q substituting group also can further independently be selected from tert-butoxycarbonyl, formamido-, C except the paragraph of front 1-6Alkyl, 5-9 unit heterocyclic radical, N (C 1-6Alkyl) (5-9 unit heterocyclic radical), NH (5-9 unit heterocyclic radical), O (5-9 unit heterocyclic radical), (5-9 unit heterocyclic radical) C 1-3Alkylidene group, phenyl, C 1-2-hydroxy alkylidene, C 2-6Alkoxyl group, (C 3-6Cycloalkyl)-O-, phenyl, (phenyl) C 1-3Alkylidene group and (phenyl) C 1-3Alkylidene group-O-, wherein the described substituting group of Q can be chosen wantonly and have 1-3 and independently be selected from following substituting group: trifluoromethyl, halogen, nitro, cyano group and hydroxyl;
Described method comprises at least one following step: make following formula (VI) compound and following formula V compound reaction:
Figure A038258970003C1
With
Figure A038258970003C2
With organic bases R 1R 2NH is at the X of formula (VIII) compound 1On carry out nucleophilic substitution, wherein with the linked reaction of alkynes in, X 2Be suitable leavings group, and with the nucleophilic substitution reaction of amine in, X 1Be suitable leavings group.
2. the process of claim 1 wherein NR 1R 2Be combined together to form piperidyl, methyl piperidine base, dimethylamino, pyrrolidyl, diethylamino, methylethyl amino, ethyl propyl amino or dipropyl amino.
3. the method for claim 2, wherein NR 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin.
4. the method for claim 3, wherein NR 1R 2Be combined together to form piperidyl or pyrrolidyl.
5. the process of claim 1 wherein R 4And R 5One of be G.
6. the method for claim 5, wherein R 4Be G.
7. the method for claim 5, wherein R 5Be G.
8. the process of claim 1 wherein that n is 1.
9. the process of claim 1 wherein that Q is the nitrogen heterocycle that saturated N connects.
10. the method for claim 9, wherein Q is selected from and replaces or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl.
11. the method for claim 10 wherein replaces Q and is selected from N-(C 1-6Alkyl) piperazinyl, N-phenyl-Piperazine base, 1,3,8-three azepines-spiral shell [4.5] decyl and 1,4-two oxa-s-8-azepine-spiral shell [4.5] decyl.
12. the method for claim 9, wherein Q is the univalent perssad that is selected from following amine: aziridine, 1,4,7-trioxa-10-azepine-cyclododecane, thiazolidine, 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone, piperidines-3-formic acid diethylamide, 1,2,3,4,5,6-six hydrogen-[2,3 '] dipyridyl, 4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazine-1-base-pyrimidine, piperidines-4-methane amide, methyl-(2-pyridine-2-base-ethyl)-amine, [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine, thio-morpholinyl, allyl group-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine, 1-piperidin-4-yl-1,3-dihydro-benzimidazolyl-2 radicals-ketone, 2-(piperidin-4-yl oxygen base)-pyrimidine, piperidin-4-yl-pyridine-2-base-amine, aniline, pyridine-2-base amine.
13. the method for claim 11, wherein Q is selected from optional by 1-3 N-morpholinyl and N-piperidyl that is selected from following substituting group replacement: hydroxyl, formamido-, C 1-6Alkyl, 5-9 unit heterocyclic radical, N (C 1-6Alkyl) (5-9 unit heterocyclic radical), NH (5-9 unit heterocyclic radical), (5-9 unit heterocyclic radical) C 1-3Alkylidene group, C 1-2-hydroxy alkylidene, O (5-9 unit heterocyclic radical), C 1-6Alkoxyl group, (C 3-6Cycloalkyl)-O-, phenyl, (phenyl) C 1-3Alkylidene group and (phenyl) C 1-3Alkylidene group-O-, wherein above-mentioned heterocyclic radical, phenyl and alkyl can choose wantonly separately by 1-3 and independently be selected from following substituting group replacement: halogen, nitro, cyano group and C 1-3Alkyl.
14. the method for claim 11, wherein Q is comprised and is selected from following C 1-6The substituting group of heterocyclic radical replaces: pyridyl, pyrimidyl, furyl, thienyl, imidazolyl, (imidazolyl) C 1-6Alkylidene group, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl-, 2-oxo benzimidazolyl-, (tetrazyl) C 1-6Alkylidene group, tetrazyl, (triazolyl) C 1-6Alkylidene group, triazolyl, (pyrryl) C 1-6Alkylidene group and pyrryl.
15. the method for claim 14, wherein Q is for replacing or unsubstituted N-morpholinyl.
16. the process of claim 1 wherein that n is 1;
R 1And R 2Independently be selected from C 2Alkyl, perhaps the nitrogen that is connected with them combines, and they form the optional first heterocyclic radical of extra heteroatomic non-aromatics 5-6 that independently is selected from O, S and N that comprises;
R 3, R 4And R 5One of be G, all the other two is H;
G is L 2Q;
L 2Be methylene radical;
Q is NR 8R 9, R wherein 8Independently be selected from hydrogen, C 1-2Alkyl, C 3Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 2Alkylidene group and (phenyl) C 2Alkylidene group; R 9Independently be selected from C 1-2Alkyl, C 3Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 2Alkylidene group and (phenyl) C 2Alkylidene group;
