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WO2006048727A1 - Ligands de latame/amine piperazinylphenalkyle pour le recepteur 5ht1b - Google Patents

Ligands de latame/amine piperazinylphenalkyle pour le recepteur 5ht1b Download PDF

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WO2006048727A1
WO2006048727A1 PCT/IB2005/003252 IB2005003252W WO2006048727A1 WO 2006048727 A1 WO2006048727 A1 WO 2006048727A1 IB 2005003252 W IB2005003252 W IB 2005003252W WO 2006048727 A1 WO2006048727 A1 WO 2006048727A1
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methyl
phenyl
ethyl
piperazin
dihydro
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Todd William Butler
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Pfizer Products Inc
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Pfizer Products Inc
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    • C—CHEMISTRY; METALLURGY
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
    • C07D209/66—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles with oxygen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/36—One oxygen atom with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/70—One oxygen atom
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen atoms
    • 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
    • C07D401/06—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 only aliphatic carbon atoms
    • 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
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel piperazinylphenyl and piperazinylpyridyl lactam and amine derivatives, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use.
  • the compounds of the present invention include selective antagonists, inverse agonists and partial agonists of serotonin 1 (5-HT 1 ) receptors, specifically, receptor antagonists of 5-HT 1B (formerly classified 5-HT 1D ) receptors. They are useful in treating or preventing depression, anxiety, obsessive compulsive disorder (OCD) and other disorders for which a 5-HT 1 agonist or antagonist is indicated.
  • European Patent Publication 434,561 published on Jun.
  • 5-HT 1 agonists and antagonists useful for the treatment of migraine, depression, anxiety, schizophrenia, stress and pain.
  • European Patent Publication 343,050 published on Nov. 23, 1989, refers to 7- unsubstituted, halogenated, and methoxy substituted-1-(4-substituted-1-piperazinyl)- naphthalenes as useful 5-HTi A ligand therapeutics.
  • GIennon et al. refers to 7-methoxy-1-(1-piperazinyl)-naphthalene as a useful 5-HT 1 ligand in their article "5-HT 1D Serotonin Receptors", Clinical Drug Res. Dev., 22, 25-36 (1991). Glennon's article “Serotonin Receptors: Clinical Implications", Neuroscience and
  • a 5-HT 10 antagonist in combination with a 5-HT 1A antagonist to treat CNS disorders such as depression, generalized anxiety, panic disorder, agoraphobia, social phobias, obsessive- compulsive disorder, post-traumatic stress disorder, memory disorders, anorexia nervosa and bulimia nervosa, Parkinson's disease, tardive dyskinesias, endocrine disorders such as hyperprolactinaemia, vasospasm (particularly in the cerebral vasculature) and hypertension, disorders of the gastrointestinal tract where changes in motility and secretion are involved, as well as sexual dysfunction.
  • CNS disorders such as depression, generalized anxiety, panic disorder, agoraphobia, social phobias, obsessive- compulsive disorder, post-traumatic stress disorder, memory disorders, anorexia nervosa and bulimia nervosa
  • Parkinson's disease tardive dyskinesias
  • endocrine disorders such as hyperprolactinaemia,
  • the present invention relates to piperazinylphenethyl lactam/amine derivatives of the formula I
  • R 1 is a group of the formula G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , G 7 , G 8 , or G 9 depicted below,
  • R 2 is hydrogen, (CVC 6 )alkyl, and (C 1 -C 6 )alkyl-phenyl;
  • R 3 is independently selected from hydrogen, (C 1 -C 6 )alkyl, (CrCeJalkyl-phenyl, and (CVC ⁇ Jalkyl-naphthyl, wherein phenyl and naphthyl may optionally be substituted with one or more substituents independently selected from (C r C 6 )alkyl, (C r C 6 )alkoxy, trifluoromethyl, chloro, fluoro, bromo, iodo, cyano, -SO t (C r C 6 )alkyl, NH(C r C 6 )alkyl, N((Ci-C 6 )alkyl) 2 , NHCO(C r C 6 )alkyl, CONhKd-C ⁇ alkyl, and CON((C 1 -C ⁇ )alkyl) 2 ; t is zero to two; R 4 is hydrogen, R 9 , or R 10 ;
  • R 5 is independently selected from hydrogen, (C ⁇ C 6 )alkyl, naphthyl-(Ci-C 6 )alkyl-, wherein phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )SIkOXy, trifluoromethyl, chloro, fluoro, bromo, iodo, cyano, and -SO t (C- ⁇ -C 6 )alkyl;
  • R 6 and R 7 are independently selected from hydrogen, (C r C 6 )alkyl, phenyl or naphthyl, wherein phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, cyano, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, trifluoromethyl, trifluoromethoxy, (C r C 6 )perfluoroalkyl, (CrC ⁇ hydroxyalkyl-, (C r C 6 )alkoxy-(Ci-
  • R 6 and R 7 together with the nitrogen to which they are attached, form a 5 to 7 membered heteroalkyl saturated or unsaturated ring that may contain up to three heteroatoms independently selected from nitrogen, sulfur and oxygen, in addition to the nitrogen to which R 6 and R 7 are attached, wherein the heteroalkyl ring may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, cyano, (Ci-C 6 )alkyl, (C 1 - C 6 )alkoxy, trifluoromethyl, trifluoromethoxy, (CrC 6 )perfluoroalkyl, (CrC 6 )hydroxyalkyl-, (C 1 - C 6 )alkoxy-(C r C 6 )alkyl-, phenyl(C r C 6 )alkyl-, naphthyl(C r C 6 )alkyi-, and -SO t (C r C 6
  • R 8 is hydrogen or optionally one to four substituents independently selected from chloro, fluoro, bromo, iodo, cyano, hydroxy, nitro, amino, -CHO 1 -CONR 6 R 7 , -(C 1 - C 6 )alkylCO 2 Rii, -(C 3 -C 8 )CyClOaIkYlCO 2 Ri 1 , (CrCeJalkylCONRn-, -SO t (C r C 6 )alkyl, (C 1 - C 6 )alkyl, (C- ⁇ -C 6 )perfluoroalkyl, trifluoromethoxy, (C r C 6 )hydroxyalkyl-, (C 4 - C 8 )hydroxycycloalkyl-, (C 3 - C 8 )cycloalkyloxy-(C 1 -C 6 )alkyl-, (C r C 6 )alkoxycycloalkyl-, R 9
  • R 9 is phenyl or naphthyl wherein said phenyl or naphthyl may contain two adjacent carbon atoms that also form part of a fused 5 or 6 membered saturated or unsaturated heterocyclic ring containing from one to three heteroatoms in the ring selected from oxygen, nitrogen and sulfur, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, wherein said phenyl, naphthyl or fused heterocyclic ring may be optionally substituted with one to three substituents as valency allows, independently selected from chloro, fluoro, bromo, iodo, nitro, amino, oxo, -CONR 6 R 7 , -(C r C 6 )alkylCO 2 Rii,
  • Ri 2 > Ri 3 .
  • R 10 is a 5 to 7 membered aromatic ring containing from one to four heteroatoms in the ring selected from oxygen, nitrogen and sulfur, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms and wherein said 5 to 7 membered aromatic ring may contain 2 adjacent carbon atoms that also form part of a fused 6 membered carbocyclic aromatic ring, wherein said 5 to 7 membered aromatic ring or fused 6 membered carbocyclic aromatic ring may be optionally substituted with one to three substituents as valency allows, independently selected from chloro, fluoro, bromo, iodo, nitro, amino, oxo, -CONR 6 R 7 , -(C 1 -
  • R 11 is hydrogen or (C 1 -C ⁇ )aikyl
  • R 12 is phenyl or naphthyl, wherein phenyl or naphthyl may optionally be substituted as valency allows, with one to three substituents independently selected from chloro, fluoro, bromo, iodo, nitro, amino, oxo, (C ⁇ C ⁇ )alkyl, (C r C 6 )perfluoroalkyl, trifluoromethoxy, (C 1 -
  • R 13 is a 5 to 7 membered aromatic ring containing from one to four heteroatoms in the ring selected from oxygen, nitrogen and sulfur, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, wherein said ring may contain two adjacent carbon atoms that also form part of a fused 6 membered carbocyclic aromatic ring; or a 5 to 7 membered non-aromatic heterocyclic ring having in addition to carbon atoms one to three heteroatoms independently selected from nitrogen, oxygen or sulfur atoms or any combination thereof with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms; or oxetanyl or oxiranyl; and wherein any ring of R 13 may optionally be substituted as valency allows, with one to three substituents independently selected from chloro, fluoro, bromo, iodo, nitro, amino, oxo,
  • R 14 is 1-8 substituents independently selected from hydrogen, (C 1 -C 6 )SIkYl, (C 1 - C 6 )alkyl-phenyl, (C r C 6 )alkyl-naphthyl, wherein phenyl or naphthyl, may optionally be substituted with one or more substituents independently selected from (C 1 -C 6 )alkyl, (C-i - C 6 )alkoxy, trifluoromethyl, chloro, fluoro, bromo, iodo, cyano, and -SO t (C r C 6 )alkyl; or,
  • R 14 is a (C r C 4 )alkylene bridge from one of the ring carbons of the piperazine ring to a ring carbon of the same ring or another ring or to a ring nitrogen of the piperazine ring having an available bonding site, or to a ring carbon of R 3 , when R 3 has a ring structure having an available bonding site, with the understanding that N of the piperazine ring or C of R 3 has an available bonding site where said N or C is bonded to a hydrogen, which would be replaced by a bond to the aklylene bridge;
  • X, Y and Z are independently CH or N; q is one or two; n is zero or one and m is zero or one, with the proviso that (a) when n is zero, m must be zero and Ri bonds directly to the aromatic ring containing X and Y, (b) when n is one, m may be zero or 1 and (c) when n is one and m is zero R 1 bonds directly to -CH 2 - and R 2 is not present; or a pharmaceutically acceptable salt thereof.
  • the invention also relates to a compound according to formula I wherein R 1 is G 1 , G 2 , or G 3 ; X, Y and Z are independently CH or N; and R 4 is selected from phenyl, naphthyl, pyridyl, pyrrolyl, pyrimidyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, benzothiazolyl, chromanyl, isochromanyl, benzofuranyl, isobenzofuranyl, and isothiazolyl, any of which may be optionally substituted, as valency allows, with one to three substituents independently selected from chloro, fluoro, bromo, iodo, nitro, amino, oxo, (C r C 6 )alkyl,
  • the invention also relates to a compound according to formula I wherein R 1 is G 4 , G 5 , G 6 , G 7 , G 8 , or G 9 ; X and Y are independently CH or N; and R 8 is H or optionally 1 to 4 substituents independently selected from chloro, fluoro, bromo, iodo, cyano, hydroxy, nitro, amino, and CHO.
