WO2006048727A1 - Piperazinylphenalkyl lactam/amine ligands for the 5ht1b receptor - Google Patents

Piperazinylphenalkyl lactam/amine ligands for the 5ht1b receptor 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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PCT/IB2005/003252
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French (fr)
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Todd William Butler
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Pfizer Products Inc.
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    • 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
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    • 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
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    • 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
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • 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
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    • 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

The present invention relates to novel derivatives, that are compounds of Formula (I), wherein R1, R2, R3, R14, X, Y, n and m are defined herein, their pharmaceutically acceptable salts, pharmaceutical compositions and methods using said compounds in treating or preventing depression, anxiety, obsessive compulsive disorder (OCD) and other disorders for which selective antagonists, inverse agonists and partial agonists of serotonin 1 (5-HT1) receptors, specifically, antagonists of 5-HT1B are useful.

Description

PIPERAZINYLPHENALKYL LACTAM/AMINE LIGANDS FOR THE 5HT1 B RECEPTOR
Background of the Invention
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-HT1) receptors, specifically, receptor antagonists of 5-HT1B (formerly classified 5-HT1D) receptors. They are useful in treating or preventing depression, anxiety, obsessive compulsive disorder (OCD) and other disorders for which a 5-HT1 agonist or antagonist is indicated. European Patent Publication 434,561 , published on Jun. 26, 1991 , refers to 7-alkyl alkoxy, and hydroxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compounds are referred to as 5-HT1 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-HTiA ligand therapeutics.
PCT publication WO 94/21619, published Sep. 29, 1994, refers to naphthalene derivatives as 5-HT1 agonists and antagonists.
PCT publication WO 96/00720, published Jan. 11 , 1996, refers to naphthyl ethers as useful 5-HTi agonists and antagonists.
European Patent Publication 701 ,819, published Mar. 20, 1996, refers to the use of 5- HT1 agonists and antagonists in combination with a 5-HT re-uptake inhibitor.
GIennon et al., refers to 7-methoxy-1-(1-piperazinyl)-naphthalene as a useful 5-HT1 ligand in their article "5-HT1D Serotonin Receptors", Clinical Drug Res. Dev., 22, 25-36 (1991). Glennon's article "Serotonin Receptors: Clinical Implications", Neuroscience and
Behavioral Reviews, 14, 35-47 (1990), refers to the pharmacological effects associated with serotonin receptors including appetite suppression, thermoregulation, cardiovascular/hypotensive effects, sleep, psychosis, anxiety, depression, nausea, emesis, Alzheimer's disease, Parkinson's disease and Huntington's disease. World Patent Application WO 95/31988, published Nov. 30, 1995, refers to the use of a 5-HT10 antagonist in combination with a 5-HT1A 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. G. Maura et al., J. Neurochem, 66 (1 ), 203-209 (1996), have stated that administration of agonists selective for 5-HT1A receptors or for both 5-HT1A and 5-HT10 receptors might represent a great improvement in the treatment of human cerebellar ataxias, a multifaceted syndrome for which no established therapy is available. European Patent Publication 666,261 , published Aug. 9, 1995 refers to thiazine and thiomorpholine derivatives which are claimed to be useful for the treatment of cataracts.
Summary of the Invention
The present invention relates to piperazinylphenethyl lactam/amine derivatives of the formula I
Figure imgf000003_0001
wherein R1 is a group of the formula G1, G2, G3, G4, G5, G6, G7, G8, or G9 depicted below,
Figure imgf000003_0002
G4
Figure imgf000003_0003
R2 is hydrogen, (CVC6)alkyl, and (C1 -C6)alkyl-phenyl;
R3 is independently selected from hydrogen, (C1-C6)alkyl, (CrCeJalkyl-phenyl, and (CVCβJalkyl-naphthyl, wherein phenyl and naphthyl may optionally be substituted with one or more substituents independently selected from (CrC6)alkyl, (CrC6)alkoxy, trifluoromethyl, chloro, fluoro, bromo, iodo, cyano, -SOt(CrC6)alkyl, NH(CrC6)alkyl, N((Ci-C6)alkyl)2, NHCO(CrC6)alkyl, CONhKd-C^alkyl, and CON((C1-Cβ)alkyl)2; t is zero to two; R4 is hydrogen, R9, or R10;
R5 is independently selected from hydrogen, (CτC6)alkyl,
Figure imgf000004_0001
naphthyl-(Ci-C6)alkyl-, wherein phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)SIkOXy, trifluoromethyl, chloro, fluoro, bromo, iodo, cyano, and -SOt(C-ι-C6)alkyl;
R6 and R7 are independently selected from hydrogen, (CrC6)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-C6)alkyl, (Ci-C6)alkoxy, trifluoromethyl, trifluoromethoxy, (CrC6)perfluoroalkyl, (CrC^hydroxyalkyl-, (CrC6)alkoxy-(Ci-
C6)alkyl-, phenyl(C1-C6)aIkyl-, naphthyl(CrC6)alkyl-, and -SOt(CrC6)alkyl; or
R6 and R7, 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 R6 and R7 are attached, wherein the heteroalkyl ring may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, cyano, (Ci-C6)alkyl, (C1- C6)alkoxy, trifluoromethyl, trifluoromethoxy, (CrC6)perfluoroalkyl, (CrC6)hydroxyalkyl-, (C1- C6)alkoxy-(CrC6)alkyl-, phenyl(CrC6)alkyl-, naphthyl(CrC6)alkyi-, and -SOt(CrC6)alkyl;
R8 is hydrogen or optionally one to four substituents independently selected from chloro, fluoro, bromo, iodo, cyano, hydroxy, nitro, amino, -CHO1 -CONR6R7, -(C1- C6)alkylCO2Rii, -(C3-C8)CyClOaIkYlCO2Ri1, (CrCeJalkylCONRn-, -SOt(CrC6)alkyl, (C1- C6)alkyl, (C-ι-C6)perfluoroalkyl, trifluoromethoxy, (CrC6)hydroxyalkyl-, (C4- C8)hydroxycycloalkyl-,
Figure imgf000004_0002
(C3- C8)cycloalkyloxy-(C1-C6)alkyl-, (CrC6)alkoxycycloalkyl-, R9, R10, and a 5 to 7 membered non- aromatic heterocyclic ring having in addition to carbon atoms 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur atoms or any combination thereof with the proviso that said non-aromatic heterocyclic ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, wherein any of said non-aromatic heterocyclic rings can be the same or different and wherein each said non-aromatic heterocyclic ring may be optionally substituted with one to three substituents, as valency allows, independently selected from chloro, fluoro, bromo, iodo, (C1-C6)SIkYl1 (d-CeJperfluoroalkyl, (CrC6)hydroxyalkyl-, (C1- C6)alkoxy, (CrC6)alkoxy-(CrC6)alkyl-, or R12(CrC6)alkyl-; or
R8 is -CH=CH-CH=CH- wherein said -CH=CH-CH=CH- is linked to 2 adjacent carbon atoms to form a fused 6 membered aromatic ring; R9 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, -CONR6R7, -(CrC6)alkylCO2Rii, -(C3-C8)cycloalkylC02Rii, (C1-
C6)alkylCONRir, -SOt(CrC6)alkyl, (CrC6)alkyl, (C1-C6)perfluoroalkyl, trifluoromethoxy, (C1-
C6)hydroxyalkyl-, (C4-C8)hydroxycycloalkyl-, (C1-C6)BIkOXy, (C3-C8)cycloalkyloxy-, (C1-
C6)alkoxy-(C1-C6)alkyl-, (C3-C8)cycloalkyloxy-(C1-C6)alkyl-, (C1-C6)alkoxy(C3-C8)cycloalkyl-,
Ri2> Ri3. Ri2(CrC6)alkyl-, R12(C3-C8)cycloalkyl-, R12(C1-C6)BIkOXy-, R12(C4-C8)cycloalkyloxy-, R13(C1-C6)alkyl-, R13(C3-C8)cycloalkyl-, R13(C1-C6)BIkOXy-, or R13(C3-C8)cycloalkyloxy-;
R10 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, -CONR6R7, -(C1-
CfOaIRyICO2R11, -(C3-C8)cycloalkylCO2R1i, (CrCeJalkylCONRn-, -SOt(CrC6)alkyI, (Ci-C6)alkyl, (CτC6)perfluoroaIkyl, trifluoromethoxy, (CrC6)hydroxyalkyl-, (C4-C8)hydroxycycloalkyl-, (C1-
C6)alkoxy, (C3-C8)cycloalkyloxy-, (C1-C6)alkoxy-(C1-C6)alkyl-, (C3-C8)cycloalkyloxy-(C1-
C6)alkyl-, (C1-C6)alkoxy(C3-C8)cycloalkyl-, R12, R13, R12(CrC6)alkyl-, R12(C3-C8)cycloalkyl-,
R^CrC^alkoxy-, R12(C4-C8)cycloalkyloxy-, R13(CrC6)alkyl-, R13(C3-C8)cycioalkyl-, R13(C1-
C6)alkoxy-, or R13(C3-C8)cycloalkyloxy-; R11 is hydrogen or (C1-Cβ)aikyl;
R12 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, (CτCβ)alkyl, (CrC6)perfluoroalkyl, trifluoromethoxy, (C1-
C6)hydroxyalkyl-, (C4-C8)hydroxycycloalkyl-, (C1-C6JaIkOXy, (C3-C8)cycloalkyloxy-, (C1- CeJalkoxy-^^CeJalkyl-, (C3-C8)cycloalkyloxy-(C1-C6)alkyl-, or (C1-C6)alkoxy(C3-C8)cycloalkyl-;
R13 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 R13 may optionally be substituted as valency allows, with one to three substituents independently selected from chloro, fluoro, bromo, iodo, nitro, amino, oxo,
(Ci-C6)alkyl, (Ci-C6)perfluoroalkyl, trifluoromethoxy, (C1-C6)hydroxyalkyl-, (C4-
Ca)hydroxycycloalkyl-, (CrC6)alkoxy, (C3-C8)cycloalkyloxy-, (CVCeOalkoxy^CrCfOalkyl-, (C3-
C8)cycloalkyloxy-(C1-C6)alkyl-, or (C1-C6)alkoxy(C3-C8)cycloalkyl-;
R14 is 1-8 substituents independently selected from hydrogen, (C1-C6)SIkYl, (C1- C6)alkyl-phenyl, (CrC6)alkyl-naphthyl, wherein phenyl or naphthyl, may optionally be substituted with one or more substituents independently selected from (C1 -C6)alkyl, (C-i - C6)alkoxy, trifluoromethyl, chloro, fluoro, bromo, iodo, cyano, and -SOt(CrC6)alkyl; or,
R14 is a (CrC4)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 R3, when R3 has a ring structure having an available bonding site, with the understanding that N of the piperazine ring or C of R3 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 R1 bonds directly to -CH2- and R2 is not present; or a pharmaceutically acceptable salt thereof.