Or
Q is the heterocyclic radical that the saturated N of 3-13 unit connects, and wherein, except that N connected nitrogen, 3-13 unit heterocyclic radical also can be chosen wantonly and contain 1-3 extra heteroatoms that is selected from O, S and N;
Wherein each abovementioned alkyl, alkylidene group, thiazolinyl, alkenylene, heterocyclic radical and carbocylic radical can independently separately and optional be selected from following substituting group replacement by 1-3: methoxyl group, halogen, amino, nitro, hydroxyl and C 1-3Alkyl;
Wherein the substituting group of Q can further be selected from tert-butoxycarbonyl, formamido-, 5-9 unit heterocyclic radical, NH (6 yuan of heterocyclic radicals), O (6 yuan of heterocyclic radicals), phenyl, C 2-hydroxy alkylidene, hydroxyl and benzyl, and wherein each above-mentioned heterocyclic radical, phenyl and the alkyl substituent of Q can be chosen wantonly by trifluoromethyl and replace.
17. the process of claim 1 wherein
(a) NR 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin and
(b) Q is selected from and replaces or unsubstituted piperidyl, piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl.
18. the process of claim 1 wherein described organic bases R 1R 2NH is a piperidines, and described nucleophilic substitution is at room temperature carried out.
19. the process of claim 1 wherein in the presence of ethanol, at room temperature, carry out described nucleophilic substitution with 10 equivalent piperidines.
20. the process of claim 1 wherein in the presence of ethanol, and at X 1Under the situation for the methylsulfonic acid ester group, at room temperature, carry out described nucleophilic substitution, generate replacement alkali and eliminate mixture of products with 10 equivalent piperidines.
Described mixture is exposed among the HCl and obtains salts solution 21. the method for claim 20, described method also comprise, selective precipitation and crystallization obtain the benzyne dihydrochloride from described salts solution.
22. the method for claim 21, wherein said benzyne dihydrochloride are 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl] the morpholine dihydrochloride.
23. the process of claim 1 wherein NR 1R 2Be combined together to form piperidyl or pyrrolidyl, n is 1, and Q is selected from morpholinyl and piperidyl.
24. the process of claim 1 wherein NR 1R 2Be combined together to form piperidyl or pyrrolidyl, n is 1, and Q is morpholinyl or replaces morpholinyl.
25. the process of claim 1 wherein n=1, R 3Be H, R 5Be H, R 4Be L 2Q, wherein Q is a morpholinyl, L 2As claim 1 definition, and NR 1R 2Be combined together to form piperidyl.
26. the process of claim 1 wherein described organic bases R 1R 2NH is a piperidines.
27. the process of claim 1 wherein in the presence of ethanol, at room temperature carry out described nucleophilic substitution.
28. the process of claim 1 wherein in the presence of ethanol, at room temperature carry out described nucleophilic substitution, and described organic bases R 1R 2NH is a piperidines.
29. the method for claim 28, the consumption of wherein said piperidines are 10 equivalents.
30. the process of claim 1 wherein n=1, R 3Be H, R 5Be H, R 4Be L 2Q, wherein Q is a morpholinyl, L 2As claim 1 definition, described organic bases R 1R 2NH is a piperidines, and in the presence of ethanol, at room temperature carries out described nucleophilic substitution.
31. the process of claim 1 wherein that described nucleophilic substitution obtains substitution product and eliminates mixture of products, and be in containing pure medium, obtaining carrying out under the temperature of at least 80% described substitution product.
32. the process of claim 1 wherein that described nucleophilic substitution obtains substitution product and eliminates mixture of products, and be in the presence of ethanol, at room temperature carry out and described organic bases R 1R 2NH is a piperidines; Described method also comprises described mixture is obtained salts solution with acid treatment, and selective precipitation and the described salts solution of crystallization, obtains salt.
33. the method for claim 32, wherein said acid are HCl.
34. the method for claim 32, wherein ether and ethanol are used for described crystallization.
35. the method for claim 34, n=1 wherein, R 3Be H, R 5Be H, R 4Be L 2Q, wherein Q is a morpholinyl, L 2As claim 1 definition, and NR 1R 2Be combined together to form piperidyl, described substitution product is 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine, described salt is the dihydrochloride of described substitution product.
36. the method for claim 28, described method comprise that also the alcohol with formula (VII) compound is transformed into described formula (VIII) compound.