  • the invention also relates to a compound according to formula I wherein R 1 is G 4 , G 5 , G 6 , G 7 , G 8 , or G 9 ; X and Y are independently CH or N; and R 8 is 1 to 4 substituents independently selected from -CONR 3 R 7 wherein R 6 and R 7 together with the nitrogen to which they are attached, form a heteroalkyl saturated and unsaturated ring moiety selected from the group consisting of pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl, diazepinyl, and triazepinyl wherein each said heteroalkyl ring moiety may be substituted with from zero to three substituents independently selected from chloro, fluoro, bromo, iodo, (Ci-C 6 )alkyl, (Ci-C 6 )perfluoroalkyl, (C 1 -C 6 )
  • X and Y are independently CH or N; and
  • R 8 is 1 to 4 substituents independently selected from the group consisting of pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl, diazepinyl, oxazepinyl, thiazepinyl, oxadiazepinyl, thiadiazepinyl and triazepinyl, any of which may be substituted with from zero to three substituents independently selected from chloro, fluoro, bromo, iodo, (Ci-C ⁇ )alkyl, (C ⁇ C ⁇ perfluoroalkyl, (C ⁇ C f Ohydroxyalkyl-, (C 1 -C 6 JaIkOXy, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alky
  • the invention also relates to a compound according to formula I wherein Ri is G 4 , G 5 , G 6 , G 7 , G 8 , or G 9 ; X and Y are independently CH or N; and R 8 is 1 to 4 substituents independently selected from phenyl, naphthyl, pyridyl, pyrrolyl, pyrimidyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, benzothiazolyl, chromanyl, isochromanyl, benzofuranyl, isobenzofuranyl, and isothiazolyl, any of which may be optionally substituted, as valency allows, with one to three substituents independently selected from chloro, fluoro, bromo, iodo, nitro, amino,
  • the invention also relates to a compound according to formula I wherein R 2 is hydrogen, methyl, or benzyl.
  • the invention also relates to a compound according to formula I wherein R 3 is H, methyl, or benzyl.
  • the invention also relates to a compound according to formula I wherein R 1 is G 1 or G 4 , and R 5 is H, methyl, or benzyl.
  • the invention also relates to a compound according to formula I wherein R 1 is G 1 , G 2 ,
  • X, Y and Z are independently CH or N;
  • n is zero, m is zero, so R 2 is absent and R 1 bonds directly to the aromatic ring containing X and Y.
  • the invention also relates to a compound according to formula I wherein R 1 is G 1 , G 2 , G 31 G 4 , G 5 , G 6 , G 7 , G 8 , or G 9 ; X, Y and Z are independently CH or N; n is one, m is zero, so R 2 is absent and R 1 bonds directly to -CH 2 -.
  • the invention also relates to a compound according to formula I wherein Ri is Gi, G 2 , G 3 , G 4 , G 5 , G 6 , G 7 , G 8 , or G 9 ; X, Y and Z are independently CH or N; n is one and m is one.
  • the invention also relates to a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 14 , X, Y, n, m and q have any definition discussed herein.
  • Specific examples of the compounds of the present invention are independently any one or more or combination of the following:
  • halo includes fluoro, chloro, bromo and iodo.
  • alkyl includes straight or branched alkyl.
  • Halogenated alkyl e.g., perfluoroalkyl, as used herein, includes straight or branched halogenated alkyl moieties unless otherwise indicated.
  • cycloalkyl as used herein includes moieties derived from cyclic hydrocarbons which have a linkage from a ring carbon to another group and includes cyclic hydrocarbon moieties substituted with straight or branched alkyl moieties.
  • alkoxy means “alkyl-O-", wherein “alkyl” is defined as above.
  • cycloalkyl- O- or the term “cycloalkyloxy-” as used herein means "cycloalkyl” as defined above in which the cycloalkyl moiety is linked by a single bond to an oxygen atom with the oxygen atom having an available bonding site for formation of an ether linkage.
  • alkylene as used herein, means an alkyl radical having two available bonding sites ⁇ i.e., -alkyl-), wherein “alkyl” is defined as above.
  • alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration comprising one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. Alkenyl groups typically will have 2 to about 12 carbon atoms, more typically 2 to about 8 carbon atoms.
  • alkynyl is intended to include hydrocarbon chains of either a straight or branched configuration comprising one or more triple carbon- carbon bonds, which may occur in any stable point along the chain, such as ethynyl and propynyl. Alkynyl groups typically will have 2 to about 12 carbon atoms, more typically 2 to about 8 carbon atoms.
  • aryl is intended to include groups that, in accordance with the theory of H ⁇ ckel, have a cyclic, delocalized (4n+2) pi-electron system.
  • aryl groups include, but are not limited to, arenes and their substitution products, e.g., phenyl, naphthyl and toluyl, among numerous others.
  • heteroaryl is intended to include aromatic heterocyclic groups and includes the non-limiting examples furanyl, thiophene-yl, pyridyl, pyrimidyl, pyridazyl, oxazolyl, isooxazolyl, thiazolyl, thiadiazol and isothiazolyl, among others.
  • heterocycloalkyl or “non-aromatic heterocyclic ring” as used herein includes a cyclic hydrocarbon in which one or more of the ring carbon atoms has been replaced with a nitrogen, oxygen or sulfur atom or any combination thereof and includes the non-limiting examples tetrahydrofuran, dioxane, morpholine, piperidine and pyrazine among others.
  • substituents refers to from one to the maximum number of substituents possible based on the number of available bonding sites.
  • PP# the intermediate made by that preparation is refered to as PP#, where the number is the number of the preparation.
  • 2-(4-bromophenyl)-propan-2-ol is refered to herein as PP51.
  • the compounds of formula I may have chiral centers and therefore may occur in different enantiomeric configurations.
  • the invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of formula I, as well as racemic and other mixtures thereof.
  • the present invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I.
  • Examples of pharmaceutically acceptable acid addition salts of the compounds of formula I are the salts of hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, malate, di-p-toluoyl tartaric acid, and mandelic acid.
  • the present invention also, relates to all radiolabeled forms of the compounds of the formula I.
  • Preferred radiolabeled compounds of formula I are those wherein the radiolabels are selected from as 3 H, 11 C, 14 C, 18 F, 123 I and 125 I. Such radiolabeled compounds are useful as research and diagnostic tools in metabolism pharmacokinetics studies and in binding assays in both animals and man.
  • the present invention also relates to a pharmaceutical composition for treating a disorder or condition in a mammal, including a human, selected from depression, anxiety, depression with concomitant anxiety, post traumatic stress disorder, panic phobias, obsessive compulsive disorder (OCD), borderline personality disorder, sleep disorder, psychosis, seizures, dyskinesis, symptoms of Huntington's or Parkinson's diseases, spasticity, suppression of seizures resulting from epilepsy, cerebral ischemia, anorexia, faintness attacks, hypokinesia, cranial traumas, chemical dependencies, premature ejaculation, premenstrual syndrome (PMS) associated mood and appetite disorder, inflammatory bowel disease, modification of feeding behavior, blocking carbohydrate cravings, late luteal phase dysphoric disorder, tobacco withdrawal-associated symptoms, panic disorder, bipolar disorder, sleep disorders, jet lag, cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, chemical dependencies and addictions (e.g., dependencies on
  • the present invention also relates to a method of treating a disorder or condition in a mammal, including a human, selected from depression, anxiety, depression with concomitant anxiety, post traumatic stress disorder, panic phobias, obsessive compulsive disorder (OCD), borderline personality disorder, sleep disorder, psychosis, seizures, dyskinesis, symptoms of Huntington's or Parkinson's diseases, spasticity, suppression of seizures resulting from epilepsy, cerebral ischemia, anorexia, faintness attacks, hypokinesia, cranial traumas, chemical dependencies, premature ejaculation, premenstrual syndrome (PMS) associated mood and appetite disorder, inflammatory bowel disease, modification of feeding behavior, blocking carbohydrate cravings, late luteal phase dysphoric disorder, tobacco withdrawal- associated symptoms, panic disorder, bipolar disorder, sleep disorders, jet lag, cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, chemical dependencies and addictions (e.g., dependencies on,
  • reaction schemes include an inert atmosphere commonly used in the art such as nitrogen or argon.
  • Scheme 1 refers to general methods suitable for the preparation of compounds of formula Ia and Ib wherein R 2 is hydrogen, (C r C 6 )alkyl, and (C 1 -C 6 )alkyl-phenyl and R 3 is hydrogen, and (C r C 6 )alkyl-naphthyl.
  • an aldehyde of the formula Vl is prepared by treating an aldehyde of the formula VII with a substituted piperazine of the formula VIII in a solvent such as water, dioxane, n-butanol, DMF, DMSO or acetonitrile, preferably water, with a base such as an alkali metal carbonate, preferably potassium carbonate, at reaction temperatures of from about 40°C to about 150 0 C, preferably about 90° to about 120 0 C.
  • a solvent such as water, dioxane, n-butanol, DMF, DMSO or acetonitrile, preferably water
  • a base such as an alkali metal carbonate, preferably potassium carbonate
  • step 2a of Scheme 1 the nitroethylene substituted phenylpiperazine of formula V is prepared by condensation of the aldehyde of formula Vl with a nitroalkane in the presence of an ammonium salt such as ammonium acetate in an acidic medium, preferably acetic acid.
  • an ammonium salt such as ammonium acetate in an acidic medium, preferably acetic acid.
  • step 3a of Scheme 1 the aminoethylphenyl piperazine of formula IV is prepared by reduction of the nitroethylene group of the compound of formula V using procedures known in the art such as palladium catalyzed hydrogenation, treatment with zinc in acetic acid or zinc -mercury amalgam in hydrochloric acid or treatment with metal hydrides such as lithium aluminum hydride, diisobutyl aluminum hydride, sodium borohydride or lithium borohydride, preferably lithium aluminum hydride, in polar, nonreactive solvents such as diethyl ether or tetrahydrofuran, preferably tetrahydrofuran.
  • metal hydrides such as lithium aluminum hydride, diisobutyl aluminum hydride, sodium borohydride or lithium borohydride, preferably lithium aluminum hydride, in polar, nonreactive solvents such as diethyl ether or tetrahydrofuran, preferably tetrahydrofuran.
  • step 4a of Scheme 1 the chloroalkyl urea compound HIa is prepared by addition of a primary chloroalkylisocyanate to the aminoethylphenyl piperazine of formula IV in a non- polar, non-reactive solvent such as benzene, xylene or toluene, preferably toluene, at temperatures of from about 0° to about 50 0 C, preferably about room temperature (rt).
  • a non- polar, non-reactive solvent such as benzene, xylene or toluene, preferably toluene
  • step 5a of Scheme 1 the cyclic urea Ha is prepared by treating chloroalkyl urea compound Ilia with a base such as sodium hydride, sodium t-butoxide or potassium t-butoxide, preferably potassium t-butoxide, in non-protic solvent such as tetrahydrofuran, diethylether, or methylene chloride, preferably tetrahydrofuran.