The invention also relates to a compound according to formula I wherein R1 is G1, G2, or G3; X, Y and Z are independently CH or N; and R4 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, (CrC6)alkyl,
Figure imgf000006_0001
trifluoromethoxy, (Cr C6)hydroxyalkyl-, (C4-C8)hydroxycycloalkyl-, (CrC6)alkoxy, (C3-C8)cycloalkyloxy-, (C1- C6)alkoxy-(CrC6)alkyl-, (C3-C8)cycloalkyloxy-(C1-C6)alkyI-, (CrC6)alkoxy-(C3-C8)cycloalkyl-, R12, R13, R12(Ci-C6)alkyl-, R12(C3-C8)cycloalkyl-, R12(C1-C6JaIkOXy-, R12(C4-C8)cycloalkyloxy-, R13(CrC6)aIkyI-, R13(C3-C8)cycloalkyl-, R13(C1-C6)alkoxy-, and R13(C3-C8)cycloalkyloxy-, wherein R12 is phenyl or naphthyl and R13 is selected from pyridyl, pyrrolyl, pyrimidyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, tetrahydropyranyl, dioxanyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, and oxetanyl, wherein said R12 or R13 may be optionally substituted as valency allows, with one to three substituents independently selected from chloro, fluoro, bromo, iodo, nitro, amino, oxo, (C1-C6)alkyl, (CrC6)perfluoroalkyl, trifluoromethoxy, (Ci-C6)hydroxyalkyl-, (C4-C8)hydroxyl(C3- C8)cycloalkyl-, (CrC^alkoxy and (CrCeJalkoxy^CrC^alkyl.
The invention also relates to a compound according to formula I wherein R1 is G4, G5, G6, G7, G8, or G9; X and Y are independently CH or N; and R8 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 R1 is G4, G5, G6, G7, G8, or G9; X and Y are independently CH or N; and R8 is 1 to 4 substituents independently selected from -CONR3R7 wherein R6 and R7 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-C6)alkyl, (Ci-C6)perfluoroalkyl, (C1-C6)hydroxyalkyl-, (CrC^alkoxy, (C1- CeJalkoxy-lCrCfOalkyl-, phenyl(CrC6)alkyl-, and naphthyKCrC^alkyk The invention also relates to a compound according to formula I wherein R1 is G4, G5,
G6, G7, G8, or G9; X and Y are independently CH or N; and R8 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-Cβ)alkyl, (C^C^perfluoroalkyl, (C^CfOhydroxyalkyl-, (C1-C6JaIkOXy, (C1-C6)alkoxy-(C1-C6)alkyl-, and R12(C1-C6)alkyl.
The invention also relates to a compound according to formula I wherein Ri is G4, G5, G6, G7, G8, or G9; X and Y are independently CH or N; and R8 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, oxo, (CrC6)alkyl, (C1- C6)perfluoroalkyl, trifluoromethoxy, (CrCfOhydroxyalkyl-, (C4-C8)hydroxycycloalkyl-, (C1- C6)alkoxy, (C3-C8)cycloalkyloxy-, (C1-C6)alkoxy-(C1-C6)alkyl-, (C3-C8)cycloalkyloxy-(Cr C6)alkyl-, (C1-C6)alkoxy-(C3-C8)cycloalkyl-, R12, R13, R12(CrC6)alkyl-, R12(C3-C8)cycloalkyl-, Ri2(Ci-C6)alkoxy-, R12(C4-C8)cycloalkyloxy-, R13(CrC6)alkyl-, R13(C3-C8)cycloalkyl-, R13(C1- C6)alkoxy-, or R13(C3-C8)cycloalkyloxy-, and wherein Ri2 is phenyl or napthyl and Ri3 is selected from pyridyl, pyrrolyl, pyrimidyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, tetrahydropyranyl, dioxanyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, and oxetanyl, wherein said Ri2 and R13 may be optionally substituted as valency allows, with one to three substituents independently selected from chloro, fluoro, bromo, iodo, nitro, amino, oxo, (CrC6)alkyl, (CrC6)perfluoroalkyl, trifluoromethoxy, (CrC^hydroxyalkyl-, (C4-C8)hydroxycycloalkyl-, (Ci-C6)alkoxy, and (C1- C6)alkoxy-(Ci-C6)alkyk The invention also relates to a compound according to formula I wherein R1 is G4, G5,
G6, G7, G8, or G9; X and Y are independently CH or N; and R8 is -CH=CH-CH=CH- wherein said -CH=CH-CH=CH- is linked to two adjacent carbon atoms to form a fused 6 membered aromatic ring.
The invention also relates to a compound according to formula I wherein R2 is hydrogen, methyl, or benzyl.
The invention also relates to a compound according to formula I wherein R3 is H, methyl, or benzyl.
The invention also relates to a compound according to formula I wherein R1 is G1 or G4, and R5 is H, methyl, or benzyl. The invention also relates to a compound according to formula I wherein R1 is G1, G2,
G31G4, G5, G6, G7, G8, or G9; X, Y and Z are independently CH or N; n is zero, m is zero, so R2 is absent and R1 bonds directly to the aromatic ring containing X and Y.
The invention also relates to a compound according to formula I wherein R1 is G1, G2, G31G4, G5, G6, G7, G8, or G9; X, Y and Z are independently CH or N; n is one, m is zero, so R2 is absent and R1 bonds directly to -CH2-.
The invention also relates to a compound according to formula I wherein Ri is Gi, G2, G3, G4, G5, G6, G7, G8, or G9; 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 R1, R2, R3, R4, R5, R8, R14, 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:
1 -{2-[2-(4-Methyl-piperazin-1 -yl)-phenyl]-ethyl}-3-(4-trifluoromethyl-phenyl)-1 ,3- dihydro-imidazol-2-one;
1-(4-lsopropoxy-phenyl)-3-{2-[2-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-1 ,3- dihydro-imidazol-2-one;
1-[4-(1-Hydroxy-cyclopentyl)-phenyl]-3-{2-[3-(4-methyl-piperazin-1-yl)-pyridin-2-yl]- ethyl}-1 ,3-dihydro-imidazol-2-one; 1-[4-(1-Hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl-3,4,5,6-tetrahydro-2H- [1 ,2']bipyrazinyl-3'-yI)-ethyl]-1 ,3-dihydro-imidazol-2-one;
1-[4-(1-Hydroxy-1 -methyl-ethyl )-phenyl]-3-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]- ethyl}-imidazolidin-2-one; 1-[4-(1-Hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-pyridin-3-yl]- imidazolidin-2-one;
1-[4-(1-Hydroxy-cyclobutyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}- tetrahydro-pyrimidin-2-one;
1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]- ethyl}-1 ,3-dihydro-benzoimidazol-2-one;
1-[4-(1-Hydroxy-cyclopentyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}- 1 ,3-dihydro-imidazo[4,5-b]pyridin-2-one;
3-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-7-phenyl-1 H-quinazoline-2,4-dione;
5-tert-Butyl-2-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}-isoindole-1 ,3-dione; 2-[2-(4-Methyl-piperazin-1-yl)-benzyl]-7-phenyl-3,4-dihydro-2H-isoquinolin-1-one;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-5-phenyl-2,3-dihydro-isoindol-1-one;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-6-phenyl-3,4-dihydro-2H-isoquinolin-1- one;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-6-phenyl-1 ,2,3,4-tetrahydro- isoquinoline;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-5-phenyl-2,3-dihydro-1 H-isoindole; and, pharmaceuticaliy acceptable salts thereof.
Other specific examples of the compounds of the present invention are independently any one or more or combination of the examples presented herein. Unless otherwise indicated, the term "halo", as used herein, includes fluoro, chloro, bromo and iodo. Unless otherwise indicated, the term "alkyl", as used herein, includes straight or branched alkyl. Halogenated alkyl, e.g., perfluoroalkyl, as used herein, includes straight or branched halogenated alkyl moieties unless otherwise indicated. Unless otherwise indicated the term "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. The term "alkoxy", as used herein, means "alkyl-O-", wherein "alkyl" is defined as above. The term "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.