37. also comprising, the method for claim 36, described method use amine R 8R 9NH reductive amination following formula (VIIa) compound, production (VII) compound:
Figure A038258970007C1
R wherein 3 ', R 4 'And R 5 'One of be C (O) H, all the other two are selected from H, chlorine and bromine, wherein R 3, R 4And R 5One of be NR 8R 9, all the other two are selected from H, chlorine and bromine.
38. the method for claim 37, wherein said amine are morpholine.
39. the method for claim 37, described method also is included in the mantoquita existence of palladium-containing catalyst and formula (II) compound and carries out linked reaction with dibasic benzene down, production (VIIa) compound, one in the wherein said benzene substituting group is C (O) H, and in the described benzene substituting group another is selected from chlorine and bromine.
40. method for preparing following formula (I) compound and the acceptable salt of medicine, ester or acid amides:
Figure A038258970008C1
Wherein n is the integer of 0-1;
R 1And R 2Independently be selected from C 1-3Alkyl, allyl group and C 3-8Cycloalkyl, perhaps the nitrogen that is connected with them combines, and they form optional 2 the first heterocyclic radicals of extra heteroatomic non-aromatics 4-7 that independently are selected from O, S and N at the most that comprise;
R 3And R 5One of be G, all the other one and R 4One of be H, and another is selected from hydrogen, fluorine and chlorine;
G is L 2Q;
L 2Be methylene radical;
Q is NR 8R 9, R wherein 8Independently be selected from hydrogen, C 1-6Alkyl, C 3-6Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 1-6Alkylidene group and (phenyl) C 1-6Alkylidene group; R 9Independently be selected from C 1-6Alkyl, C 3-6Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 1-6Alkylidene group and (phenyl) C 1-6Alkylidene group;
Or
Q is the heterocyclic radical that the saturated N of 3-13 unit connects, and wherein, except that N connected nitrogen, 3-13 unit heterocyclic radical also can be chosen wantonly and contain 1-3 extra heteroatoms that independently is selected from O, S and N;
Each abovementioned alkyl, alkylidene group, thiazolinyl, heterocyclic radical, cycloalkyl, carbocylic radical and aryl can independently separately and optional independently be selected from following substituting group replacement by 1-3 in its Chinese style (I): methoxyl group, halogen, amino, nitro, hydroxyl and C 1-3Alkyl;
Wherein the 1-3 of a Q substituting group also can further independently be selected from tert-butoxycarbonyl, formamido-, C except the paragraph of front 1-6Alkyl, 5-9 unit heterocyclic radical, N (C 1-6Alkyl) (5-9 unit heterocyclic radical), NH (5-9 unit heterocyclic radical), O (5-9 unit heterocyclic radical), (5-9 unit heterocyclic radical) C 1-3Alkylidene group, phenyl, C 1-2-hydroxy alkylidene, C 2-6Alkoxyl group, (C 3-6Cycloalkyl)-O-, phenyl, (phenyl) C 1-3Alkylidene group and (phenyl) C 1-3Alkylidene group-O-, wherein the described substituting group of Q can be chosen wantonly and have 1-3 and independently be selected from following substituting group: trifluoromethyl, halogen, nitro, cyano group and hydroxyl;
Described method comprises at least one following formula (XXIIIw) compound and following formula (XXIIIow) compound and the reaction of formula V compound:
Figure A038258970009C1
Wherein W is C (O) H or G, X 2With the linked reaction of alkynes in be suitable leavings group.
41. the method for claim 40, wherein said W is C (O) H, and described method also comprises the organic bases R with described W 9R 8NH carries out reductive amination.
42. the method for claim 40, wherein NR 1R 2Be combined together to form piperidyl, methyl piperidine base, dimethylamino, pyrrolidyl, diethylamino, methylethyl amino, ethyl propyl amino or dipropyl amino.
43. the method for claim 42, wherein NR 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin.
44. the method for claim 43, wherein NR 1R 2Be combined together to form piperidyl or pyrrolidyl.
45. the method for claim 40, wherein R 5Be G.
46. the method for claim 40, wherein R 3Be G.
47. the method for claim 40, wherein n is 1.
48. the method for claim 40, wherein Q is the nitrogen heterocycle that saturated N connects.
49. the method for claim 40, wherein Q is selected from and replaces or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl.
50. the method for claim 49 wherein replaces Q and is selected from N-(C 1-6Alkyl) piperazinyl, N-phenyl-Piperazine base, 1,3,8-three azepines-spiral shell [4.5] decyl and 1,4-two oxa-s-8-azepine-spiral shell [4.5] decyl.