  • a base such as sodium hydride, sodium t-butoxide or potassium t-butoxide, preferably potassium t-butoxide
  • non-protic solvent such as tetrahydrofuran, diethylether, or methylene chloride, preferably tetrahydrofuran.
  • step 6a of Scheme 1 the compound of formula Ia, wherein R 4 is an optionally substituted aryl (R 9 ) or heteroaryl (R 10 ), is prepared by treating a mixture of the compound Na and an aryl or heteroaryl chloride, bromide, iodide or sulfonate, preferably the bromide, with a base such as an alkali metal carbonate, an alkali metal amine base, an alkali metal phosphonate or an alkali metal alkoxide, preferably cesium carbonate, a phosphine ligand, preferably 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOSTM), a palladium species such as palladium (II) acetate or tris(dibenzylideneacetone)dipalladium (0) or the corresponding chloroform adduct, preferably tris(dibenzylideneacetone)dipalladium (0), in
  • the compound of formula Ia wherein R 4 is an optionally substituted aryl (R 9 ) or heteroaryl (Ri 0 ), is prepared by treating a mixture of the compound of the formula Na, and an aryl or heteroaryl chloride, bromide, iodide, or sulfonate, preferably the bromide, with a base such as potassium phosphate, potassium carbonate, sodium carbonate, thallium carbonate, cesium carbonate, potassium terf-butoxide, lithium ferf-butoxide, or sodium ferf-butoxide, preferably potassium carbonate, a diamine, such as 1 ,2- ethylenediamine, ⁇ /, ⁇ /'-dimethylethylenediamine, or cis-1 ,2-diaminocyclohexane, preferably ⁇ /, ⁇ /'-dimethylethylenediamine, cuprous chloride, bromide or iodide, preferably cuprous iodide, and
  • Steps 4b, 5b, 6b and 7 of Scheme 1 refer to an alternate method suitable for the preparation of compounds of formula Ia and Ib wherein q is 1.
  • the substituted urea of formula MIb is prepared by treating aminoethylphenyl piperazine IV with a substituted aminoacetaldehyde dimethylacetal isocyanate generated from a substituted aminoacetaldehyde dimethylacetal and a phosgene source such as diphosgene, triphosgene or phosgene, preferably triphosgene in the presence of a tertiary amine such as diisopropylethylamine or preferably triethylamine, in an inert solvent preferably methylene chloride.
  • step 5b of Scheme 1 the substituted cyclic urea of formula lib is prepared by treating substituted urea of formula MIb with an aqueous acid such as acetic acid, sulfuric acid or hydrochloric acid, preferably hydrochloric acid, in an alcoholic solvent such as methanol, ethanol, isopropanol or t-butanol, preferably methanol.
  • an aqueous acid such as acetic acid, sulfuric acid or hydrochloric acid, preferably hydrochloric acid
  • an alcoholic solvent such as methanol, ethanol, isopropanol or t-butanol, preferably methanol.
  • step 6b of Scheme 1 the compound of the formula Ib wherein R 4 is an optionally substituted aryl (R 9 ) or heteroaryl (R 10 ) is prepared by treating a mixture of the cyclic urea of formula lib and an aryl or heteroaryl chloride, bromide, iodide or sulfonate, preferably the bromide with a base such as potassium phosphate, potassium carbonate, sodium carbonate, thallium carbonate, cesium carbonate, potassium terf-butoxide, lithium terf-butoxide, or sodium terf-butoxide, preferably potassium carbonate, a diamine, such as 1 ,2-ethylenediamine, N,N'- dimethylethylenediamine, or cis-i ⁇ -diaminocyclohexane, preferably N 1 N- dimethylethylenediamine, cuprous chloride, bromide or iodide, preferably cuprous iodide, and a small amount of water,
  • step 7 of Scheme 1 the compound of formula Ia, wherein q is 1 is prepared by reducing the compound of formula 1b by means of catalytic hydrogenation using conditions such as 10% palladium on carbon under a pressure of about 1 to about 5 atmospheres of hydrogen or by means of transfer hydrogenation with ammonium formate and 10% palladium on carbon, preferably transfer hydrogenation, in a solvent such as EtOAc, ethanol or methanol, preferably methanol, at temperature of from about 20 0 C to about 100 0 C preferably about 65°C.
  • a solvent such as EtOAc, ethanol or methanol, preferably methanol
  • Scheme 2 refers to general methods suitable for the preparation of compounds of formula Ic wherein X is N and Y is CH, R 2 is hydrogen, (C r C 6 )alkyl, and (C 1 -C 6 )alkyl-phenyl and R 3 is hydrogen, (Ci-C 6 )alkyl, (CrQOalkyl-phenyl, and (C 1 -C 6 )alkyl-naphthyl.
  • the aldehyde of formula Via is prepared by treating 2-fluoro-pyridine-3- carbaldehyde (compound Vila) and with a substituted piperazine of the formula VIII in a solvent such as water, dioxane, n-butanol, DMF, DMSO or acetonitrile, preferably water, with a base such as a trialkylamine or an alkali metal carbonate, preferably potassium carbonate, at reaction temperatures of from about 4O 0 C to about 15O 0 C, preferably about 90° to about 12O 0 C.
  • a solvent such as water, dioxane, n-butanol, DMF, DMSO or acetonitrile, preferably water
  • a base such as a trialkylamine or an alkali metal carbonate, preferably potassium carbonate
  • step 2 of Scheme 2 the nitroethylene substituted pyridylpiperazine of formula Va is prepared by condensation of the aldehyde of formula Via with nitromethane or a nitroalkane in the presence of a catalytic amount of a base such as potassium t-butoxide in an alcoholic solvent preferably t-butanol.
  • a base such as potassium t-butoxide
  • an alcoholic solvent preferably t-butanol
  • aminoethylpyridylpiperazine IVa is prepared by reduction of the nitroethylene group of the compound of formula Va using procedures known in the art such as palladium catalyzed hydrogenation, treatment with zinc in acetic acid or treatment with metal hydrides such as lithium aluminum hydride, diisobutyl aluminum hydride, sodium borohydride or lithium borohydride, preferably lithium aluminum hydride, in polar, nonreactive solvents such as diethyl ether or tetrahydrofuran, preferably tetrahydrofuran.
  • metal hydrides such as lithium aluminum hydride, diisobutyl aluminum hydride, sodium borohydride or lithium borohydride, preferably lithium aluminum hydride
  • polar, nonreactive solvents such as diethyl ether or tetrahydrofuran, preferably tetrahydrofuran.
  • the substituted urea of formula INc is prepared by treating aminoethylpyridylpiperazine IVa with a substituted aminoacetaldehyde dimethylacetal isocyanate generated from a substituted aminoacetaldehyde dimethylacetal and a phosgene source such as diphosgene, triphosgene or phosgene, preferably triphosgene in the presence of a tertiary amine such as diisopropylethylamine or preferably triethylamine, in an inert solvent preferably methylene chloride.
  • a phosgene source such as diphosgene, triphosgene or phosgene, preferably triphosgene in the presence of a tertiary amine such as diisopropylethylamine or preferably triethylamine, in an inert solvent preferably methylene chloride.
  • step 5 of Scheme 2 the substituted cyclic urea of formula Mc is prepared by treating substituted urea of formula INc with an aqueous acid such as acetic acid, sulfuric acid or hydrochloric acid, preferably hydrochloric acid, in an alcoholic solvent such as methanol, ethanol, isopropanol or t-butanol, preferably methanol.
  • an aqueous acid such as acetic acid, sulfuric acid or hydrochloric acid, preferably hydrochloric acid
  • an alcoholic solvent such as methanol, ethanol, isopropanol or t-butanol, preferably methanol.
  • step 6 of Scheme 2 the compound of the formula Ic wherein R 4 is an optionally substituted aryl (R 9 ) or heteroaryl (R 10 ) is prepared by treating a mixture of the cyclic urea of formula Hc and an aryl or heteroaryl chloride, bromide, iodide or sulfonate, preferably the bromide with a base such as potassium phosphate, potassium carbonate, sodium carbonate, thallium carbonate, cesium carbonate, potassium terf-butoxide, lithium ferf-butoxide, or sodium terf-butoxide, preferably potassium carbonate, a diamine, such as 1 ,2-ethylenediamine, ⁇ /./V-dimethylethylenediamine, or cis-1 ,2- diaminocyclohexane, preferably ⁇ /, ⁇ /'-dimethylethylenediamine, cuprous chloride, bromide or iodide, preferably cuprous iodide, and a
  • Scheme 3 refers to general methods suitable for the preparation of compounds of formula Id wherein X is CH and Y is N, R 2 is hydrogen, (C r C 6 )alkyl, and (C 1 -C 6 )alkyl-phenyl and R 3 is hydrogen, (Ci-C 6 )alkyl, (C r C 6 )alkyl-phenyl and (C r C 6 )alkyl-naphthyl.
  • the aldehyde of formula VIb is prepared by treating 3-fluoro-pyridine-2- carbaldehyde (compound VIIb) and with a substituted piperazine of the formula VIII in a solvent such as water, dioxane, n-butanol, DMF, DMSO or acetonitrile, preferably water, with a base such as a trialkylamine or an alkali metal carbonate, preferably potassium carbonate, at reaction temperatures of from about 40 0 C to about 150 0 C, preferably about 90° to about 120 0 C.
  • a solvent such as water, dioxane, n-butanol, DMF, DMSO or acetonitrile, preferably water
  • a base such as a trialkylamine or an alkali metal carbonate, preferably potassium carbonate
  • step 2 of Scheme 3 the nitroethylene substituted pyridylpiperazine of formula Vb is prepared by condensation of the aldehyde of formula VIb with nitromethane or a nitroalkane in the presence of a catalytic amount of a base such as potassium t-butoxide in an alcoholic solvent preferably t-butanol.
  • a base such as potassium t-butoxide
  • an alcoholic solvent preferably t-butanol
  • aminoethylpyridylpiperazine IVb is prepared by reduction of the nitroethylene group of the compound of formula Vb using procedures known in the art such as palladium catalyzed hydrogenation, treatment with zinc in acetic acid or treatment with metal hydrides such as lithium aluminum hydride, diisobutyl aluminum hydride, sodium borohydride or lithium borohydride, preferably lithium aluminum hydride, in polar, nonreactive solvents such as diethyl ether or tetrahydrofuran, preferably tetrahydrofuran.
  • metal hydrides such as lithium aluminum hydride, diisobutyl aluminum hydride, sodium borohydride or lithium borohydride, preferably lithium aluminum hydride
  • polar, nonreactive solvents such as diethyl ether or tetrahydrofuran, preferably tetrahydrofuran.