The term "alkylene, as used herein, means an alkyl radical having two available bonding sites {i.e., -alkyl-), wherein "alkyl" is defined as above. The term "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. The term "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.
The term "aryl" is intended to include groups that, in accordance with the theory of Hϋckel, have a cyclic, delocalized (4n+2) pi-electron system. Examples of aryl groups include, but are not limited to, arenes and their substitution products, e.g., phenyl, naphthyl and toluyl, among numerous others. The term "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. Unless otherwise indicated the term "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. Unless otherwise indicated, the term "one or more substituents", as used herein, refers to from one to the maximum number of substituents possible based on the number of available bonding sites.
When identifying intermediates made herein using a preparation, the intermediate made by that preparation is refered to as PP#, where the number is the number of the preparation. For example, 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 3H, 11C, 14C, 18F, 123I and 125I. 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, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome, comprising administering to a mammal in need of such treatment an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition.
Detailed Description of the Invention Except where otherwise stated, R1, R2, R3, R4, R5-R14, G1-G9, X, Y, Z, q, n and m in the reaction schemes and discussion that follow are defined as above. Each of the following reaction schemes apply to X and Y independently defined as either CH or N, even if only one definition of X and Y is given in the scheme itself. Unless otherwise stated, reaction conditions 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 R2 is hydrogen, (CrC6)alkyl, and (C1 -C6)alkyl-phenyl and R3 is hydrogen,
Figure imgf000012_0001
and (CrC6)alkyl-naphthyl. In step 1 a of Scheme 1 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 1500C, preferably about 90° to about 1200C. In 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. In 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.
In 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 500C, preferably about room temperature (rt). In 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. In step 6a of Scheme 1 the compound of formula Ia, wherein R4 is an optionally substituted aryl (R9) or heteroaryl (R10), 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 (XANTPHOS™), a palladium species such as palladium (II) acetate or tris(dibenzylideneacetone)dipalladium (0) or the corresponding chloroform adduct, preferably tris(dibenzylideneacetone)dipalladium (0), in an inert solvent such as 1 ,4-dioxane or toluene, preferably 1 ,4-dioxane, at a temperature of from about 40° to about 160°C, preferably about 80° to about 1OfJ0C.
In an alternate procedure, the compound of formula Ia, wherein R4 is an optionally substituted aryl (R9) or heteroaryl (Ri0), 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, Λ/,Λ/'-dimethylethylenediamine, or cis-1 ,2-diaminocyclohexane, preferably Λ/,Λ/'-dimethylethylenediamine, cuprous chloride, bromide or iodide, preferably cuprous iodide, and a small amount of water, preferably about 1 percent to about 4 percent of said mixture, in a reaction inert solvent such as 1 ,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran, benzene, toluene, preferably toluene, at a temperature of about 40°C to about 150°C, preferably about 8O0C to about 12O0C. 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. In step 4b of Scheme 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. In 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. In step 6b of Scheme 1 the compound of the formula Ib wherein R4 is an optionally substituted aryl (R9) or heteroaryl (R10) 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 N1N- dimethylethylenediamine, cuprous chloride, bromide or iodide, preferably cuprous iodide, and a small amount of water, preferably about 1 percent to about 4 percent of said mixture, in a reaction inert solvent such as 1 ,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran, benzene, toluene, preferably toluene, at a temperature of about 400C to about 1500C, preferably about 80°C to about 120°C. In 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 200C to about 1000C preferably about 65°C.
SCHEME 1
Figure imgf000015_0001
Scheme 2 refers to general methods suitable for the preparation of compounds of formula Ic wherein X is N and Y is CH, R2 is hydrogen, (CrC6)alkyl, and (C1 -C6)alkyl-phenyl and R3 is hydrogen, (Ci-C6)alkyl, (CrQOalkyl-phenyl, and (C1-C6)alkyl-naphthyl. In step 1 of Scheme 2, 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 4O0C to about 15O0C, preferably about 90° to about 12O0C. In 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. In step 3 of Scheme 2 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. In step 4 of Scheme 2 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.
In 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. In step 6 of Scheme 2 the compound of the formula Ic wherein R4 is an optionally substituted aryl (R9) or heteroaryl (R10) 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, Λ/./V-dimethylethylenediamine, or cis-1 ,2- diaminocyclohexane, preferably Λ/,Λ/'-dimethylethylenediamine, cuprous chloride, bromide or iodide, preferably cuprous iodide, and a small amount of water, preferably about 1 percent to about 4 percent of said mixture, in a reaction inert solvent such as 1 ,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran, benzene, toluene, preferably toluene, at a temperature of about 400C to about 150°C, preferably about 80°C to about 120°C. The compound of formula Ic may be further reduced to a saturated cyclic urea using the procedure of step 7 of Scheme 1. SCHEME 2
Figure imgf000017_0001
lie
Figure imgf000017_0002
Scheme 3 refers to general methods suitable for the preparation of compounds of formula Id wherein X is CH and Y is N, R2 is hydrogen, (CrC6)alkyl, and (C1 -C6)alkyl-phenyl and R3 is hydrogen, (Ci-C6)alkyl, (CrC6)alkyl-phenyl and (CrC6)alkyl-naphthyl. In step 1 of Scheme 3, 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 400C to about 1500C, preferably about 90° to about 1200C. In 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. in step 3 of Scheme 3 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. In 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. In 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. In step 6 of Scheme 3 the compound of the formula Id wherein R4 is an optionally substituted aryl (R9) or heteroaryl (R10) 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, Λ/,/V- dimethylethylenediamine, or cis-1 ,2-diaminocyclohexane, preferably Λ/,/V- dimethylethylenediamine, cuprous chloride, bromide or iodide, preferably cuprous iodide, and a small amount of water, preferably about 1 percent to about 4 percent of said mixture, in a reaction inert solvent such as 1 ,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran, benzene, toluene, preferably toluene, at a temperature of about 4O0C to about 1500C, preferably about 8O0C to about 1200C. The compound of formula Id may be further reduced to a saturated cyclic urea using the procedure of step 7 of Scheme 1. SCHEME 3
Figure imgf000019_0001
Id1 Id
Scheme 4 refers to general methods suitable for the preparation of compounds of formula Ie wherein n is one and m is zero. In step 1 of Scheme 4 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. In step 2 of Scheme 4 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. In 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 5O0C, preferably about room temperature.
In step 4 of Scheme 4 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. In step 5 of Scheme 4 the compound of the formula Ie wherein R4 is an optionally substituted aryl (R9) or heteroaryl (R10) 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 (XANTPHOS™), 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 an inert solvent such as 1 ,4-dioxane or toluene, preferably 1,4-dioxane at a temperature of from about 40° to about 1600C, preferably about 80° to about 100°C.
SCHEME 4
Figure imgf000020_0001
Scheme 5 refers to general methods suitable for the preparation of compounds of formula If wherein n is zero and m is zero. In step 1 of Scheme 5 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 400C to about 1500C, preferably about 90°C to about 120°C. In 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. In 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 00C to about 500C, preferably about room temperature. In step 4 of Scheme 5 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. In step 5 of Scheme 5 the compound of formula If, wherein R4 is an optionally substituted aryl (R9) or heteroaryl (R10), 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, /V1W- dimethylethylenediamine, or cis-1 ,2-diaminocyclohexane, preferably /V1W- dimethylethylenediamine, cuprous chloride, cuprous bromide or cuprous iodide, preferably cuprous iodide, a small amount of water, preferably about 1 percent to about 4 percent, of said mixture in a reaction inert solvent such as 1 ,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran, benzene, toluene, preferably toluene, from about 400C to about 15O0C, preferably about 80°C to about 120°C.
Figure imgf000022_0001
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. In step 1 of Scheme 6, 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) with 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 O0C to about 15O0C, preferably about 600C to 12O0C. In 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. In 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. In step 4 of Scheme 6 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. In step 5 of Scheme 6 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.
In 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. In step 7 of Scheme 6 the compound of the formula Ig wherein R4 is an optionally substituted aryl (R9) or heteroaryl (R10) 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, Λ/./V-dimethylethylenediamine, or cis-1 ,2-diaminocyclohexane, preferably /V.W-dimethylethylenediamine, cuprous chloride, bromide or iodide, preferably cuprous iodide, and a small amount of water, preferably about 1 percent to about 4 percent of said mixture, in a reaction inert solvent such as 1 ,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran, benzene, toluene, preferably toluene, at a temperature of about 400C to about 1500C, preferably about 80°C to about 120°C.
SCHEME 6
Figure imgf000024_0001
Scheme 7 refers to general methods suitable for the preparation of compounds of formula Ih wherein X is CH, Y is CH or N, R1 is G2 wherein Z is independently CH or N and n and m are one. In step 1 of Scheme 7 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 400C to about 1500C, preferably about 90°C to about 1200C.
In step 2 of Scheme 7 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. In step 3 of Scheme 7 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 -100C to about 300C, preferably about O0C to about 200C. In step 4 of Scheme 7 a compound of the formula Ih wherein R4 is an optionally substituted aryl (Rg) or heteroaryl (R10) 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, Λ/./V-dimethylethylenediamine, or cis-i ^-diaminocyclohexane, preferably Λ/,/V- dimethylethylenediamine, cuprous chloride, bromide or iodide, preferably cuprous iodide, and a small amount of water, preferably about 1 percent to about 4 percent of said mixture, in a reaction inert solvent such as 1 ,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran, benzene, toluene, preferably toluene, at a temperature of about 400C to about 1500C, preferably about 800C to about 120°C. 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 3O0C, preferably at about 2O0C to about 250C.