51. the method for claim 48, wherein Q is the univalent perssad that is selected from following amine: aziridine, 1,4,7-trioxa-10-azepine-cyclododecane, thiazolidine, 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone, piperidines-3-formic acid diethylamide, 1,2,3,4,5,6-six hydrogen-[2,3 '] dipyridyl, 4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazine-1-base-pyrimidine, piperidines-4-methane amide, methyl-(2-pyridine-2-base-ethyl)-amine, [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine, thio-morpholinyl, allyl group-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine, 1-piperidin-4-yl-1,3-dihydro-benzimidazolyl-2 radicals-ketone, 2-(piperidin-4-yl oxygen base)-pyrimidine, piperidin-4-yl-pyridine-2-base-amine, aniline, pyridine-2-base amine.
52. the method for claim 40, wherein Q is selected from optional by 1-3 N-morpholinyl and N-piperidyl that is selected from following substituting group replacement: hydroxyl, formamido-, C 1-6Alkyl, 5-9 unit heterocyclic radical, N (C 1-6Alkyl) (5-9 unit heterocyclic radical), NH (5-9 unit heterocyclic radical), (5-9 unit heterocyclic radical) C 1-3Alkylidene group, C 1-2-hydroxy alkylidene, O (5-9 unit heterocyclic radical), C 1-6Alkoxyl group, (C 3-6Cycloalkyl)-O-, phenyl, (phenyl) C 1-3Alkylidene group and (phenyl) C 1-3Alkylidene group-O-, wherein above-mentioned heterocyclic radical, phenyl and alkyl can choose wantonly separately by 1-3 and independently be selected from following substituting group replacement: halogen, nitro, cyano group and C 1-3Alkyl.
53. the method for claim 40, wherein Q is comprised and is selected from following C 1-6The substituting group of heterocyclic radical replaces: pyridyl, pyrimidyl, furyl, thienyl, imidazolyl, (imidazolyl) C 1-6Alkylidene group, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl-, 2-oxo benzimidazolyl-, (tetrazyl) C 1-6Alkylidene group, tetrazyl, (triazolyl) C 1-6Alkylidene group, triazolyl, (pyrryl) C 1-6Alkylidene group and pyrryl.
54. the method for claim 40, wherein Q is for replacing or unsubstituted N-morpholinyl.
55. the method for claim 40, wherein n is 1;
R 1And R 2Independently be selected from C 2Alkyl, perhaps the nitrogen that is connected with them combines, and they form the optional first heterocyclic radical of extra heteroatomic non-aromatics 5-6 that independently is selected from O, S and N that comprises;
R 3And R 5One of be G, all the other one and R 4Be H;
G is L 2Q;
L 2Be methylene radical;
Q is NR 8R 9, R wherein 8Independently be selected from hydrogen, C 1-2Alkyl, C 3Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 2Alkylidene group and (phenyl) C 2Alkylidene group; R 9Independently be selected from C 1-2Alkyl, C 3Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 2Alkylidene group and (phenyl) C 2Alkylidene group;
Or
Q is the heterocyclic radical that the saturated N of 3-13 unit connects, and wherein, except that N connected nitrogen, 3-13 unit heterocyclic radical also can be chosen wantonly and contain 1-3 extra heteroatoms that independently is selected from O, S and N;
Wherein each abovementioned alkyl, alkylidene group, thiazolinyl, alkenylene, heterocyclic radical and carbocylic radical can independently separately and optional be selected from following substituting group replacement by 1-3: methoxyl group, halogen, amino, nitro, hydroxyl and C 1-3Alkyl;
Wherein the substituting group of Q can further be selected from tert-butoxycarbonyl, formamido-, 5-9 unit heterocyclic radical, NH (6 yuan of heterocyclic radicals), O (6 yuan of heterocyclic radicals), phenyl, C 2-hydroxy alkylidene, hydroxyl and benzyl, wherein the above-mentioned heterocyclic radical of each of Q, phenyl and alkyl substituent can be chosen wantonly by trifluoromethyl and replace.
56. the method for claim 40, wherein
NR 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin, Q is selected from and replaces or unsubstituted piperidyl, piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl.
57. the method for claim 40, wherein NR 1R 2Be combined together to form piperidyl or pyrrolidyl, n is 1, and Q is selected from morpholinyl and piperidyl.
58. the method for claim 40, wherein NR 1R 2Be combined together to form piperidyl or pyrrolidyl, n is 1, and Q is morpholinyl or replaces morpholinyl.
59. the method for claim 40, wherein n is 1, R 4Be H, R 3And R 5In one be H, R 3And R 5In another be L 2Q, Q are morpholinyl, L 2As claim 40 definition, NR 1R 2Be combined together to form piperidyl.
60. method for preparing following formula (I) compound and the acceptable salt of medicine, ester or acid amides:
Figure A038258970012C1
Wherein n is the integer of 0-1;
R 1And R 2Independently be selected from C 1-3Alkyl, allyl group and C 3-8Cycloalkyl, perhaps the nitrogen that is connected with them combines, and they form optional 2 the first heterocyclic radicals of extra heteroatomic non-aromatics 4-7 that independently are selected from O, S and N at the most that comprise;
R 3, R 4And R 5One of be G, one in all the other two is hydrogen, and another is selected from hydrogen, fluorine and chlorine;
G is L 2Q;
L 2Be methylene radical;