  • step 4 of Scheme 3 the substituted urea of formula IHd is prepared by treating aminoethylpyridylpiperazine IVb with a substituted aminoacetaldehyde dimethylacetal isocyanate generated from a substituted aminoacetaldehyde dimethylacetal and a phosgene source such as diphosgene, triphosgene or phosgene, preferably triphosgene in the presence of a tertiary amine such as diisopropylethylamine or preferably triethylamine, in an inert solvent preferably methylene chloride.
  • a substituted aminoacetaldehyde dimethylacetal isocyanate generated from a substituted aminoacetaldehyde dimethylacetal and a phosgene source such as diphosgene, triphosgene or phosgene, preferably triphosgene in the presence of a tertiary amine such as diisopropylethylamine or preferably tri
  • step 5 of Scheme 3 the substituted cyclic urea of formula Hd is prepared by treating substituted urea of formula NId with an aqueous acid such as acetic acid, sulfuric acid or hydrochloric acid, preferably hydrochloric acid, in an alcoholic solvent such as methanol, ethanol, isopropanol or t-butanol, preferably methanol.
  • an aqueous acid such as acetic acid, sulfuric acid or hydrochloric acid, preferably hydrochloric acid
  • an alcoholic solvent such as methanol, ethanol, isopropanol or t-butanol, preferably methanol.
  • step 6 of Scheme 3 the compound of the formula Id wherein R 4 is an optionally substituted aryl (R 9 ) or heteroaryl (R 10 ) is prepared by treating a mixture of the cyclic urea of formula Hc and an aryl or heteroaryl chloride, bromide, iodide or sulfonate, preferably the bromide with a base such as potassium phosphate, potassium carbonate, sodium carbonate, thallium carbonate, cesium carbonate, potassium fe/f-butoxide, lithium terf-butoxide, or sodium tert- butoxide, preferably potassium carbonate, a diamine, such as 1 ,2-ethylenediamine, ⁇ /,/V- dimethylethylenediamine, or cis-1 ,2-diaminocyclohexane, preferably ⁇ /,/V- dimethylethylenediamine, cuprous chloride, bromide or iodide, preferably cuprous iodide, and a
  • Scheme 4 refers to general methods suitable for the preparation of compounds of formula Ie wherein n is one and m is zero.
  • oxime IX is prepared by treating compound Vl with hydroxylamine hydrochloride in the presence of a base such as an alkali metal bicarbonate, alkali metal carbonate, tertiary amines or pyridine preferably pyridine, in a solvent such as ethanol, methanol or in the absence of a solvent, preferably in the absence of a solvent.
  • benzylic amine IVe is prepared by reducing oxime IX using procedures known in the art such as palladium or nickel catalyzed hydrogenation or metal hydrides preferably lithium aluminum hydride.
  • step 3 of Scheme 4 the chloroethyl urea compound IHe is prepared by treating benzylic amine IVe with 2- chloroethylisocyanate in a non-polar, non-reactive solvent such as benzene, xylene or toluene, preferably toluene, at temperatures of from about 0° to about 5O 0 C, preferably about room temperature.
  • a non-polar, non-reactive solvent such as benzene, xylene or toluene, preferably toluene
  • cyclic urea lie is prepared by cydization of chloroethyl urea compound INe with a non-nucleophile base such as sodium hydride, sodium t-butoxide or potassium t-butoxide, preferably sodium hydride, in a non-protic solvent such as tetrahydrofuran, diethylether, or methylene chloride, preferably tetrahydrofuran.
  • a non-nucleophile base such as sodium hydride, sodium t-butoxide or potassium t-butoxide, preferably sodium hydride
  • a non-protic solvent such as tetrahydrofuran, diethylether, or methylene chloride, preferably tetrahydrofuran.
  • step 5 of Scheme 4 the compound of the formula Ie wherein R 4 is an optionally substituted aryl (R 9 ) or heteroaryl (R 10 ) is prepared by treating a mixture of the compound lie and an aryl or heteroaryl chloride, bromide, iodide or sulfonate, preferably the bromide, with a base such as an alkali metal carbonate, an alkali metal amine base, an alkali metal phosphonate or an alkali metal alkoxide, preferably cesium carbonate, a phosphine ligand, preferably 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (XANTPHOSTM), and a palladium species such as palladium (II) acetate or tris(dibenzylideneacetone)dipalladium (0) or the corresponding chloroform adduct, preferably tris(dibenzylideneacetone)dipalladium (0), in
  • Scheme 5 refers to general methods suitable for the preparation of compounds of formula If wherein n is zero and m is zero.
  • the compound of the formula X is prepared by treating a 2-halo-3-nitropyridine (formula Xl), preferably 2-chloro-3- nitropyridine Xl with a substituted piperazine of the formula VIII in a solvent such as water, dioxane, n-butanol, DMF, DMSO or acetonitrile, preferably water, with a base such as an alkali metal carbonate, preferably potassium carbonate, at reaction temperatures of from about 40 0 C to about 150 0 C, preferably about 90°C to about 120°C.
  • a base such as an alkali metal carbonate, preferably potassium carbonate
  • step 2 of Scheme 5 the compound of the formula IVf is prepared by reducing the compound of formula X using procedures known in the art such as palladium or nickel catalyzed hydrogenation, transfer hydrogenation or metal hydrides preferably palladium catalyzed transfer hydrogenation.
  • step 3 of Scheme 5 the chloroethyl urea of the formula IHf is prepared by treating the compound of formula IVf with 2-chloroethylisocyanate in a non-polar, non-reactive solvent such as benzene, xylene or toluene, preferably toluene, at temperatures of from about 0 0 C to about 50 0 C, preferably about room temperature.
  • a non-polar, non-reactive solvent such as benzene, xylene or toluene, preferably toluene
  • the cyclic urea of the formula Hf is prepared by cyclization of the chloroethyl urea of the formula HIf with a non- nucleophile base such as sodium hydride, sodium t-butoxide or potassium t-butoxide, preferably sodium hydride, in a non-protic solvent such as dimethylformamide, tetrahydrofuran, diethylether, or methylene chloride, preferably dimethylformamide.
  • a non- nucleophile base such as sodium hydride, sodium t-butoxide or potassium t-butoxide, preferably sodium hydride
  • a non-protic solvent such as dimethylformamide, tetrahydrofuran, diethylether, or methylene chloride, preferably dimethylformamide.
  • step 5 of Scheme 5 the compound of formula If, wherein R 4 is an optionally substituted aryl (R 9 ) or heteroaryl (R 10 ), is prepared by treating a mixture of the cyclic urea of the formula Mf and an aryl or heteroaryl chloride, bromide, iodide or sulfonate, preferably the bromide, with a base such as potassium phosphate, potassium carbonate, sodium carbonate, thallium carbonate, cesium carbonate, potassium terf-butoxide, lithium tert-butoxide, or sodium terf-butoxide, preferably potassium phosphate, a diamine, such as 1 ,2-ethylenediamine, /V 1 W- dimethylethylenediamine, or cis-1 ,2-diaminocyclohexane, preferably /V 1 W- dimethylethylenediamine, cuprous chloride, cuprous bromide or cuprous iodide, preferably cuprous iodide,
  • Scheme 6 refers to general methods suitable for the preparation of compounds of formula Ig wherein X and Y are N and n and m are one.
  • an aldehyde of formula VIc is prepared by treating a 2-halo-3-formylpyrazine of the formula VIIc, wherein L is F, Cl, Br or I (prepared according to the methods of A. Turck, et al., Synthesis, 1988, 881-884 and N.
  • PIe A et al., Tetrahedron, 1998, 54, 4899-4912
  • a substituted piperazine of the formula VIII in a solvent such as water, a lower alcohol, acetonitrile, tetrahydrofuran, 1 ,4- dioxane or mixtures thereof, preferably 1 ,4-dioxane, in the-presence of a base such as a trialkyiamine an alkali metal carbonate or an alkali metal hydrogen carbonate, preferably potassium carbonate at a temperature of about O 0 C to about 15O 0 C, preferably about 60 0 C to 12O 0 C.
  • a base such as a trialkyiamine an alkali metal carbonate or an alkali metal hydrogen carbonate, preferably potassium carbonate at a temperature of about O 0 C to about 15O 0 C, preferably about 60 0 C to 12O 0 C.
  • step 2 of Scheme 6 the nitroethylene substituted pyrazylpiperazine of the formula Vc is prepared by condensation of the aldehyde of formula VIc with nitromethane or a nitroalkane in the presence of a catalytic amount of a base such as potassium t-butoxide in an alcoholic solvent preferably t-butanol.
  • step 3 of Scheme 6 the nitroethyl compound of formula Vd is prepared by treating the nitroethylene substituted pyrazylpiperazine of the formula Vc with a metal hydride reducing agent, preferably sodium borohydride, in an alcoholic solvent such as methanol, ethanol or t-butanol, preferably ethanol.
  • aminoethylpyrazylpiperazine of formula IVc is prepared by hydrogenation of the nitroethyl compound of formula Vd with an activated metal catalyst such as Raney nickel, palladium on carbon, or platinum oxide, preferably Raney nickel in an alcoholic solvent such as methanol or ethanol, preferably ethanol.
  • an activated metal catalyst such as Raney nickel, palladium on carbon, or platinum oxide, preferably Raney nickel in an alcoholic solvent such as methanol or ethanol, preferably ethanol.
  • the substituted urea of formula MIg is prepared by treating aminoethylpyrazylpiperazine IVc with a substituted aminoacetaldehyde dimethylacetal isocyanate generated from a substituted aminoacetaldehyde dimethylacetal and a phosgene source such as diphosgene, triphosgene or phosgene, preferably triphosgene in the presence of a tertiary amine such as diisopropylethylamine or preferably triethylamine, in an inert solvent preferably methylene chloride.
  • a substituted aminoacetaldehyde dimethylacetal isocyanate generated from a substituted aminoacetaldehyde dimethylacetal and a phosgene source
  • diphosgene, triphosgene or phosgene preferably triphosgene in the presence of a tertiary amine such as diisopropylethylamine or preferably triethylamine, in an
  • step 6 of Scheme 6 the substituted cyclic urea of the formula Hg is prepared by treating substituted urea of formula INg with an aqueous acid such as acetic acid, sulfuric acid or hydrochloric acid, preferably hydrochloric acid, in an alcoholic solvent such as methanol, ethanol, isopropanol or t-butanol, preferably methanol.
  • an aqueous acid such as acetic acid, sulfuric acid or hydrochloric acid, preferably hydrochloric acid
  • an alcoholic solvent such as methanol, ethanol, isopropanol or t-butanol, preferably methanol.