SCHEME 7
Figure imgf000025_0001
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, R1 is G5 or G6 and n and m are one. In step 1 of Scheme 8 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 00C to about 500C preferably about 200C to about 25°C. In step 2 of Scheme 8 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 500C to about 150°C, preferably about 1000C to about 1200C. Those skilled in the art will recognize that the R8 group of compound Ii may be further modified into other R8 groups by methods that are well known in the art. Scheme 8 also depicts an alternate procedure for the preparation of a compound of the formula Ii.
In step 1a of Scheme 8 a compound of the formula XV, wherein R9 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 00C to about 500C preferably about 20°C to about 25°C. In step 2a of Scheme 8 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 00C to about 100°C, preferably about 2O0C to about 25°C. In step 3 of Scheme 8 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 O0C to about 1000C, preferably about 500C to about 700C. Those skilled in the art will recognize that the R8 group of compound Ij may be further modified into other R8 groups by methods that are well known in the art.
SCHEME 8
Figure imgf000027_0001
Ij
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, R1 is G4 and n and m are one. In step 1 of Scheme 9 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 O0C to about 5O0C, preferably about 200C to about 25°C.
In 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 O0C to about 100°C, preferably about 20°C to about 25°C. Steps 1a and 2a of Scheme 9 depict an alternate preparation of the compound of the formula Ik. In step 1a of Scheme 9 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 -100C to about 300C, preferably about 0°C to about 200C.
In step 2a of Scheme 9 the compound of formula Ik, wherein R5 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 00C to about
100°C preferably about 40°C to about 800C. The compound of the formula Ik, wherein R5 is
(Ci-C6)alkyl or aryl-(C1-C6)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 R5 is hydrogen by means known in the art. The R8 group of compound Ik may be further modified into other R8 groups by methods familiar to those skilled in the art.
SCHEME 9
Figure imgf000028_0001
Scheme 10 refers to general methods suitable for the preparation of compounds of the formula IL and Im wherein X and Y are CH, R1 is G7 or G8, n is one, m is zero and R2 is absent. In step 1 of Scheme 10 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 00C to about 50°C, preferably about 200C to about 25°C.
In step 2 of Scheme 10 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.
In 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 -200C to about 300C preferably about -100C to about 5°C. In 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 6O0C to about 1400C preferably 900C to about 1100C. In 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 400C to about 1500C, preferably about 90°C to about 120 °C. In step 6 of Scheme 10 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 500C to about 700C. The R8 group of compounds IL and Im may be further modified into other R8 groups by methods familiar to those skilled in the art. SCHEME 10
Figure imgf000030_0001
Im
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, R1 is G7, n is one, m is zero and R2 is absent. In step 1 of Scheme 11 the compound of formula XXIII is prepared by treating the compound of formula XXII (prepared according to J. Med. Chem., 1996, 39, 4583 with 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 1000C preferably about 500C to about 7O0C. In 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 200C to about 25°C. The R8 group of compound In may be further modified into other R8 groups by methods familiar to those skilled in the art. SCHEME 11
Figure imgf000031_0001
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, R1 is G8, n is one, m is one and R2 is hydrogen, (CrC6)alkyl or (C1 -C6)alkyl-phenyl. In 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 1000C to about 180°C preferably about 1300C to about 150°C. In 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 800C, preferably at ambient temperature. In 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 2O0C to about 24°C.
In 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 00C to about 1000C preferably about 400C to about 80°C. The R8 group of compound Io may be further modified into other R8 groups by methods familiar to those skilled in the art.
SCHEME 12
Figure imgf000032_0001
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 G9, n is one, m is one and R2 is hydrogen, (CrC6)alkyl or (C1 -C6)alkyl-phenyl and an alternative preparation of compounds of the formula Ij wherein X and Y are independently CH or N, R1 is G5, n is one, m is one and R2 is hydrogen, (CrC6)alkyl or (C1 -C6)alkyl-phenyl. In 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 00C 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 300C to about 1200C preferably about 50°C to about 80°C.)
In 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 1000C preferably about 50°C to about 700C. Those skilled in the art will recognize that the R8 group of compound Ip and compound Ii may be further modified into other R8 groups by methods that are well known in the art. SCHEME 13
Figure imgf000033_0001
Biological Assay
The activity of the compounds of the present invention with respect to 5HT1B (formerly 5HT10) binding ability can be determined using standard radioligand binding assays as described in the literature. The 5-HT1A affinity can be measured using the procedure of Hoyer et al. (Brain Res., 1986, 376, 85). The 5-HT1D affinity can be measured using the procedure of
Heuring and Peroutka {J. Neurosci., 1987, 7, 894).
The in vitro activity of the compounds of the present invention at the 5-HT1D 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 370C, 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 μM pargyline and 4 mM calcium chloride (CaCI2). 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. To 50 μl of a 20 percent dimethylsulfoxide (DMSO)/80 percent distilled water solution is added 200 μl 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 μM pargyline and 4 μM calcium chloride, plus 100 nM of 8-hydroxy-DPAT (dipropylaminotetraline) and 100 nM of mesulergine. To this mixture is added 750 μl of bovine caudate tissue, and the resulting suspension is vortexed to ensure a homogenous suspension. The suspension is then incubated in a shaking water bath for 30 minutes at 250C. 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 2™) and allowed to sit overnight. The percent inhibition can be calculated for each dose of the compound. An IC50 value can then be calculated from the percent inhibition values. Of the compounds tested, 5HT1B IC50 was less than about 500 nM.
The activity of the compounds of the present invention for 5-HT1A 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 μm 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 μl of tritiated DPAT at a concentration of 1.5 nM in a buffer of 50 mM TRIS. hydrochloride at pH 7.7 containing 4 mM calcium chloride, 0.01 percent ascorbic acid and pargyline. To this solution is then added 750 μl of tissue and the resulting suspension is vortexed to ensure homogeneity. The suspension is then incubated in a shaking water bath for 30 minutes at 37°C. The solution is then filtered, washed twice with 4 ml of 10 mM TRIS. hydrochloride at pH 7.5 containing 154 mM of sodium chloride. The percent inhibition is calculated for each dose of the compound, control or vehicle. IC50 values are calculated from the percent inhibition values. The agonist and antagonist activities of the compounds of the invention at 5-HT1A and
5-HT1 receptors can be determined using a single saturating concentration according to the following procedure. Male Hartley guinea pigs are decapitated and 5-HT1A receptors are dissected out of the hippocampus, while 5-HTiD 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 MgCI2, 0.5 mM ATP, 1.0 mM cAMP, 0.5 mM IBMX, 10 mM phosphocreatine, 0.31 mg/mL creatine phosphokinase, 100 μM GTP and 0.5-1 microcuries of [32P]-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 μl_ tissue, 10 μL drug or buffer (at 10x final concentration), 10 μL 32 nM agonist or buffer (at 10x final concentration), 20 μL forskolin (3 μM final concentration) and 40 μL of the preceding reaction mix. Incubation is terminated by the addition of 100 μL 2% SDS, 1.3 mM cAMP, 45 mM ATP solution containing 40,000 dpm [3H]-CAMP (30 Ci/mmol: NET- 275— New England Nuclear) to monitor the recovery of cAMP from the columns. The separation of [32P]-ATP and [32P]-CAMP is accomplished using the method of Salomon et al., Analytical Biochemistry, 1974, 58, 541-548. Radioactivity is quantified by liquid scintillation counting. Maximal inhibition is defined by 10 μM (R)-δ-OH-DPAT for 5-HT1A receptors, and 320 nM 5-HT for 5-HT1D receptors. Percent inhibitions by the test compounds are then calculated in relation to the inhibitory effect of (R)-8-OH-DPAT for 5-HT1A receptors or 5-HT for 5-HT10 receptors. The reversal of agonist induced inhibition of forskolin-stimulated adenylate cyclase activity is calculated in relation to the 32 nM agonist effect.
The compounds of the invention can be tested for in vivo activity for antagonism of 5- HT10 agonist-induced hypothermia in guinea pigs according to the following procedure. Male artley guinea pigs from Charles River, weighing 250-275 grams on arrival and 300-600 grams at testing, serve as subjects in the experiment. 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-HT1D 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. Animals are then returned to the same shoe box after each temperature reading. Prior to each temperature measurement each animal is firmly held with one hand for a 30-second period. A digital thermometer with a small animal probe is used for temperature measurements. The probe is made of semi-flexible nylon with an epoxy tip. The temperature probe is inserted 6 cm. into the rectum and held there for 30 seconds or until a stable recording is obtained. Temperatures are then recorded.
In p.o. screening experiments, 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-HTiD agonist is then administered at 0 minutes and temperatures are taken 30, 60, 120 and 240 minutes later. In subcutaneous screening experiments, a pre-drug baseline temperature reading is made at -30 minutes. The test compound and 5-HTiD agonists are given concurrently and temperatures are taken at 30, 60, 120 and 240 minutes later.
Data are analyzed with two-way analysis of variants with repeated measures in Newman-Keuls post hoc analysis. 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-HT1 agonist activity can be determined by the in vitro receptor binding assays, as described for the 5-HT1A receptor using rat cortex as the receptor source and [3H]-8-OH-DPAT as the radioligand (D. Hoyer et al. Eur. J. Pharm., 118, 13 (1985)) and as described for the 5-HT1D receptor using bovine caudate as the receptor source and [3H]serotonin as the radioligand (R. E. Heuring and S. J. Peroutka, J. Neuroscience, 1987, 7, 894).