Q is NR 8R 9, R wherein 8Independently be selected from hydrogen, C 1-6Alkyl, C 3-6Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 1-6Alkylidene group and (phenyl) C 1-6Alkylidene group; R 9Independently be selected from C 1-6Alkyl, C 3-6Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 1-6Alkylidene group and (phenyl) C 1-6Alkylidene group;
Or
Q is the heterocyclic radical that the saturated N of 3-13 unit connects, and wherein, except that N connected nitrogen, 3-13 unit heterocyclic radical also can be chosen wantonly and contain 1-3 extra heteroatoms that independently is selected from O, S and N;
Each abovementioned alkyl, alkylidene group, thiazolinyl, heterocyclic radical, cycloalkyl, carbocylic radical and aryl can independently separately and optional independently be selected from following substituting group replacement by 1-3 in its Chinese style (I): methoxyl group, halogen, amino, nitro, hydroxyl and C 1-3Alkyl;
Wherein the 1-3 of a Q substituting group also can further independently be selected from tert-butoxycarbonyl, formamido-, C except the paragraph of front 1-6Alkyl, 5-9 unit heterocyclic radical, N (C 1-6Alkyl) (5-9 unit heterocyclic radical), NH (5-9 unit heterocyclic radical), O (5-9 unit heterocyclic radical), (5-9 unit heterocyclic radical) C 1-3Alkylidene group, phenyl, C 1-2-hydroxy alkylidene, C 2-6Alkoxyl group, (C 3-6Cycloalkyl)-O-, phenyl, (phenyl) C 1-3Alkylidene group and (phenyl) C 1-3Alkylidene group-O-, wherein the described substituting group of Q can be chosen wantonly and have 1-3 and independently be selected from following substituting group: trifluoromethyl, halogen, nitro, cyano group and hydroxyl;
Described method is included in halogenation San Wan Ji Phosphonium and alkali exists down, makes following formula (VII) compound and organic bases R 1R 2The NH reaction:
Figure A038258970013C1
61. the method for claim 60, wherein said halogenation San Wan Ji Phosphonium are iodate (cyano methyl) San Jia Ji Phosphonium, described alkali is DIPEA.
62. the method for claim 60, wherein NR 1R 2Be combined together to form piperidyl, methyl piperidine base, dimethylamino, pyrrolidyl, diethylamino, methylethyl amino, ethyl propyl amino or dipropyl amino.
63. the method for claim 60, wherein NR 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin.
64. the method for claim 60, wherein NR 1R 2Be combined together to form piperidyl or pyrrolidyl.
65. the method for claim 60, wherein R 4And R 5One of be G.
66. the method for claim 65, wherein R 4Be G.
67. the method for claim 66, wherein R 5Be G.
68. the method for claim 60, wherein n is 1.
69. the method for claim 60, wherein Q is the nitrogen heterocycle that saturated N connects.
70. the method for claim 60, wherein Q is selected from and replaces or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl.
71. the method for claim 60, wherein NR 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin, Q is selected from and replaces or unsubstituted piperidyl, piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl.
72. the method for claim 60, wherein NR 1R 2Be combined together to form piperidyl or pyrrolidyl, n is 1, and Q is selected from morpholinyl and piperidyl.
73. the method for claim 60, wherein NR 1R 2Be combined together to form piperidyl or pyrrolidyl, n is 1, and Q is morpholinyl or replaces morpholinyl.
74. the method for claim 60, n=1 wherein, R 3Be H, R 5Be H, R 4Be L 2Q, wherein Q is a morpholinyl, L 2As claim 60 definition, and NR 1R 2Be combined together to form piperidyl.
75. method for preparing following formula (I) compound and the acceptable salt of medicine, ester or acid amides:
Wherein n is the integer of 0-1;
R 1And R 2Independently be selected from C 1-3Alkyl, allyl group and C 3-8Cycloalkyl, perhaps the nitrogen that is connected with them combines, and they form optional 2 the first heterocyclic radicals of extra heteroatomic non-aromatics 4-7 that independently are selected from O, S and N at the most that comprise;
R 4Be G, R 3And R 5One of be hydrogen, all the other one is selected from hydrogen, fluorine and chlorine;
G is L 2Q;
L 2Be methylene radical;
Q is NR 8R 9, R wherein 8Independently be selected from hydrogen, C 1-6Alkyl, C 3-6Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 1-6Alkylidene group and (phenyl) C 1-6Alkylidene group; R 9Independently be selected from C 1-6Alkyl, C 3-6Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 1-6Alkylidene group and (phenyl) C 1-6Alkylidene group;
Or
Q is the heterocyclic radical that the saturated N of 3-13 unit connects, and wherein, except that N connected nitrogen, 3-13 unit heterocyclic radical also can be chosen wantonly and contain 1-3 extra heteroatoms that independently is selected from O, S and N;
Each abovementioned alkyl, alkylidene group, thiazolinyl, heterocyclic radical, cycloalkyl, carbocylic radical and aryl can independently separately and optional independently be selected from following substituting group replacement by 1-3 in its Chinese style (I): methoxyl group, halogen, amino, nitro, hydroxyl and C 1-3Alkyl;