  • step 7 of Scheme 6 the compound of the formula Ig wherein R 4 is an optionally substituted aryl (R 9 ) or heteroaryl (R 10 ) is prepared by treating a mixture of the cyclic urea of formula Hg and an aryl or heteroaryl chloride, bromide, iodide or sulfonate, preferably the bromide with a base such as potassium phosphate, potassium carbonate, sodium carbonate, thallium carbonate, cesium carbonate, potassium fe/f-butoxide, lithium terf-butoxide, or sodium tert-butoxide, preferably potassium carbonate, a diamine, such as 1 ,2-ethylenediamine, ⁇ /./V-dimethylethylenediamine, or cis-1 ,2-diaminocyclohexane, preferably /V.W-dimethylethylenediamine, cuprous chloride, bromide or iodide, preferably cuprous iodide, and
  • Scheme 7 refers to general methods suitable for the preparation of compounds of formula Ih wherein X is CH, Y is CH or N, R 1 is G 2 wherein Z is independently CH or N and n and m are one.
  • a compound of the formula XII is prepared by treating a compound of the formula IV (Scheme 1 ) or IVb (Scheme 3) with 2-halo-1 -nitrobenzene or 2- halo-3-nitropyridine, preferably 2-fluoro-1 -nitrobenzene or 2-chloro-3-nitropyridine in a solvent such as water, dioxane, n-butanol, DMF, DMSO or acetonitrile, preferably water, with a base such as an alkali metal carbonate, preferably potassium carbonate, at reaction temperatures of from about 40 0 C to about 150 0 C, preferably about 90°C to about 120 0 C.
  • a compound of the formula XIII is prepared by reduction of the nitro group of the compound of the formula XII by means of hydrogenation with an activated metal catalyst such as Raney nickel, palladium on carbon, or platinum oxide, preferably Raney nickel and palladium on carbon, in an alcoholic solvent such as methanol or ethanol.
  • an activated metal catalyst such as Raney nickel, palladium on carbon, or platinum oxide, preferably Raney nickel and palladium on carbon, in an alcoholic solvent such as methanol or ethanol.
  • a benzimidizone of the formula Hh is prepared by treating the compound of formula XIII with a phosgene source such as diphosgene, triphosgene or phosgene, preferably triphosgene, in a reaction inert solvent preferably methylene chloride, in the presence of a trialkylamine base such as triethylamine or diisopropyl-ethyl amine preferably triethylamine at temperatures of from about -10 0 C to about 30 0 C, preferably about O 0 C to about 20 0 C.
  • a phosgene source such as diphosgene, triphosgene or phosgene, preferably triphosgene
  • a reaction inert solvent preferably methylene chloride
  • a compound of the formula Ih wherein R 4 is an optionally substituted aryl (Rg) or heteroaryl (R 10 ) is prepared by treating a mixture of the benzimidizone of formula Nh and an aryl or heteroaryl chloride, bromide, iodide or sulfonate, preferably the bromide with a base such as potassium phosphate, potassium carbonate, sodium carbonate, thallium carbonate, cesium carbonate, potassium tert-butoxide, lithium terf-butoxide, or sodium terf-butoxide, preferably potassium carbonate, a diamine, such as 1 ,2- ethylenediamine, ⁇ /./V-dimethylethylenediamine, or cis-i ⁇ -diaminocyclohexane, preferably ⁇ /,/V- dimethylethylenediamine, cuprous chloride, bromide or iodide, preferably cuprous iodide, and a
  • a compound of the formula Ih may also be prepared by treating the benzimidizone of formula Hh and an aryl or heteroaryl boronic acid with a tertiary amine base such as diisopropylethylamine or preferably triethylamine, and copper (II) acetate in a reaction inert solvent such as methylene chloride at temperatures of from about 0°C to about 3O 0 C, preferably at about 2O 0 C to about 25 0 C.
  • a reaction inert solvent such as methylene chloride
  • Scheme 8 refers to general methods suitable for the preparation of compounds of formula Ii and Ij wherein X and Y are independently CH or N, R 1 is G 5 or G 6 and n and m are one.
  • a compound of the formula XIV is prepared by treating a compound of the formula IV with an optionally substituted phthalic anhydride in a solvent or mixture of solvents preferably a mixture of methylene chloride and tetrahydrofuran, at temperatures ranging from about 0 0 C to about 50 0 C preferably about 20 0 C to about 25°C.
  • a phthalamide of the formula Ii is prepared by treating a compound of the formula XIV with an organic or inorganic acid such as sulfuric acid, hydrochloric acid or acetic acid, preferably acetic acid, at temperatures ranging from about 50 0 C to about 150°C, preferably about 100 0 C to about 120 0 C.
  • an organic or inorganic acid such as sulfuric acid, hydrochloric acid or acetic acid, preferably acetic acid
  • a compound of the formula XV, wherein R 9 is (Ci-Cejalkyl or benzyl may be prepared by coupling a compound of the formula IV with optionally substituted phthalic acid monoesters using coupling agents such as EDC, DCC or BOP reagent preferably BOP reagent, in the presence of a non-reactive tertiary amine such as triethylamine or preferably diisopropylethyl amine in polar non-reactive solvents such as tetrahydrofuran, dioxane or preferably methylene chloride, at temperatures ranging from about 0 0 C to about 50 0 C preferably about 20°C to about 25°C.
  • coupling agents such as EDC, DCC or BOP reagent preferably BOP reagent
  • a compound of the formula Ii is prepared by treating a compound of the formula XV with an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, preferably lithium hydroxide, in an alcoholic solvent, preferably ethanol, at temperatures ranging from about 0 0 C to about 100°C, preferably about 2O 0 C to about 25°C.
  • an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, preferably lithium hydroxide
  • an alcoholic solvent preferably ethanol
  • a compound of the formula Ij is prepared by treating a compound of the formula Ii with a metal hydride reducing agent such as lithium aluminum hydride, diisobutyllaluminum hydride or borane, preferably lithium aluminum hydride, in a suitably inert solvent, preferably tetrahydrofuran, at temperatures ranging from about O 0 C to about 100 0 C, preferably about 50 0 C to about 70 0 C.
  • a metal hydride reducing agent such as lithium aluminum hydride, diisobutyllaluminum hydride or borane, preferably lithium aluminum hydride, in a suitably inert solvent, preferably tetrahydrofuran, at temperatures ranging from about O 0 C to about 100 0 C, preferably about 50 0 C to about 70 0 C.
  • Scheme 9 refers to general methods suitable for the preparation of a compound of the formula Ik wherein X and Y are independently CH or N, R 1 is G 4 and n and m are one.
  • the amido compound of the formula XVI is prepared by treating a compound of the formula IV with an optionally substituted anthranilic acid in the presence of a coupling agent such as EDC, DCC or BOP reagent, preferably BOP reagent and a non- reactive tertiary amine such as triethylamine or preferably diisopropylethyl amine in a polar non-reactive solvent such as tetrahydrofuran, dioxane or methylene chloride, preferably methylene chloride, at temperatures ranging from about O 0 C to about 5O 0 C, preferably about 20 0 C to about 25°C.
  • a coupling agent such as EDC, DCC or BOP reagent, preferably BOP reagent and a non- reactive
  • step 2 of Scheme 9 the compound of formula Ik is prepared by treating the compound of the formula XVI with a reactive carbonylating agent such as triphosgene, diphosgene, phosgene or methylchloroformate, preferably methylchloroformate, in the presence of a base such as triethylamine, diisopropylethyl amine, or alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably potassium hydroxide, in a mixture of water and an alcoholic solvent, preferably ethanol, at temperatures ranging from about O 0 C to about 100°C, preferably about 20°C to about 25°C.
  • a reactive carbonylating agent such as triphosgene, diphosgene, phosgene or methylchloroformate, preferably methylchloroformate
  • a base such as triethylamine, diisopropylethyl amine, or alkali metal hydroxides such as
  • Steps 1a and 2a of Scheme 9 depict an alternate preparation of the compound of the formula Ik.
  • the urea compound of formula XVII is prepared by treating the compound of the formula IV with an optionally substituted anthranilic acid ester isocyanate, said isocyanate generated by treatment of an optionally substituted anthranilic acid ester with a phosgene source such as diphosgene, triphosgene or phosgene, preferably triphosgene, in an inert solvent, preferably methylene chloride, in the presence of a trialkylamine base such as triethylamine or diisopropyl-ethyl amine, preferably triethylamine at temperatures of from about -10 0 C to about 30 0 C, preferably about 0°C to about 20 0 C.
  • step 2a of Scheme 9 the compound of formula Ik, wherein R 5 is H, is prepared by treating the urea of formula XVII with an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, calcium hydroxide or lithium hydroxide, preferably lithium hydroxide, in an alcoholic solvent, preferably methanol, at temperatures ranging from about 0 0 C to about
  • an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, calcium hydroxide or lithium hydroxide, preferably lithium hydroxide
  • an alcoholic solvent preferably methanol
  • (Ci-C 6 )alkyl or aryl-(C 1 -C 6 )alkyl- wherein said aryl moiety is phenyl or naphthyl, wherein said aryl moiety may optionally be substituted, may prepared from the compound of formula Ik wherein R 5 is hydrogen by means known in the art.
  • the R 8 group of compound Ik may be further modified into other R 8 groups by methods familiar to those skilled in the art.
  • Scheme 10 refers to general methods suitable for the preparation of compounds of the formula IL and Im wherein X and Y are CH, R 1 is G 7 or G 8 , n is one, m is zero and R 2 is absent.
  • the imine of formula XIXa is prepared by treating an optionally substituted phenethylamine of the formula XVIII with 2-bromobenzaldehyde in a polar protic solvent such as methanol or ethanol, preferably ethanol, at temperatures ranging from about 0 0 C to about 50°C, preferably about 20 0 C to about 25°C.
  • a polar protic solvent such as methanol or ethanol, preferably ethanol
  • amino compound XIX is prepared by treating the imine XIXa with a metal hydride reducing agent such as lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, preferably sodium borohydride.
  • a metal hydride reducing agent such as lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, preferably sodium borohydride.
  • step 3 of Scheme 10 the compound of formula XX is prepared by treating the amino compound of formula XIX with methylchloroformate and a tertiary amine such as diisopropylethylamine or preferably triethylamine in a reaction inert solvent such as methylene chloride, tetrahydrofuran or diethylether, preferably diethylether, at temperatures ranging from about -20 0 C to about 30 0 C preferably about -10 0 C to about 5°C.
  • a reaction inert solvent such as methylene chloride, tetrahydrofuran or diethylether, preferably diethylether
  • step 4 of Scheme 10 the compound of formula XXI is prepared by treating the compound of formula XX with strongly acidic, dehydrating media preferably a mixture of phosphorus pentoxide and phosphorus oxychloride at temperatures ranging from about 6O 0 C to about 140 0 C preferably 90 0 C to about 110 0 C.
  • step 5 of Scheme 10 the compound of formula IL is prepared from the compound of formula XXI by use of a transition metal such as palladium preferably by the method described in Buchwald, et al., J. Org. Chem. 2000, 65, 1144-1157 and 1158-1174.