EXAMPLES General Procedures The following procedures apply to all examples provided herein: All reactions are run under a nitrogen atmosphere. Melting points are uncorrected. Chromatography refers to flash chromatography on silica gel. NMR refers to proton [1H] NMR. NMR spectra are obtained at 400 MHz, unless otherwise indicated, and are reported in parts per million (δ) relative to the deuterium lock signal of the specified solvent. 13C NMR spectra are referred to as such. Procedures requiring evaporation or concentration employed a rotary evaporation apparatus. Procedures for synthesis of basic starting materials referenced in the Examples are given in the Preparations section.
EXAMPLE 1 1 -(2-r2-(4-Methyl-piperazin-1 -yl)-phenvH-ethyl}-3-(4-trif luoromethyl-phenvD-1 ,3-dihydro- imidazol-2-one.
PP1 (0.10 g, 0.35 mmol), 4-bromobenzotrifluoride (0.060 mL, 0.43 mmol), copper (I) iodide (7 mg, 0.037 mmol), N, N'-dimethylethylenediamine (8//L, 0.075 mmol) and K2CO3 ( 0.12 g, 0.87 mmol) in toluene (1mL) were combined, purged with N2 gas for 2 min. and heated to 110-1200C in a sealed tube for 24 hrs. After cooling, the mixture was diluted with EtOAc and washed twice with water then brine, dried (IvIgSO4) and concentrated to give a tan oil (0.126 g). Chromatography with 20-30% MeOH/ EtOAc gave 0.100g (66%) of Example 1 as a white solid which had: mp 100-1030C; NMR (CDCI3) 7.74 (d, J= 8.7 Hz, 2H), 7.62 (d, J= 8.7 Hz, 2H), 7.22 -7.11 (m, 3H), 7.01 (dt, J = 7.5, 1.2 Hz, 1 H), 6.49 (d, J = 2.9 Hz, 1 H), 6.09 (d, J = 2.9 Hz, 1 H), 3.93 (t, J = 7.3 Hz, 2H), 3.02 (t, J = 7.1 Hz, 2H), 2.89 (t, J = 4.8 Hz, 4H), 2.55 (br s, 4H), 2.32 (s, 3H); 13C NMR (CDCI3) 173.33, 152.15, 151.66, 140.56, 133.96, 130.66, 128.05, 126.59, 126.55, 124.76, 121.14, 120.82, 113.10, 107.94, 55.93, 53.02, 46.33, 44.75, 31.34.
EXAMPLE 2
Syntheses of the compounds below are essentially the same procedure as described in Example 1 with the noted substitutions for 4-bromobenzotrifluoride:
A: 1 -rø-d -Hvdroxy-1 -methyl-ethyl)-phenyll-3-( 2-f2-(4-methyl-piperazin-1 -vD- phenvπ-ethylM,3-dihvdro-imidazol-2-one. Using PP51 , 13C NMR (100 MHz, CDCI3) d
148.4, 131.4, 126.6, 120.8, 72.5, 31.9; MS (AP/CI) 197.1 , 199.1 (M+H)+, yield 70%: mp 130-
130.50C; NMR (CDCI3) 7.53 (s, 4H), 7.25-7.13 (m, 3H), 7.05 (t, J = 7.3 Hz, 1 H), 6.46 (d, J =
2.9 Hz, 1 H), 6.08 (d, J = 2.9 Hz, 1 H), 3.94 (t, J = 7.3 Hz, 2H), 3.05 (t, J = 7.3 Hz, 2H), 2.94-
2.91 (m, 4H), 2.60 (br s, 4H), 2.35 (s, 3H), 1.57 (s, 6H); 13C NMR (CDCI3) 152.11 , 151.85, 136.16, 134.18, 130.72, 127.99, 125.53, 124.78, 121.49, 121.16, 112.08, 109.07, 72.45,
55.92, 52.94, 46.31 , 44.69, 32.01 , 31.48.
B. 1-f4-(1-Hvdroxy-cvclopentyl)-phenvn-3-f2-r2-(4-methyl-piperazin-1-yl)- phenvn-ethyl>-1,3-dihvdro-imidazol-2-one. Using PP49, yield = 76%: mp 161-161.5°C; NMR (CDCI3) 7.54 (s, 4H), 7.25-7.17 (m, 2H), 7.13 (d, J= 7.5 Hz, 1 H), 7.04 (t, J= 7.1 Hz, 1 H), 6.45 (d, J= 2.9 Hz, 1H), 6.08 (d, J = 2.9 Hz, 1 H), 3.94 (t, J = 7.3 Hz, 2H), 3.04 (t, J = 7.3 Hz, 2H), 2.93-2.90 (m, 4H), 2.58 (br s, 4H), 2.34 (br s, 6H), 1.82 (br s, 2H); 13C NMR (CDCI3) 152.12, 151.83, 144.93, 136.19, 134.18, 130.71 , 127.98, 126.19, 124.77, 121.44, 112.07, 109.08, 83.27, 55.93, 52.94, 46.32, 44.69, 42.15, 31.46, 24.08.
C. 1-r6-(1-Hvdroxy-1-methylethyl)pyridin-3-vn-3-f2-r2-(4-methylpiperazin-1- yl)phenvnethyl)-1,3-dihvdroimidazol-2-one. Using PP53, yield 60%: mp 126-127.5°C;
NMR (CDCI3) 8.63 (d, J = 2.1 Hz, 1 H), 8.09 (dd, J = 8.7, 2.5 Hz, 1 H), 7.43 (d, J = 8.7 Hz, 1 H), 7.25-7.13 (m, 3H), 7.04 (t, J = 7.3 Hz, 1 H), 6.49 (d, J = 2.9 Hz, 2H), 6.13 (d, J = 2.9 Hz, 1 H), 3.96 (t, J = 7.1 Hz, 2H), 3.04 (t, J = 7.3 Hz, 2H), 2.93-2.90 (m, 4H), 2.57 (br s, 4H), 2.34 (s, 3H), 1.53 (s, 6H); 13C NMR (CDCI3) 163.31, 152.15, 151.84, 140.26, 133.93, 132.91, 130.68, 130.21 , 128.10, 124.78, 121.19, 119.11 , 113.07, 108.15, 72.06, 55.96, 53.02, 46.38, 44.76, 31.45, 30.87.
D. 1-{2-r2-(4-Methylpiperazin-1-yl)phenvnethyl>-3-pyridin-2-yl-1,3- dihydroimidazol-2-one. Using 2-bromopyridine, yield 65%; HCI salt had: mp 66-730C; NMR (DMSO-d6) 8.38-8.36 (m, 1 H), 8.29 (d, J = 8.3 Hz, 1 H), 7.88-7.84 (m, 1 H), 7.24-7.17 (m, 4H), 7.09 (d, J = 7.1 Hz, 1 H), 7.06-7.02 (m, 1 H), 6.70 (d, J = 3.3 Hz, 1 H), 3.85 (t, J = 7.5 Hz, 2H), 3.41-3.37 (m, 2H), 3.30-3.18 (m, 2H), 3.07 (d, J = 5.8 Hz, 4H), 2.93 (t, J = 7.9 Hz, 2H), 2.76 (d, J = 4.6 Hz, 3H); 13C NMR (DMSO-d6) 151.5, 150.9, 148.8, 139.4, 134.3, 131.2, 128.4, 125.5, 121.4, 121.2, 113.9, 113.4, 107.1 , 53.7, 49.8, 43.9, 42.8, 31.3.
E. 1-(4-tert-Butylphenyl)-3-{2-f2-(4-methylpiperazin-1-yl)-phenvn-ethyl)-1,3- dihydroimidazol-2-one. Using 1-bromo-4-ferf-butylbenzene, yield 46%: mp 123- 129°C; NMR (CDCI3) 7.43 (AB quartet, Δu = 27.8, J = 8.7 Hz, 4H), 7.20-7.12 (m, 3H), 7.04
(m, 1 H), 6.42 (d, J = 2.9 Hz, 1 H), 6.06 (d, J = 2.9 Hz, 1 H), 3.91 (t, J = 7.1 Hz, 2H), 3.01 (t, J =
7.1 Hz, 2H), 2.96 (br s, 4H), 2.70 (br s, 4H), 2.41 (s, 3H), 1.29 (s, 9H); 13C NMR (CDCI3)
173.3, 173.2, 151.9, 149.0, 135.1 , 134.2, 130.7, 128.1 , 126.3, 125.1 , 121.4, 1 12.0, 109.2, 55.4, 52.3, 45.6, 44.8, 34.7, 31.7, 31.5. F. 1 -{2-r2-(4-Methylpiperazin-1 -yl)phenyllethyl)-3-(4-oxazol-2-ylphenyl)-1 ,3- dihydroimidazol-2-one. Using 2-(4-bromophenyl)oxazole (see US 5,612,359), yield
36%; HCI salt had: NMR (MeOH-d4) 7.99 (AB quartet, Δu = 112.8, J = 8.7 Hz, 4H), 8.11 (br s, 1 H), 7.48 (br s, 1 H), 7.28-7.18 (m, 3H), 7.13-7.10 (m, 1 H), 6.91 (d, J = 2.9 Hz, 1 H), 6.54 (d, J = 3.3 Hz, 1 H), 3.95 (t, J = 7.5 Hz, 2H), 3.49 (br d, J = 12.0 Hz, 2H), 3.40-3.22 (m, 2H), 3.19- 3.04 (m, 6H), 2.92 (m, 3H); 13C NMR (MeOH-d4) 151.9, 150.2, 140.5, 140.2, 134.2, 130.9, 128.0, 127.7, 126.1 , 125.8, 122.8, 121.5, 121.0, 113.7, 108.9, 54.2, 50.4, 50.1 , 44.6, 42.4, 31.0.