Wherein the 1-3 of a Q substituting group also can further independently be selected from tert-butoxycarbonyl, formamido-, C except the paragraph of front 1-6Alkyl, 5-9 unit heterocyclic radical, N (C 1-6Alkyl) (5-9 unit heterocyclic radical), NH (5-9 unit heterocyclic radical), O (5-9 unit heterocyclic radical), (5-9 unit heterocyclic radical) C 1-3Alkylidene group, phenyl, C 1-2-hydroxy alkylidene, C 2-6Alkoxyl group, (C 3-6Cycloalkyl)-O-, phenyl, (phenyl) C 1-3Alkylidene group and (phenyl) C 1-3Alkylidene group-O-, wherein the described substituting group of Q can be chosen wantonly and have 1-3 and independently be selected from following substituting group: trifluoromethyl, halogen, nitro, cyano group and hydroxyl;
Described method comprises following formula (XXIIImw) compound and the reaction of formula V compound:
Wherein W is C (O) H or G, X 2With the linked reaction of alkynes in be suitable leavings group.
76. the method for claim 75, wherein said W is C (O) H, and described method also comprises the organic bases R with described W 9R 8NH carries out reductive amination.
77. the method for claim 75, wherein NR 1R 2Be combined together to form piperidyl, methyl piperidine base, dimethylamino, pyrrolidyl, diethylamino, methylethyl amino, ethyl propyl amino or dipropyl amino.
78. the method for claim 75, wherein NR 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin.
79. the method for claim 75, wherein NR 1R 2Be combined together to form piperidyl or pyrrolidyl.
80. the method for claim 75, wherein n is 1.
81. the method for claim 75, wherein Q is the nitrogen heterocycle that saturated N connects.
82. the method for claim 75, wherein Q is selected from and replaces or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl.
83. the method for claim 75 wherein replaces Q and is selected from N-(C 1-6Alkyl) piperazinyl, N-phenyl-Piperazine base, 1,3,8-three azepines-spiral shell [4.5] decyl and 1,4-two oxa-s-8-azepine-spiral shell [4.5] decyl.
84. the method for claim 75, wherein Q is the univalent perssad that is selected from following amine: aziridine, 1,4,7-trioxa-10-azepine-cyclododecane, thiazolidine, 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone, piperidines-3-formic acid diethylamide, 1,2,3,4,5,6-six hydrogen-[2,3 '] dipyridyl, 4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazine-1-base-pyrimidine, piperidines-4-methane amide, methyl-(2-pyridine-2-base-ethyl)-amine, [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine, thio-morpholinyl, allyl group-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine, 1-piperidin-4-yl-1,3-dihydro-benzimidazolyl-2 radicals-ketone, 2-(piperidin-4-yl oxygen base)-pyrimidine, piperidin-4-yl-pyridine-2-base-amine, aniline, pyridine-2-base amine.
85. the method for claim 75, wherein Q is selected from optional by 1-3 N-morpholinyl and N-piperidyl that is selected from following substituting group replacement: hydroxyl, formamido-, C 1-6Alkyl, 5-9 unit heterocyclic radical, N (C 1-6Alkyl) (5-9 unit heterocyclic radical), NH (5-9 unit heterocyclic radical), (5-9 unit heterocyclic radical) C 1-3Alkylidene group, C 1-2-hydroxy alkylidene, O (5-9 unit heterocyclic radical), C 1-6Alkoxyl group, (C 3-6Cycloalkyl)-O-, phenyl, (phenyl) C 1-3Alkylidene group and (phenyl) C 1-3Alkylidene group-O-, wherein above-mentioned heterocyclic radical, phenyl and alkyl can choose wantonly separately by 1-3 and independently be selected from following substituting group replacement: halogen, nitro, cyano group and C 1-3Alkyl.
86. the method for claim 75, wherein Q is comprised and is selected from following C 1-6The substituting group of heterocyclic radical replaces: pyridyl, pyrimidyl, furyl, thienyl, imidazolyl, (imidazolyl) C 1-6Alkylidene group, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl-, 2-oxo benzimidazolyl-, (tetrazyl) C 1-6Alkylidene group, tetrazyl, (triazolyl) C 1-6Alkylidene group, triazolyl, (pyrryl) C 1-6Alkylidene group and pyrryl.
87. the method for claim 75, wherein Q is for replacing or unsubstituted N-morpholinyl.
88. the method for claim 75, wherein n is 1;
R 1And R 2Independently be selected from C 2Alkyl, perhaps the nitrogen that is connected with them combines, and they form the optional first heterocyclic radical of extra heteroatomic non-aromatics 5-6 that independently is selected from O, S and N that comprises;
R 3And R 5Be H;
G is L 2Q;
L 2Be methylene radical;
Q is NR 8R 9, R wherein 8Independently be selected from hydrogen, C 1-2Alkyl, C 3Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 2Alkylidene group and (phenyl) C 2Alkylidene group; R 9Independently be selected from C 1-2Alkyl, C 3Thiazolinyl, 6-9 unit carbocylic radical, 3-12 unit heterocyclic radical, phenyl, (5-9 unit heterocyclic radical) C 2Alkylidene group and (phenyl) C 2Alkylidene group;