  • Compound XXI and an N-substituted, optionally ring substituted, piperazine are treated in a solvent such as toluene, benzene, or DME, preferably toluene, with a base such as sodium or potassium tert-butoxide, sodium or potassium carbonate, potassium phosphonate, preferably sodium tert-butoxide, and a palladium source such as tetrakis(triphenyiphosphine)palladium, palladium acetate, tris(dibenzylideneacetone)dipalladium, dichlorobis(triphenylphosphine)palladium and an optionally added phosphine ligand such as BINAP or triphenylphosphine preferably palladium acetate and BINAP at a temperature of about 40 0 C to about 150 0 C, preferably about 90°C to about 120 °C.
  • a solvent such as toluene, benzene
  • the compound of formula Im is prepared by treating the compound of the formula IL with a metal hydride reducing agent such as borane, diisobutylaluminum hydride or lithium aluminum hydride, preferably lithium aluminum hydride, in an inert solvent, preferably tetrahydrofuran, at temperatures ranging from about 30°C to about 100°C preferably about 50 0 C to about 70 0 C.
  • a metal hydride reducing agent such as borane, diisobutylaluminum hydride or lithium aluminum hydride, preferably lithium aluminum hydride
  • an inert solvent preferably tetrahydrofuran
  • Scheme 11 refers to general methods suitable for the preparation of compounds of the formula In wherein X and Y are independently CH or N, R 1 is G 7 , n is one, m is zero and R 2 is absent.
  • step 1 of Scheme 11 the compound of formula XXIII is prepared by treating the compound of formula XXII (prepared according to J. Med.
  • a metal hydride metal hydride reducing agent such as borane, diisobutylaluminum hydride or lithium aluminum hydride, preferably lithium aluminum hydride, in an inert solvent, preferably an ethereal solvent, most preferably tetrahydrofuran at temperatures ranging from about 30°C to about 100 0 C preferably about 50 0 C to about 7O 0 C.
  • step 2 of Scheme 11 the compound of formula In is prepared from the compound of formula XXIII by reductive amination with an aldehyde of formula Vl, Via, VIb or VIc in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, preferably sodium triacetoxyborohydride, in a suitably inert solvent such as methylene chloride or 1 ,2-dichloroethane, preferably 1 ,2- dichloroethane, at about 20 0 C to about 25°C.
  • a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, preferably sodium triacetoxyborohydride
  • a suitably inert solvent such as methylene chloride or 1 ,2-dichloroethane, preferably 1 ,2- dichloroethane, at about 20 0 C to about 25°C.
  • the R 8 group of compound In may be further modified into other R 8 groups by methods familiar to
  • Scheme 12 refers to general methods suitable for the preparation of compounds of the formula Io wherein X and Y are independently CH or N, R 1 is G 8 , n is one, m is one and R 2 is hydrogen, (C r C 6 )alkyl or (C 1 -C 6 )alkyl-phenyl.
  • step 1 of Scheme 12 the compound of formula XXV is prepared from optionally substituted 2-methyl-benzonitrile of formula XXIV by treatment with t-butoxybis(dimethylamino)methane at a temperature of about 100 0 C to about 180°C preferably about 130 0 C to about 150°C.
  • step 2 of Scheme 12 the aldehyde of formula XXVI is prepared by hydrolysis of the compound of formula XXV with an aqueous acid such as hydrochloric acid, sulfuric acid or acetic acid, preferably acetic acid, at temperatures of about 0° to about 80 0 C, preferably at ambient temperature.
  • an aqueous acid such as hydrochloric acid, sulfuric acid or acetic acid, preferably acetic acid
  • step 3 of Scheme 12 the compound of formula XXVII is prepared by treating the aldehyde of formula XXVI with a substituted ethylamine of formula IV, IVa, IVb or IVc in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, preferably sodium triacetoxyborohydride, in a suitably inert solvent such as methylene chloride or 1 ,2- dichloroethane, preferably 1 ,2-dichloroethane, at about 2O 0 C to about 24°C.
  • a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, preferably sodium triacetoxyborohydride
  • a suitably inert solvent such as methylene chloride or 1 ,2- dichloroethane, preferably 1 ,2-dichloroethane, at about 2O 0 C to about 24°C.
  • step 4 of Scheme 12 the compound of formula Io is prepared by treating the compound of formula XXVII with an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, calcium hydroxide or lithium hydroxide, preferably lithium hydroxide, in an alcoholic solvent, preferably methanol, at temperatures ranging from about 0 0 C to about 100 0 C preferably about 40 0 C to about 80°C.
  • an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, calcium hydroxide or lithium hydroxide, preferably lithium hydroxide
  • an alcoholic solvent preferably methanol
  • Scheme 13 refers to general methods suitable for the preparation of compounds of the formula Ip wherein X and Y are independently CH or N, Ri is G 9 , n is one, m is one and R 2 is hydrogen, (C r C 6 )alkyl or (C 1 -C 6 )alkyl-phenyl and an alternative preparation of compounds of the formula Ij wherein X and Y are independently CH or N, R 1 is G 5 , n is one, m is one and R 2 is hydrogen, (CrC 6 )alkyl or (C 1 -C 6 )alkyl-phenyl.
  • step 1 of Scheme 13 the compound of formula Ip is prepared by treating a substituted ethylamine of formula IV, IVa, IVb or IVc, with a trialkyl amine such as diisopropylethylamine or triethylamine, preferably triethylamine, and an optionally substituted 2-(halomethyl)-benzoic acid ester, wherein halo is Cl, Br or I, preferably Br, at temperatures ranging from about 0 0 C to about 50°C, preferably ambient temperature.
  • a trialkyl amine such as diisopropylethylamine or triethylamine, preferably triethylamine
  • 2-(halomethyl)-benzoic acid ester wherein halo is Cl, Br or I, preferably Br, at temperatures ranging from about 0 0 C to about 50°C, preferably ambient temperature.
  • the 2-(bromomethyl)-benzoic acid ester may be prepared by treating an optionally substituted 2-methylbenzoic acid ester with N-bromosuccinimide in an inert solvent such as carbon tetrachloride or benzene, preferably benzene, in the presence of a radical initiator such as AIBN or benzoyl peroxide, preferably benzoyl peroxide, at temperatures ranging from about 30 0 C to about 120 0 C preferably about 50°C to about 80°C.)
  • an inert solvent such as carbon tetrachloride or benzene, preferably benzene
  • a radical initiator such as AIBN or benzoyl peroxide, preferably benzoyl peroxide
  • step 2 of Scheme 13 compound Ij is prepared by reduction of compound Ip with a metal hydride reducing agent such as borane, diisobutylaluminum hydride or lithium aluminum hydride, preferably lithium aluminum hydride, in an inert solvent, preferably an ethereal solvent, most preferably tetrahydrofuran at temperatures ranging from about 30°C to about 100 0 C preferably about 50°C to about 70 0 C.
  • a metal hydride reducing agent such as borane, diisobutylaluminum hydride or lithium aluminum hydride, preferably lithium aluminum hydride
  • an inert solvent preferably an ethereal solvent, most preferably tetrahydrofuran at temperatures ranging from about 30°C to about 100 0 C preferably about 50°C to about 70 0 C.
  • the activity of the compounds of the present invention with respect to 5HT 1B (formerly 5HT 10 ) binding ability can be determined using standard radioligand binding assays as described in the literature.
  • the 5-HT 1A affinity can be measured using the procedure of Hoyer et al. (Brain Res., 1986, 376, 85).
  • the 5-HT 1D affinity can be measured using the procedure of
  • the in vitro activity of the compounds of the present invention at the 5-HT 1D binding site may be determined according to the following procedure.
  • Bovine caudate tissue is homogenized and suspended in 20 volumes of a buffer containing 50 mM TRIS. hydrochloride (tris[hydroxymethyl]aminomethane hydrochloride) at a pH of 7.7.
  • the homogenate is then centrifuged at 45,000 G for 10 minutes.
  • the supernatant is then discarded and the resulting pellet resuspended in approximately 20 volumes of 50 mM TRIS. hydrochloride buffer at pH 7.7.
  • This suspension is then pre-incubated for 15 minutes at 37 0 C, after which the suspension is centrifuged again at 45,000 G for 10 minutes and the supernatant discarded.
  • the resulting pellet (approximately 1 gram) is resuspended in 150 ml of a buffer of 15 mM TRIS. hydrochloride containing 0.01 percent ascorbic acid with a final pH of 7.7 and also containing 10 ⁇ M pargyline and 4 mM calcium chloride (CaCI 2 ).
  • the suspension is kept on ice at least 30 minutes prior to use.
  • the inhibitor, control or vehicle is then incubated according to the following procedure.
  • a 20 percent dimethylsulfoxide (DMSO)/80 percent distilled water solution is added 200 ⁇ l of tritiated 5-hydroxytryptamine (2 nM) in a buffer of 50 mM TRIS.hydrochloride containing 0.01 percent ascorbic acid at pH 7.7 and also containing 10 ⁇ M pargyline and 4 ⁇ M calcium chloride, plus 100 nM of 8-hydroxy-DPAT (dipropylaminotetraline) and 100 nM of mesulergine.
  • DMSO dimethylsulfoxide
  • distilled water solution is added 200 ⁇ l of tritiated 5-hydroxytryptamine (2 nM) in a buffer of 50 mM TRIS.hydrochloride containing 0.01 percent ascorbic acid at pH 7.7 and also containing 10 ⁇ M pargyline and 4 ⁇ M calcium chloride, plus 100 nM of 8-hydroxy-DPAT (dipropy
  • the suspension is then incubated in a shaking water bath for 30 minutes at 25 0 C. After incubation is complete, the suspension is filtered using glass fiber filters (e.g., Whatman GF/B-filters.TM.). The pellet is then washed three times with 4 ml of a buffer of 50 mM TRIS.hydrochloride at pH 7.7. The pellet is then placed in a scintillation vial with 5 ml of scintillation fluid (aquasol 2TM) and allowed to sit overnight. The percent inhibition can be calculated for each dose of the compound. An IC 50 value can then be calculated from the percent inhibition values. Of the compounds tested, 5HT 1B IC 50 was less than about 500 nM.
  • the activity of the compounds of the present invention for 5-HT 1A binding ability can be determined according to the following procedure. Rat brain cortex tissue is homogenized and divided into samples of 1 gram lots and diluted with 10 volumes of 0.32 M sucrose solution. The suspension is then centrifuged at 900G for 10 minutes and the supernate separated and recentrifuged at 70,000 G for 15 minutes. The supernate is discarded and the pellet re-suspended in 10 volumes of 15 mM TRIS. hydrochloride at pH 7.5. The suspension is allowed to incubate for 15 minutes at 37°C. After pre-incubation is complete, the suspension is centrifuged at 70,000 G for 15 minutes and the supernate discarded.