G. 1-(2-r2-(4-Methylpiperazin-1-yl)-phenvπethyl>-3-(4-oxazol-5-yl-phenyl)- 1 ,3-dihydroimidazol-2-one. Using 5-(4-bromophenyl)oxazole (see US 5,612,359), yield 13%; HCI salt had: NMR (MeOH-d4) 8.40 (s, 1 H), 7.77 (AB quartet, Δu = 49.4, J = 8.7Hz, 4H), 7.62 (br s, 1 H), 7.28-7.12 (m, 4H), 6.83 (d, ,J = 3.3 Hz, 1 H), 6.50 (d, J = 3.3 Hz, 1 H), 3.95 (t, J = 7.1 Hz, 2H), 3.50-3.28 (m, 4H), 3.27-3.04 (m, 6H), 2.91 (s, 3H).
H. 1-r4-(2-Methyloxazol-4-yl)phenvn-3-f2-r2-(4-methylpiperazin-1-yl)- phenyll-ethyl'M,3-dihv-droimidazol-2-one. Using 4-(4-bromophenyl)-2-methyloxazole (see US 5,612,359), yield 26%: MP-158-161°C; NMR (CDCI3) 7.78 (s, 1 H), 7.68 (AB quartet, Δu = 28.6, J = 2.1 Hz, 4H), 7.20-7.11 (m, 3H), 7.03-7.01 (m, 1 H), 6.47 (d, J = 2.9 Hz, 1 H), 6.06 (d, J = 3.3 Hz, 1H), 3.93 (t, J = 7.9 Hz, 2H), 3.03 (t, J = 7.5 Hz, 2H), 2.90 (br s, 4H), 2.58 (br s, 4H), 2.49 (s, 3H), 2.33 (s, 3H); 13C NMR (CDCI3) 162.1 , 134.2, 133.3, 130.7, 129.9, 128.0, 126.3, 124.7, 121.5, 121.1 , 120.2, 112.3, 108.6, 55.9, 53.0, 46.4, 44.7, 31.4, 14.2. I. 1 -f 2-r2-(4-Methylpiperazin-1 -yl)phenvπethyl}-3-(4-oxazol-4-ylphenyl)-1 ,3- dihydroimidazol-2-one. Using 4-(4-Bromophenyl)oxazole (see US 5,612,359), yield 27%; mp 167-169°C; NMR (CDCI3) 7.92 (d, J = 4.2 Hz, 2H), 7.72 (AB quartet, Δu = 43.1 Hz, J = 8.7 Hz, 4H), 7.20-7.12 (m, 3H), 7.05-7.01 (m, 1 H), 6.49 (d, J = 2.9 Hz, 1 H), 6.08 (d, J = 2.9 Hz, 1 H), 3.93 (t, J = 7.1 Hz, 2H), 3.04 (t, J = 7.5 Hz, 2H), 2.91 (br s, 4H), 2.58 (br s, 4H), 2.33 (s, 3H); 13C NMR (CDCI3) 151.5, 134.2, 133.9, 130.7, 128.1 , 128.0, 126.5, 124.8, 121.6, 121.1 ,
112.4, 107.6, 55.9, 53.0, 46.3, 44.7, 31.4. J. 1-{2-r2-(4-Methylpiperazin-1-yl)phenvnethyl>-3-r4-(tetrahydropyran-4- yl)phenvπ-1,3-di-hvdroimidazol-2-one. Using 4-(4-bromophenyl)tetrahydropyran., 13CNMR (100 MHZ, CDCI3) 34.0, 41.3, 68.5, 120.2, 128.7, 131.8, 145.0.), yield 22%: mp 137-139°C; NMR (CDCI3) 7.37 (AB quartet, Δu = 101.6 Hz, J = 7.9 Hz, 4H), 7.20-7.14 (m, 3H), 7.05-7.02 (m, 1 H), 6.43 (d, J = 3.3 Hz, 1 H), 6.06 (d, J = 2.9 Hz, 1 H), 4.05 (dd, J = 10.4, 3.3 Hz, 2H), 3.92 (t, J = 7.1 Hz, 2H), 3.53-3.44 (m, 2H), 3.02 (t, J = 7.5 Hz, 2H), 2.95 (br s, 4H), 2.77-2.66 (br s, 5H), 2.38 (s, 3H); 13C NMR (CDCI3) 134.2, 130.7, 128.1 , 127.7, 125.0, 121.9, 121.3, 112.0, 109.1 , 68.5, 55.6, 44.8, 41.3, 34.1 , 31.6.
Preparation of 4-(4-bromophenyl)tetrahydropyran: A solution of 4-(4-bromophenyl)- tetrahydropyran-4-ol (859 mg, 3.3 mmol) and triethylsilane (596 uL, 3.7 mmol) in 12 mL dichloromethane was chilled in an ice bath. Trifluoroacetic acid (2.54 mL, 33 mmol) was added in a dropwise manner over 20 min. After 1h at 0° C the reaction mixture was stirred at room temperature (rt) for 3h. 1 N aqueous NaOH was added until the aqueous pH remained basic, and the mixture was extracted three times with dichloromethane. The organic extracts were combined, dried (Na2SO4) and concentrated to an oily solid. Purification by silica gel chromatography (5:95, ethyl acetate: hexanes) afforded the title compound as a white solid (640mg, 80% yield).
K. 1 -(4-lsopropoxyphenyl)-3-(2-r2-(4-methylpiperazin-1 -yl)phenyl1ethyl}-1.3- dihydroimidazol-2-one. Using 1-bromo-4-isopropoxybenzene, yield 41 %; HCI salt had: (MeOH-d4) 7.38-7.36 (), 6.96(AB quartet, Δu = 165.9, J = 8.7 Hz, 4H), 7.23-7.12 (m, 4H), 6.64 (d, J = 2.9Hz, 1 H) ,6.43 (d, J = 2.9 Hz, 1 H), 4.60-4.56 (m, 1 H), 3.93 (t, J = 7.5 Hz, 2H), 3.48 (d, J = 12.0 Hz, 2H), 3.35-3.31 (m, 2H), 3.14-3.02 (m, 6H), 2.91 (s, 3H), 1.28 (d, J = 5.8 Hz, 6H); 13C NMR (MeOH-d4) 156.7, 150., 134.3, 130.9, 128.0, 127.9, 125.8, 124.1 , 121.0, 116.2, 112.4, 110.6, 70.1 , 54.2, 50.1 , 44.7, 42.4, 31.2, 21.0. L. 1-f2-r2-(4-Methylpiperazin-1-yl)-phenvn-ethyl>-3-(3-oxo-1,3- dihvdroisobenzofuran-5-yl)-1,3-dihydro-imidazol-2-one. Using PP17, yield = 9.6%: mp- 167-1710C; NMR (CDCI3) 8.27 (d, J = 7.9 Hz, 1 H), 7.89 (s, 1 H), 7.52 (d, J = 8.3 Hz, 1 H), 7.21- 7.13 (m, 3H), 7.05-7.01 (m, 1 H), 6.51 (d, J = 2.9 Hz, 1H), 6.12 (d, J = 2.9 Hz, 1 H), 3.95 (t, J = 7.1 Hz, 2H), 3.04 (t, J = 7.1 Hz, 2H), 2.91 (br s, 4H), 2.57 (br s, 4H), 2.33 (s, 3H); 13C NMR (CDCI3) 170.74, 152.15, 151.67, 143.17, 138.89, 133.92, 130.68, 128.10, 127.77, 126.96, 124.79, 123.19, 121.19, 117.21, 113.13, 108.27, 69.82, 66.07, 55.97, 53.04, 46.36, 44.77, 31.43, 15.49.
M. 1 -r4-(5-M ethyl -H ,3,41oxadiazol-2-yl)-phenyll-3-{2-r2-(4-methylpiperazin-1 - yl)-phenvπ-ethyl|-1,3-dihydroimidazol-2-one. Using PP18, yield 26%: mp 151-154°C; NMR (CDCI3) 7.92 (AB quartet, Δu = 102.4, J = 8.7 Hz, 4H), 7.21-7.13 (m, 3H), 7.06-7.02 (m, 1 H), 6.53 (d, J = 3.3 Hz, 1 H), 6.10 (d, J = 2.9 Hz, 1 H), 3.94 (t, J = 7.1 Hz, 2H), 3.04 (t, J = 7.5 Hz, 2H), 2.92 (br s, 4H), 2.59 (br s, 7H), 2.32 (s, 3H); 13C NMR (CDCI3) 163.80, 152.11, 151.68, 140.35, 134.00, 130.69, 128.09, 127.89, 124.83, 121.19, 121.03, 120.86, 113.11 , 107.93, 66.06, 55.88, 52.94, 46.27, 44.82, 31.39, 15.48, 11.36.