Or
Q is the heterocyclic radical that the saturated N of 3-13 unit connects, and wherein, except that N connected nitrogen, 3-13 unit heterocyclic radical also can be chosen wantonly and contain 1-3 extra heteroatoms that is selected from O, S and N;
Wherein each abovementioned alkyl, alkylidene group, thiazolinyl, alkenylene, heterocyclic radical and carbocylic radical can independently separately and optional independently be selected from following substituting group replacement by 1-3: methoxyl group, halogen, amino, nitro, hydroxyl and C 1-3Alkyl;
Wherein the substituting group of Q can further be selected from tert-butoxycarbonyl, formamido-, 5-9 unit heterocyclic radical, NH (6 yuan of heterocyclic radicals), O (6 yuan of heterocyclic radicals), phenyl, C 2-hydroxy alkylidene, hydroxyl and benzyl, and wherein each above-mentioned heterocyclic radical, phenyl and the alkyl substituent of Q can be chosen wantonly by trifluoromethyl and replace.
89. the method for claim 75, wherein
NR 1R 2Be combined together to form piperidyl, pyrrolidyl or diethylin and
Q is selected from and replaces or unsubstituted piperidyl, piperazinyl, pyrrolinyl, pyrrolidyl, thio-morpholinyl and morpholinyl.
90. the method for claim 75, wherein NR 1R 2Be combined together to form piperidyl or pyrrolidyl, n is 1, and Q is selected from morpholinyl and piperidyl.
91. the method for claim 90, wherein NR 1R 2Be combined together to form piperidyl or pyrrolidyl, n is 1, and Q is morpholinyl or replaces morpholinyl.
92. the method for claim 75, wherein n is 1, R 5Be H, R 3Be H, R 4Be L 2Q, wherein Q is a morpholinyl, L 2As claim 75 definition, NR 1R 2Be combined together to form piperidyl.
93. the method for claim 75, wherein n is 1, R 3Be H, R 5Be H, W is C (O) H, X 2Be chlorine or bromine, the formula V compound is 1-fourth-3-alkynyl-piperidines, to make benzyne.
94. the method for claim 93 wherein in the presence of tetramethyleneimine, is carried out described reaction and is obtained benzyne under about 50 ℃ temperature.
95. the method for claim 94 is wherein carried out described reaction in the presence of palladium-containing catalyst and mantoquita.
96. the method for claim 93, wherein X 2Be bromine, and be at least at the yield of described benzyne under 80% the condition and carry out described reaction.
97. also comprising, the method for claim 93, described method use R 8R 9The described benzyne of NH reductive amination obtains alkali.
98. the method for claim 97, wherein said R 8R 9NH is a morpholine, and described alkali is 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine.
99. also comprising with HCl, the method for claim 97, described method form salts solution.
100. the method for claim 99, described method also comprises the dihydrochloride that obtains described alkali by crystallization.
101. the method for claim 100, wherein said alkali are 4-[3-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine.
102. the method for claim 40, wherein n is 1, R 4Be H, R 3Be H, R 5Be C (O) H, NR 1R 2Be combined together to form piperidyl, wherein said reaction is at room temperature carried out.
103. the method for claim 40, wherein n is 1, R 4Be H, R 3Be H, R 5Be C (O) H, NR 1R 2Be combined together to form piperidyl, wherein said reaction is in the presence of palladium-containing catalyst and mantoquita, at room temperature carries out, and described reaction obtains benzyne.
104. the method for claim 40, wherein n is 1, R 4Be H, R 3Be H, R 5Be C (O) H, NR 1R 2Be combined together to form piperidyl, X 2Be bromine; Wherein said reaction is in the presence of palladium-containing catalyst and mantoquita, at room temperature carries out, and described reaction obtains benzyne.
105. the method for claim 40, wherein n is 1, R 4Be H, R 3Be H, R 5Be C (O) H, NR 1R 2Be combined together to form piperidyl; Wherein said reaction is in the presence of palladium-containing catalyst and mantoquita, at room temperature carries out, and described reaction obtains benzyne; Described method also comprises uses R 8R 9The described benzyne of NH reductive amination obtains alkali.
106. the method for claim 105, wherein said R 8R 9NH is a morpholine, and described alkali is 4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine.
107. also comprising with HCl, the method for claim 105, described method form salts solution.
108. the method for claim 107, described method also comprises the dihydrochloride that obtains described alkali by crystallization.
109. the method for claim 108, wherein said alkali are 4-[4-(4-piperidines-1-Ji-Ding-1-alkynyl)-benzyl]-morpholine.
CNA038258978A 2002-12-02 2003-06-17 Methods for preparing phenylalkyne derivatives Pending CN1738799A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/US2002/038480 WO2003050099A1 (en) 2001-12-10 2002-12-02 Phenylalkynes
USPCT/US02/38480 2002-12-02