  • the resulting tissue pellet is resuspended in a buffer of 50 mM TRIS. hydrochloride at pH 7.7 containing 4 mM of calcium chloride and 0.01 percent ascorbic acid.
  • the tissue is stored at -70° C until ready for an experiment.
  • the tissue can be thawed immediately prior to use, diluted with 10 ⁇ m pargyline and kept on ice.
  • the tissue is then incubated according to the following procedure. Fifty microliters of control, inhibitor, or vehicle (1 percent DMSO final concentration) is prepared at various dosages. To this solution is added 200 ⁇ l of tritiated DPAT at a concentration of 1.5 nM in a buffer of 50 mM TRIS.
  • 5-HT 1 receptors can be determined using a single saturating concentration according to the following procedure. Male Hartley guinea pigs are decapitated and 5-HT 1A receptors are dissected out of the hippocampus, while 5-HTi D receptors are obtained by slicing at 350 mM on a Mcllwain tissue chopper and dissecting out the substantia nigra from the appropriate slices. The individual tissues are homogenized in 5 mM HEPES buffer containing 1 mM EGTA (pH 7.5) using a hand-held glass-Teflon ® homogenizer and centrifuged at 35,000xg for 10 minutes at 4°C.
  • the pellets are resuspended in 100 mM HEPES buffer containing 1 mM EGTA (pH 7.5) to a final protein concentration of 20 mg (hippocampus) or 5 mg (substantia nigra) of protein per tube.
  • the following agents are added so that the reaction mix in each tube contained 2.0 mM MgCI 2 , 0.5 mM ATP, 1.0 mM cAMP, 0.5 mM IBMX, 10 mM phosphocreatine, 0.31 mg/mL creatine phosphokinase, 100 ⁇ M GTP and 0.5-1 microcuries of [ 32 P]-ATP (30 Ci/mmol: NEG-003-New England Nuclear).
  • Incubation is initiated by the addition of tissue to siliconized microfuge tubes (in triplicate) at 30° C. for 15 minutes. Each tube receives 20 ⁇ l_ tissue, 10 ⁇ L drug or buffer (at 10x final concentration), 10 ⁇ L 32 nM agonist or buffer (at 10x final concentration), 20 ⁇ L forskolin (3 ⁇ M final concentration) and 40 ⁇ L of the preceding reaction mix. Incubation is terminated by the addition of 100 ⁇ L 2% SDS, 1.3 mM cAMP, 45 mM ATP solution containing 40,000 dpm [ 3 H]-CAMP (30 Ci/mmol: NET- 275— New England Nuclear) to monitor the recovery of cAMP from the columns.
  • the compounds of the invention can be tested for in vivo activity for antagonism of 5- HT 10 agonist-induced hypothermia in guinea pigs according to the following procedure.
  • the guinea pigs are housed under standard laboratory conditions on a 7 a.m. to 7 p.m. lighting schedule for at least seven days prior to experimentation. Food and water are available ad libitum until the time of testing.
  • the compounds of the invention can be administered as solutions in a volume of 1 ml/kg.
  • the vehicle used is varied depending on compound solubility.
  • Test compounds are typically administered either sixty minutes orally (p.o.) or 0 minutes subcutaneously (s.c.) prior to a 5-HT 1D agonist, such as [3-(1-methylpyrrolidin-2-ylmethyl)-1 H-indol-5-yl]-(3-nitropyridin-3- yl)-amine, which can be prepared as described in PCT publication WO93/11106, published Jun. 10, 1993 which is administered at a dose of 5.6 mg/kg, s.c. Before a first temperature reading is taken, each guinea pig is placed in a clear plastic shoe box containing wood chips and a metal grid floor and allowed to acclimate to the surroundings for 30 minutes.
  • a 5-HT 1D agonist such as [3-(1-methylpyrrolidin-2-ylmethyl)-1 H-indol-5-yl]-(3-nitropyridin-3- yl)-amine
  • a "pre-drug" baseline temperature reading is made at - 90 minutes, the test compound is given at -60 minutes and an additional -30 minute reading is taken.
  • the 5-HTi D agonist is then administered at 0 minutes and temperatures are taken 30, 60, 120 and 240 minutes later.
  • a pre-drug baseline temperature reading is made at -30 minutes.
  • the test compound and 5-HTi D agonists are given concurrently and temperatures are taken at 30, 60, 120 and 240 minutes later.
  • the active compounds of the invention can be evaluated as anti-migraine agents by testing the extent to which they mimic sumatriptan in contracting the dog isolated saphenous vein strip (P. PA Humphrey et al., Br. J. Pharmacol., 94, 1128 (1988)). This effect can be blocked by methiothepin, a known serotonin antagonist.
  • Sumatriptan is known to be useful in the treatment of migraine and produces a selective increase in carotid vascular resistance in the anesthetized dog. The pharmacological basis of sumatriptan efficacy has been discussed in W. Fenwick et al., Br. J. Pharmacol., 96, 83 (1989).
  • the serotonin 5-HT 1 agonist activity can be determined by the in vitro receptor binding assays, as described for the 5-HT 1A receptor using rat cortex as the receptor source and [ 3 H]-8-OH-DPAT as the radioligand (D. Hoyer et al. Eur. J. Pharm., 118, 13 (1985)) and as described for the 5-HT 1D receptor using bovine caudate as the receptor source and [ 3 H]serotonin as the radioligand (R. E. Heuring and S. J. Peroutka, J. Neuroscience, 1987, 7, 894).
  • EXAMPLE 1 1 -(2-r2-(4-Methyl-piperazin-1 -yl)-phenvH-ethyl ⁇ -3-(4-trif luoromethyl-phenvD-1 ,3-dihydro- imidazol-2-one.
  • Example 1 (0.013 g, 0.03 mmol), ammonium formate (0.03 g, 0.48 mmol) and 10% palladium on carbon (0.014 g) were refluxed in methanol for 16 hrs. Additional portions of ammonium formate (0.20 g, 3.2 mmol) and 10% palladium on carbon (0.050 g) were added and the reflux continued for another 24 hrs, then filtered (Celite) and concentrated. The residue was partitioned between EtOAc and aq. K 2 CO 3 , the organics were then washed with brine, dried (MgSO 4 ) and concentrated to yield 11 mg (84%) of the title compound as a white solid. The NMR spectrum of this mate ⁇ al was identical to that prepared above.
  • Example 12 0.466 mmol and copper (ll)acetate (0.056 g, 0.4308 mmol) in CH 2 CI 2 (2mL) were stirred for 4 days at rt. The mixture was concentrated, EtOAc and aq. K 2 CO 3 were added and the mixture was stirred vigorously for 90 min, then filtered (Celite) to remove insoluble copper salts. The organic phase was washed with brine, dried (MgSO 4 ) and concentrated to yield 16 mg (22%) of Example 12 as a light tan oil. The maleate salt had: mp ⁇ 120-140°C (amorphous); NMR
  • PP27 (0.100 g, 0.297 mmol), PP49 (0.086 g, 0.356 mmol), copper (I) iodide (66 mg, 0.35 mmol), N, N'-dimethylethylenediamine (66 ⁇ L, 0.61 mmol), K 2 CO 3 (0.094 g, 0.713 mmol) and toluene (1 mL) were degassed with N 2 and heated in a sealed tube at 115°C for 48 hrs. Following cooling, EtOAc was added and the mixture washed with water and brine. The organics were dried (MgSO 4 ) and concentrated to give a yellow oil (153 mg).
  • EXAMPLE 16 Syntheses of the compounds below are essentially the same procedure as described in Example 15 with the noted changes: A. 3- ⁇ 2-r2-(4-M ⁇ thylpiperazin-1-yl)phenv ⁇ ethyl ⁇ -7-phenyl-1 H-quinazoline- 2,4-dione. Using PP35 in place of PP34, yield 30%.
  • EXAMPLE 18 5-tert-Butyl-2- ⁇ 2-r2-(4-methylpiperazin
  • the aqueous phase was acidified with 1 N HCI and extracted with EtOAC (2x200 mL). The extracts were washed with water and brine, dried (MgSO 4 ) and concentrated to a sticky white solid (1.17g) which was shown by NMR to be a mixture of mono esterified regioisomers, biphenyl-3,4-dicarboxylic acid 3-ethyl ester and biphenyl-3,4- dicarboxylic acid 4-ethyl ester (MS-AP/CI - 271 , MH+). These were used as a mixture without purification.
  • Step 2 The mixture of monoesters (1.17 g, 4.33 mmol), PP5 (0.95 g, 4.33 mmol), BOP reagent (2.1 g, 4.75 mmol) and diisopropylethylamine were stirred at rt in CH 2 CI 2 (30 mL) for 1.5 hrs.
  • PP 39 (0.1Og, 0.233 mmol), morpholine (0.13 mL, 1.49 mmol), BINAP (8 mg, 0.013 mmol), palladium acetate (3 mg, 0.013 mmol) and sodium t-butoxide (0.033 g, 0.31 mmol) were refluxed overnight in toluene (5 mL). Water was added and the mixture extracted into EtOAc. The extract was washed with brine, dried (MgSO 4 ) and concentrated to afford a yellow-orange oil (58mg).
  • EXAMPLE 22 EXAMPLE 22
  • Example 19C (0.175 g, 0.444 mmol), ammonium formate (0.195 g, 3.11 mmol) and 10% Pd on carbon (50 mg) were refluxed in MeOH (40 mL) for 8hrs, cooled, filtered through CeliteTM and concentrated. Aqueous K 2 CO 3 was added and the mixture was extracted with EtOAc. The extract was washed with brine, dried (MgSO 4 ) and concentrated to a yellow oil.
  • Example 30 was prepared following the same general procedure described in
  • Example 31 was prepared following the same genera! procedure described in Example 17:
  • EXAMPLE 32 6-Bromo-2-f2-r2-(4-metriylpiperazin-1-yl)phenyllethyl>-3.4-dihvdro-2H-isoquinolin-1- one.
  • Step 1 PP5 (0.20 g, 0.91 mmol) and PP47 (0.164 g, 0.73 mmol) and sodium triacetoxyborohydride (0.21 g, 0.99 mmol) were stirred at rt in 1 ,2-dichloroethane (15 mL) for 16 hrs. The reaction mixture was concentrated, EtOAc was added and the mixture was made basic with aq. K 2 CO 3 .
  • Example 32 (0.30 g, 0.70 mmol), 3-diethylboranylpyridine (0.115 g, 0.78 mmol), tetrakis(triphenylphosphine)palladium (0) (80 mg, 0.07 mmol), tetra-n-butylammonium bromide (0.12 g, 0.37 mmol) and freshly ground KOH (0.20 g, 3.56 mmol) in THF (15 mL) were refluxed for 2.5 hrs. The reaction mixture was concentrated and the residue partitioned between EtOAc and water. The organics were washed with brine, dried (MgSO 4 ) and concentrated to an orange oil.