N. 1-(6-Methoxy-pyridin-3-yl)-3-{2-r2-(4-methylpiperazin-1-yl)-phenyll- ethyl}-1,3-dihvdro-imidazol-2-one. Using 5-bromo-2-methoxypyridine, yield 20%; mp 95- 97°C; NMR (CDCI3) 8.22 (d, J = 2.5 Hz, 1 H), 7.89 (dd, J = 9.1, 2.9 Hz, 1 H), 7.20-7.13 (m, 3H), 7.05-7.01 (m, 1 H), 6.77 (d, J = 8.7 Hz, 1 H), 6.36 (d, J = 2.9 Hz, 1 H), 6.09 (d, J = 3.3 Hz, 1 H), 3.95-3.91 (m, 5H), 3.03 (t, J = 7.5 Hz, 2H), 2.92-2.90 (m, 4H), 2.56 (br s, 4H), 2.34 (s, 3H); 13C NMR (CDCI3) 162.16, 152.16, 151.93, 140.17, 133.60, 130.67, 128.61 , 128.01 , 124.74, 121.16, 112.30, 111.17, 109.03, 55.98, 53.91 , 53.05, 46.39, 44.70, 31.49. O. 1 -(2-Methylbenzothiazol-5-yl)-3-(2-r2-(4-methylpiperazin-1 - yl)phenvnethyl>-1,3-dihvdro-imidazol-2-one. Using 5-bromo-2-methylbenzothiazole, yield 26%, HCI salt had: mp 165-1700C; NMR (MeOH-d4) 8.42 (d, J = 1.7 Hz, 1 H), 8.02 (d,J = 8.7 Hz, 1 H), 7.96-7.93 (m, 1 H), 7.28-7.20 (m, 3H), 7.13-7.09 (m, 1 H), 6.92 (d,J = 2.9 Hz, 1 H), 6.60 (d, J = 2.9 Hz, 1 H), 3.98 (t, J = 7.5 Hz, 2H), 3.52 (d, J = 12.0 Hz, 2H), 3.48-3.39 (m, 2H), 3.21-3.14 (m, 4H), 3.07 (t, J = 7.5 Hz, 2H), 3.04 (s, 3H), 2.93 (s, 3H); 13C NMR (MeOH-d4) 175.19, 151.99, 150.23, 136.22, 134.13, 133.69, 130.92, 128.06, 125.79, 122.44, 121.11 , 119.31 , 115.63, 113.63, 109.49, 54.15, 50.12, 44.52, 42.44, 31.13, 17.10.
P. 1-r4-(2-lsopropyl-oxazol-4-yl)-phenvπ-3-f2-r2-(4-methyl-piperazin-1-yl)- phenvn-ethyl>-1,3-dihvdro-imidazol-2-one. Using 4-(4-bromo-phenyl)-2-isopropyloxazole (see US 5,612,359), yield 26%: mp 115-119°C; NMR (CDCI3) 7.79 (s, 1 H), 7.75-7.62 (AB quartet, Δu = 44.4 Hz, J = 8.7 Hz, 4H), 7.21-7.13 (m, 3H), 7.06-7.04 (m, 1 H), 6.49 (d, J = 2.9 Hz, 1 H), 6.07 (d, J = 2.9 Hz, 1 H), 3.93 (t, J = 7.1 Hz, 2H), 3.14-3.10 (m, 1 H), 3.04 (t, J = 7.5 Hz, 2H)1 2.93 (br s, 4H), 2.60 (br s, 4H), 2.35 (s, 3H), 1.37 (d, J = 7.1 Hz, 6H); 13C NMR (CDCI3) 152.08, 151.77, 139.88, 137.12, 134.18, 133.01 , 130.70, 128.87, 128.00, 126.42, 124.81 , 121.49, 121 .16, 112.26, 108.69, 55.93, 52.91 , 46.33, 44.78, 31.45, 28.82, 20.70
Q. 1-r4-(2-Hvdroxy-2-methylpropyl)phenvn-3-(2-r2-(4-methylpiperazin-1-yl)- phenyllethyl}-1 ,3-dihvdro-imidazol-2-one. Using PP52, yield 18%: mp 98-1000C; NMR (CDCI3) 7.51 (d, J = 8.30 Hz, 2H), 7.25-7.23 (m, 2H), 7.20-7.13 (m, 3H), 7.05-7.02 (m, 1 H), 6.44 (d, J = 2.9 Hz, 1 H), 6.07 (d, J = 2.9 Hz, 1 H), 3.93 (t, J = 7.1 Hz, 2H), 3.03 (t, J = 7.5 Hz, 2H), 2.91 (br s, 6H), 2.74 (s, 2H), 2.58 (br s, 4H), 2.34 (s, 3H), 1.21 (s, 6H); 13C NMR (CDCI3) 152.08, 151.82, 136.22, 135.42, 134.19, 131.34, 130.71, 127.99, 124.79, 121.46, 121.16, 112.08, 109.01 , 70.99, 55.89, 52.92, 49.34, 46.26, 44.71 , 31.49, 29.38 .
R. 1 -r4-(1 ■Methoxycvclobutyl)phenvn-3-{2-r2-(4-methyl-piperazin-1 -vD- phenyllethyl}1,3-dihvdroimidazol-2-orie. Using PP55, yellow oil, yield 38%: NMR (CDCI3) 7.50 (AB quartet, Δu = 51.9 Hz, J = 8.7 Hz, 4H), 7.19-7.11 (m, 3H), 7.04-7.00 (m, 1 H), 6.45 (d, J = 2.9 Hz, 1 H), 6.06 (d, J = 3.3 Hz, 1 H), 3.93 (t, J = 7.1 Hz, 2H), 2.91-2.90 (m, 4H), 2.89 (s, 3H), 2.56 ( br s, 4H), 2.35-2.33 (m, 4H), 2.32 (s, 3H), 2.00-1.88 (m, 1 H), 1.66-1.58 (m, 1 H); 13C NMR (CDCI3) 152.14, 151.84, 140.65, 136.63, 134.16, 130.69, 127.96, 127.39, 124.73, 121.46, 121.11 , 112.14, 108.95, 81.33, 55.96, 53.01 , 50.71 , 46.35, 44.68, 33.08, 31.44, 13.08.
EXAMPLE 3 Syntheses of the compounds below, using PP3, are essentially the same procedure as described in Example 1 :
A. 1 -F4-(1 -Hydroxy-cyclopentvP-phenyll-S-d -methyl-2-[2-(4-methyl- piperazin-1 -yQ-phenyli-ethylH ,3-dihydro-imidazol-2-one. Using PP49, yield 43%; NMR (CDCI3) 7.46 (d, with extra fine splitting, J = 3.7 Hz, 4H), 7.18-7.06 (m, 3H), 6.98 (dt, J = 7.3, 1.2 Hz, 1 H), 6.45 (d, J = 2.9 Hz, 1 H), 6.33 (d, J = 2.9 Hz, 1 H), 4.71-4.65 (m, 1 H), 3.02-2.85 (m, 6H), 2.71 (br s, 4H), 2.40 (s, 3H), 1.94 (br s, 6H), 1.93 (br s, 2H), 1.29 (d, J = 7.1 Hz, 3H); 13C NMR (CDCI3) 151.78, 151.49, 136.11 , 135.79, 133.89, 130.86, 127.94, 126.22, 126.13, 124.83, 121.50, 121.30, 109.41 , 108.95, 83.21 , 55.62, 52.45, 49.91 , 45.91 , 42.13, 37.74, 24.05, 19.87. B. 1 -f6-(1 -Hvdroxy-1 -methyl-ethyl)-pyridin-3-vπ-3-f 1 -methyl-2-r2-(4-methyl- piperazin-1 -yl)-phenyll-ethyl}-1 ,3-dihydro-imidazol-2-one. Using PP53, yield 24% as a yellow oil which had: NMR (CDCI3) 8.55 (dd, J = 2.5, 0.8 Hz, 1 H), 8.00 (dd, J = 8.7, 2.5 Hz, 1 H), 7.39-7.37 (m, 1 H), 7.18-7.09 (m, 3H), 6.99-6.95 (m, 1 H), 6.49 (d, J = 2.9 Hz, 1 H), 6.40 (d, J = 2.9 Hz, 1 H), 3.00 (t, J = 7.1 Hz, 2H), 2.91 (br s, 4H), 2.61 (br s, 4H), 2.34 (s, 3H), 1.50 (s, 6H), 1.34 (d, J = 7.1 Hz, 3H); 13C NMR (CDCI3) 172.70, 163.18, 152.14, 140.35, 133.68, 132.87, 130.57, 127.94, 124.62, 121.21 , 119.02, 110.01, 108.47, 72.00, 56.05, 53.00, 50.29, 46.41 , 37.29, 30.83, 21.12, 20.13.
EXAMPLE 4 Syntheses of the compounds below, using PP4A, are essentially the same procedure as described in Example 1 :
A. 3-F4-(1-Hvdroxycvclobutyl)phenvπ-4-methyl-1-(2-r2-(4-methylpiperazin-
1 -yl)phenvπethyl}-1 ,3-dihydroimidazol-2-one. Using PP50, yield 21 %; mp 147-1520C; NMR (CDCI3) 7.41 (AB quartet, Δu = 116.1 Hz, J = 8.3 Hz, 4H), 7.23-7.02 (m, 4H), 5.90 (d, J = 1.2 Hz, 1 H), 3.89 (t, J = 7.1 Hz, 2H), 3.02 (t, J = 7.9 Hz, 2H), 2.94 (br s, 4H), 2.59-2.52 (m, 6H), 2.38-2.33 (m, 5H), 2.06-1.98 (m, 1 H), 1.89 (d, J = 1.2 Hz, 3H), 1.74-1.65 (m, 1 H); 13C NMR (CDCI3) 152.95, 152.14, 145.73, 134.39, 130.67, 127.86, 127.45, 126.11 , 124.67, 121.14, 118.54, 107.74, 56.02, 53.04, 46.41 , 44.17, 37.21 , 31.62, 13.15, 11.44.