Publications (1)

Publication Number Publication Date
CN1738799A true CN1738799A (en) 2006-02-22

Family

ID=32467117

Family Applications (1)

Application Number Title Priority Date Filing Date
CNA038258978A Pending CN1738799A (en) 2002-12-02 2003-06-17 Methods for preparing phenylalkyne derivatives

Country Status (11)

Country Link
EP (1) EP1567494A1 (en)
JP (1) JP2006514939A (en)
KR (1) KR20050086801A (en)
CN (1) CN1738799A (en)
AU (1) AU2003245613A1 (en)
BR (1) BR0316971A (en)
CA (1) CA2507875A1 (en)
MX (1) MXPA05005830A (en)
RU (1) RU2005116846A (en)
WO (1) WO2004050623A1 (en)
ZA (1) ZA200505323B (en)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3894299A (en) * 1998-05-15 1999-12-06 American Home Products Corporation Compositions comprising 2-phenyl-indole compounds and estrogen formulations
WO2001066534A2 (en) * 2000-03-09 2001-09-13 Abbott Laboratories Cyclic and bicyclic diamino histamine-3 receptor antagonists
US20020147198A1 (en) * 2001-01-12 2002-10-10 Guoqing Chen Substituted arylamine derivatives and methods of use
BR0214886A (en) * 2001-12-10 2004-12-07 Ortho Mcneil Pharm Inc Phenylalkines

Also Published As

Publication number Publication date
MXPA05005830A (en) 2006-02-08
CA2507875A1 (en) 2004-06-17
BR0316971A (en) 2005-10-25
WO2004050623A1 (en) 2004-06-17
AU2003245613A1 (en) 2004-06-23
JP2006514939A (en) 2006-05-18
KR20050086801A (en) 2005-08-30
ZA200505323B (en) 2006-09-27
EP1567494A1 (en) 2005-08-31
RU2005116846A (en) 2006-01-20

Similar Documents

Publication Publication Date Title
CN1078889C (en) Non-peptide tachykinin receptor antagonists
CN1729180A (en) Piperazinyl and diazapanyl benzamides and benzthioamides
CN1468221A (en) Non-imidazole aryloxypiperidines
CN1167686C (en) Novel benzimidazole derivatives and pharmaceutical compsns. comprising these compounds
CN1284771C (en) TNF-alpha prodn. inhibitors
CN1231473C (en) Substituted arylpyrazines
CN1230431C (en) Arylmethy lamine derivatives for use as tryptase inhibitors
CN1930143A (en) MTP inhibiting aryl piperidines or piperazines substituted with 5-membered heterocycles
CN1087936C (en) Antipsychotic method
CN101035525A (en) Substituted urea derivatives for treating cardiac diseases
CN101080226A (en) Amido compounds and their use as pharmaceuticals
CN1234025A (en) 1-phenyl-benzimidazole compounds and their use as BAGA-A receptor modulator
CN1867336A (en) 1-aryl-4-substituted piperazines derivatives for use as CCR1 antagonists for the treatment of inflammation and immune disorders
CN1113236A (en) Non-peptidyl tachykinin receptor antagonists
CN1173867A (en) Indolyl neuropeptide Y receptor antagonists
CA2648687A1 (en) Azetidine derivatives as g-protein coupled receptor (gpr119 ) agonists
CN1599724A (en) Imidazole-4-carboxamide derivatives, preparation and use thereof for treatment of obesity
CN1909902A (en) Triazole, oxadiazole and thiadiazole derivatives as PPAR modulators for the treatment of diabetes
CN1617850A (en) Dibenzylamine compound and medicinal use thereof
CN1902177A (en) Novel piperidine derivative
CN1812981A (en) Heteroaryloxy nitrogenous saturated heterocyclic derivative
CN1471536A (en) Chemokine receptor antagonsis and method of use thereof
CN1427825A (en) Indolin-2-one derivatives, preparation and their use as ocytocin receptor ligands
CN1694703A (en) Use of indolyl derivatives for the manufacture of a medicament for the treatment allergic rhinitis
CN1520402A (en) Unsymmetrical cyclic diamine compound

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1086838

Country of ref document: HK

C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication
REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1086838

Country of ref document: HK