  • Example 35 was prepared following the same general procedure described in Example 21 : Substituting Example 32 for PP39, yield 72%, HCI salt had: mp ⁇ 120-140°C
  • Example 36 was prepared following the same general procedure described in
  • Example 17 Substituting Example 32 for PP34, yield 95%, HCI salt had: mp ⁇ 120-140°C;
  • Example 33A (0.172 g, 0.404 mmol) in THF (7 ml_) was added over 1 min to a slurry of LAH (0.030 g, 0.79 mmol) in THF (3 mL). The mixture was refluxed for 2.5 hrs, cooled and quenched with excess sodium sulfate decahydrate. Next the mixture was dried with anh.
  • Example 37 as a waxy yellow solid, the HCI salt of which had: mp -170-190 0 C; NMR (DMSO-d6) 11.76 (s, 1 H),
  • Example 20 (0.26 g, 0.61 mmol) in THF (5 mL) was added over 1 min to a slurry of LAH (0.050 g, 1.32 mmol) in THF (15 mL). The mixture was refluxed overnight, cooled and quenched with excess sodium sulfate decahydrate. Next the mixture was dried with anh.
  • PREPARATION 1 1 - ⁇ 2-r2-(4-Methylpiperazin-1 -yl)phenyllethyl ⁇ -1 ,3-dihydroimidazol-2-one.
  • PP8 (10.5g, 42.46 mmol) in 150 ml_ THF was added dropwise over 45 min to an ice cold slurry of LAH in 100 ml_ THF. The mixture was stirred at ambient temperature for 18 h, cooled in ice and carefully quenched by portion wise addition of excess sodium sulfate decahydrate. Anhydrous Na 2 SO 4 was added to dry the mixture. Filtration through CeliteTM with EtOAc rinse and concentration gave 9.72 g (quant) of PP5 as an orange oil: NMR
  • Th is material was hydrogenated for 2.5hrs in EtOH (50 ml_) with Raney Ni catalysis ( ⁇ 4g, water wet) under 47psi of hydrogen. The mixture was filtered and concentrated to an orange oil which was redissolved in CH 2 CI 2 and filtered through CeliteTM to remove residual inorganic impurities.
  • PREPARATION 14 4-Methyl-3,4,5,6-tetrahvdro-2H- ⁇ ,2'lbipyrazinyl-3'-carbaldehvde.
  • Step 1 6-Nitroisochroman (JOC, (1998), 63(12), 41 16-4119) (3.08 g, 17.2 mmol), ammonium formate (7.6 g, 120.5 mmol) and 10% Pd on carbon (220 mg) in MeOH (100 mL) were stirred at rt overnight, filtered (CeliteTM) and concentrated. The residue was dissolved in EtOAc and washed with sat.
  • Step 2 lsochroman-6-ylamine (2.14 g, 14.34 mmol) slurried in 48% HBr (30 mL) was cooled in ice. Sodium nitrite (1.00 g, 14.49 mmol) in water (10 mL) was added dropwise over
  • PP21 was prepared following the general procedure described in Preparation 20 by substituting PP49 for 2-(5-bromopyridin-2-yl)propan-2-ol, yield 45%, yellow oil: NMR (CDCI 3 )
  • the urea inter-mediate was prepared using PP5 in place of PP24, 3-chloropropyl isocyanate in place of 2-chloroethyl isocyanate in CH 2 CI 2 instead of THF, then cyclized using t-BuOK in place of sodium hydride.
  • PP57 (0.50 g, 2.45 mmol) and hydroxylamine hydrochloride (0.36 g, 5.18 mmol) were heated at 95°C for 6 hrs in pyridine (20 mL) then allowed to stand at rt for 18 hrs.
  • PREPARATION 27 1- ⁇ 2-r2-(4-Methylpiperazin-1-yl)phenyllethyl>-1 ,3-dihydrobenzoimidazol-2-one.
  • PREPARATION 28 The following materials were prepared according to the general procedure described in Preparation 27, with the noted changes:
  • PREPARATION 36 7-Bromo-1 -methyl-3-f 2-r2-(4-methylpiperazin-1 -yl)phenyllethyl ⁇ -1 H-quinazoline-2,4- dione.
  • PREPARATION 38 4-Bromo-2-methylaminobenzoic acid.
  • PREPARATION 40 2- ⁇ 2-[2-(4-Methylpiperazin-1-yl)phenyllethyl ⁇ -5-tributylstannanylisoindole-1,3-dione.
  • PP39 (0.259 g, 0.605 mmol), hexabutylditin (0.61 mL, 1.20 mmol), and tetrakis(triphenylphosphine)palladium (0) (4 mg) were refluxed in toluene (10 mL) for18 hrs.
  • Step 3 The crude (2-biphenyl-4-ylethyl)(2-bromobenzyl)carbamic acid methyl ester (0.332g, 0.782 mmol) was mixed with phosphorus pentoxide (0.45 g, 1.59 mmol) and phosphorus oxychloride (5 ml_) and heated to reflux for 47 hrs. The reaction was cooled, poured into ice and extracted into EtOAc. The extract was washed with sat. HaHCO 3 and brine, dried (MgSO 4 ) and concentrated to a purple oil (0.32 g).
  • PREPARATION 46 4-Bromo-2-bromomethyl-benzoic acid methyl ester. 4-Bromo-2-methyl-benzoic acid (20.35 g, 94.6 mmol) in MeOH (200 mL) was saturated with HCI gas, cooled to rt, resaturated with HCI gas and stirred overnight. The reaction was concentrated and dissolved in EtOAc, washed with sat. NaHCO 3 and brine, dried (MgSO 4 ) and concentrated to a brown oil (20.5 g).
  • PREPARATION 48 1 -(4-Bromophenyl)cyclohexanol. 4-Bromo-1-iodobenzene (5g, 17.7 mmol) in tetrahydrofuran (20 mL) at -4O 0 C was treated dropwise with isopropyl magnesium chloride (2 M solution in tetrahydrofuran, 23 mmol, 11.5 mL) and following addition was stirred 1 hour. Cyclohexanone (1.5 mL, 14.75 mmol) in tetrahydrofuran (5 mL) was added and the solution was allowed to slowly warm to rt over 3 h.
  • PREPARATION 49 1 -(4-Bromophenyl)cvclopentanol.
  • PP49 was prepared using the procedure detailed for Preparation 48 with cyclopentanone in place of cyclohexanone.
  • PREPARATION 50 1 -(4-BromophenvOcvclobutanol.
  • PP50 was prepared using the procedure detailed for Preparation 48 with cyclobutanone in place of cyclohexanone.
  • PP52 was prepared using methyl-4-bromophenyl acetate and the procedure detailed for Preparation 51.
  • 13C NMR 100 MHz, CDCI 3
  • d 137.1 , 132.4, 131.4, 120.7, 70.9, 49.3, 29.4
  • PP53 was prepared using ethyl-5-bromo-2-carboxypyridine, but otherwise followed the general procedure for Preparation 51.
  • 13C NMR 100 MHz, CDCI 3 ) d 165.1, 148.9, 139.7, 120.4, 118.9, 72.2, 30.7; MS (AP/CI) 216.0, 218.1 (M+H)+.
  • PP51 (1.77g, 8.2 mmol) and methyl iodide (0.5 mL, 8.2 mmol) in tetrahydrofuran (100 mL) were treated with sodium hydride (60% dispersion in mineral oil, 328 mg, 8.2 mmol). The mixture was stirred for 24 hours at rt, was poured into 0.5 M aqueous hydrochloric acid, and the mixture was extracted with EtOAc. The organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (200:1 hexanes-EtOAc) to afford 500 mg (27% yield) of PP54. 13C NMR (100 MHz, CDCI 3 ) ⁇ 145.4, 131.5, 127.9, 121.0, 76.7, 50.9, 28.1 ;

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Abstract

Nouveaux dérivés, qui sont des composés de formule (I), dans laquelle R1, R2, R3, R14, X, Y, n et m sont tels que définis dans le descriptif, leurs sels pharmaceutiquement acceptables, compositions pharmaceutiques et procédés utilisant de tels composés dans le traitement et la prévention de la dépression, de l'anxiété, du trouble obsessionnel-compulsif (OCD) et d'autres troubles pour lesquels on utilise des antagonistes sélectifs, des agonistes inverses et des agonistes partiels de récepteurs de la sérotonine 1 (5-HT1), des antagonistes de récepteurs 5-HT1B.
PCT/IB2005/003252 2004-11-02 2005-10-21 Ligands de latame/amine piperazinylphenalkyle pour le recepteur 5ht1b Ceased WO2006048727A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012154760A1 (fr) * 2011-05-10 2012-11-15 Gilead Sciences, Inc. Composés hétérocycliques condensés utilisés comme modulateurs des canaux sodiques
US8586732B2 (en) 2011-07-01 2013-11-19 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8952034B2 (en) 2009-07-27 2015-02-10 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8962610B2 (en) 2011-07-01 2015-02-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9079901B2 (en) 2010-07-02 2015-07-14 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
WO2015123091A1 (fr) * 2014-02-11 2015-08-20 Merck Sharp & Dohme Corp. Inhibiteurs du facteur xia
JP2018501285A (ja) * 2015-01-09 2018-01-18 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Ｒｏｃｋ阻害剤としての環状ウレア
WO2018056453A1 (fr) 2016-09-26 2018-03-29 中外製薬株式会社 Dérivé de pyrazolopyridine ayant un effet agoniste du récepteur glp-1
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
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JP2020500899A (ja) * 2016-12-09 2020-01-16 セルタクシス，インコーポレイテッド ロイコトリエンａ４ヒドロラーゼの阻害剤としてのモノアミン及びモノアミン誘導体
WO2020183011A1 (fr) 2019-03-14 2020-09-17 Institut Curie Inhibiteurs de htr1d et leurs utilisations dans le traitement du cancer
JP2023515721A (ja) * 2020-05-06 2023-04-13 メルク・シャープ・アンド・ドーム・エルエルシー Ｉｌ４ｉ１阻害剤及び使用方法
WO2023127883A1 (fr) 2021-12-28 2023-07-06 日本新薬株式会社 Composé d'indazole et produit pharmaceutique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998014433A1 (fr) * 1996-09-30 1998-04-09 Pfizer Inc. Lactames et imides heterocycliques d'aralkyle et d'aralkylidene
EP0952154A2 (fr) * 1998-04-16 1999-10-27 Pfizer Products Inc. N-acyl et N-aroyl aralkyl amides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998014433A1 (fr) * 1996-09-30 1998-04-09 Pfizer Inc. Lactames et imides heterocycliques d'aralkyle et d'aralkylidene
EP0952154A2 (fr) * 1998-04-16 1999-10-27 Pfizer Products Inc. N-acyl et N-aroyl aralkyl amides

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