B. 3-f4-(1 -Hvdroxy-1 -methylethyl)phenyll-4-methyl-1 -(2-F2-(4- methylpiperazin-1-yl)phenvn-ethyl>-1,3-dihvdroimidazol-2-one. Using PP51 , yield 19%: mp 158-1600C; NMR (CDCI3) 7.53 (d, J = 8.3 Hz, 2H), 7.24-7.13 (m, 5H), 7.06-7.02 (m, 1 H), 5.89 (d, J = 1.2 Hz, 1 H), 3.89 (t, J = 7.1 Hz, 2H), 3.02 (t, J = 7.5 Hz, 2H), 2.93 (t, J = 4.6 Hz, 4H), 2.59 (br s, 4H), 2.35 (s, 3H), 1.88 (d, J = 1.2 Hz, 3H), 1.57 (s, 6H); 13C NMR (CDCI3) 152.97, 152.13, 148.54, 134.40, 133.95, 130.67, 127.85, 127.23, 125.52, 124.67, 121.14, 118.59, 107.65, 72.62, 56.02, 53.05, 46.42, 44.17, 31.98, 31.98, 31.63, 1 1.43.
C. 3-r4-(1-Hvdroxycvclopentyl)phenvn-4-methyl-1-(2-f2-(4-methylpiperazin-
1-yl)phenvπethyl}-1,3-dihvdroimidazol-2-one. Using PP49, yield 30%: mp 149-152°C; NMR (CDCI3) 7.37 (AB quartet, Δu = 125.7 Hz, J = 8.3 Hz, 4H), 7.20-7.01 (m, 4H), 5.89 (d, J = 1.2 Hz, 1 H), 3.89 (t, J = 7.5 Hz, 2H), 3.02 (t, J = 7.9 Hz, 2H), 2.92 (t, J = 4.6 Hz, 4H), 2.58 (br s, 4H), 2.34 (s, 3H), 2.02-1.94 (m, 4H), 1.88 (s, 3H), 1.83-1.74 (m, 4H); 13C NMR (CDCI3) 152.97, 152.13, 146.60, 134.40, 133.99, 130.67, 127.85, 127.22, 126.17, 124.67, 121.13, 118.59, 107.65, 83.47, 56.02, 53.04, 46.41 , 44.17, 42.18, 31.61 , 24.07, 1 1.42. D. 3-r4-(1-Mθthoxycvclobutyl)phenvn-4-methyl-1-(2-r2-(4-methylpiperazin-
1-yl)phenvπethyl>-1,3-dihvdroimidazol-2-one. Using PP55, yield 37%: mp 73-840C; NMR (CDCI3) 7.46 (d, J = 8.3 Hz, 2H), 7.27-7.13 (m, 5H), 7.05-7.01 (m, 1 H), 5.89 (d, J = 1.2 Hz, 1 H), 3.89 (t, J = 7.1 Hz, 2H), 3.02 (t, J = 7.5 Hz, 2H), 2.94-2.91 (m, 7H), 2.58 (br s, 4H), 2.38- 2.34 (m, 7H), 1.95-1.91 (m, 1 H), 1.90 (d, J = 1.2 Hz, 3H), 1.69-1.62 (m, 1 H); 13C NMR (CDCI3) 152.94, 152.12, 142.63, 134.39, 130.67, 127.87, 127.26, 124.68, 121.14, 118.54, 107.77, 81.45, 56.02, 53.05, 50.84, 46.41 , 44.19, 33.05, 31.62, 21.27, 14.40, 13.10, 11.48. E. 3-r6-(1-Hvdroxy-1-methylethyl)pyridin-3-vn-4-methyl-1-f2-r2-(4- methylpiperazin-1-yl)-phenyllethyl}-1.3-dihydroimidazol-2-one. Using PP53, yield 14%, yellow oil: NMR (CDCI3) 8.41-8.40 (m, 1 H), 7.68 (dd, J = 8.3, 2.5 Hz, 1 H), 7.46 (dd, J = 8.3, 0.8 Hz, 1 H), 7.21-7.13 (m, 3H), 7.06-7.01 (m, 1 H), 5.94 (d, J = 1.2 Hz, 1 H), 3.90 (t, J = 7.5 Hz, 2H), 3.02 (t, J = 7.9 Hz, 2H), 2.93 (t, J = 4.6 Hz, 4H), 2.59 (br s, 4H), 2.35 (s, 3H), 1.92 (d, J = 1.2 Hz, 3H), 1.54 (s, 6H); 13C NMR (CDCI3) 165.04, 152.14, 145.73, 135.87, 134.14, 130.76, 130.64, 128.00, 124.71 , 121.23, 119.31 , 118.05, 108.60, 72.19, 56.01 , 55.88, 53.04, 46.41 , 44.25, 31.62, 20.85, 11.42. F. 3-r6-(1-Methoxy-1-methylethvnpyridin-3-vn-4-methyl-1-(2-r2-(4- methylpiperazin-1-yl)-phenvnethyl)-1,3-dihydroimidazol-2-one. Using PP20, yield 53%, tan oil: NMR (CDCI3) 8.44-8.43 (m, 1 H), 7.68-7.60 (m, 2H), 7.20-7.13 (m, 3H), 7.05-7.01 (m, 1 H), 5.93 (m, J = 1.2 Hz, 1 H), 3.90 (t, J = 7.1 Hz, 2H), 3.18 (s, 3H),3.02 (t, J = 7.5 Hz, 2H), 2.92 ( t, J = 4.6 Hz, 4H), 2.58 (br s, 4H), 2.35 (s, 3H), 1.92 (d, J = 1.2 Hz, 3H), 1.55 (s, 6H); 13C NMR (CDCI3) 164.25, 152.13, 146.69, 135.25, 134.16, 130.57, 127.93, 124.66, 121.15, 120.48, 118.08, 108.48, 78.80, 55.99, 53.05, 51.17, 46.41 , 44.22, 31.56, 26.78, 11.42.
G. 3-F6-(1 -MethoxycvclopentvDpyridin-S-vn^-methyl-i -{2-F2-(4- methylpiperazin-1-yl)phenvπ-ethyl)-1,3-dihydroimidazol-2-one. Using PP21 , yield 34%: mp 107-1120C; NMR (CDCI3) 8.45 (d, J = 2.5 Hz, 1 H), 7.69 (dd, J = 8.3, 2.5 Hz, 1 H), 7.62- 7.60 (m, 1 H), 7.24-7.15 (m, 3H), 7.08 (m, 1 H), 5.95 (d, J = 1.2 Hz, 1 H), 3.92 (t, J = 7.1 Hz, 2H), 3.11 (s, 3H), 3.04 (t, J = 7.9 Hz, 2H), 2.95 (t, J = 4.6 Hz, 4H), 2.61 (br s, 4H)1 2.37 (s, 3H), 2.12 (m, 4H), 1.94 (d, J = 1.2 Hz, 3H), 1.86-1.79 (m, 4H); 13C NMR (CDCI3) 162.49, 152.87, 152.13, 146.78, 135.21 , 134.17, 130.65, 130.59, 127.98, 124.71 , 121.50, 121.19,
118.14, 108.50, 90.50, 56.00, 55.78, 53.04, 51.58, 46.40, 44.26, 36.75, 31.59, 23.93, 11.45. H. 3-f4-(1 -Methoxy-1 -methylethyl)phenvπ-4-methyl-1 -{2-f2-(4- methylpiperazin-1-yl) phenyll-ethyl>-1,3-dihydroimidazol-2-one. Using PP54, yield 19%, yellow oil: NMR (CDCi3) 7.46 (d, J = 8.3 Hz, 2H), 7.25-7.20 (m, 5H), 7.08-7.04 (m, 1 H), 5.91 (d, J = 1.2 Hz, 1 H), 3.91 (t, J = 7.5 Hz, 2H), 3.09 (s, 3H), 3.04 (t, J = 7.9 Hz, 2H), 2.95 (t, J = 4.6 Hz, 4H), 2.61 (br s, 4H), 2.37 (s, 3H), 1.91 (d, J = 1.2 Hz, 3H), 1.53 (s, 6H); 13C NMR (CDCI3) 152.96, 152.15, 145.51 , 134.42, 134.09, 130.68, 127.86, 127.20, 126.78, 124.68,
121.15, 118.57, 107.70, 76.85, 56.04, 53.08, 50.20, 46.44, 44.19, 31.63, 28.18, 11.48. EXAMPLE 5:
Syntheses of the compounds below, using PP2, are essentially the same procedure as described in Example 1 :
A. 1-(4-lsopropoxyphenyl)-3-{2-r2-(4-methylpiperazin-1-yl)pyridin-3- yllethyl}-1,3-dihydro-imidazol-2-one. Using 1-bromo-4-isopropoxybenzene, yield 21 %, HCI salt had: NMR (MeOH-d4) 8.26 (d, J = 5.4 Hz, 1 H), 8.16 (d, J = 7.5 Hz, 1 H), 7.45 (t, J = 6.2 Hz, 1 H), 7.32 (AB quartet, Δu = 158.8, J = 8.7 Hz, 4H), 6.70 (d, J = 2.5 Hz, 1 H), 6.65 (d, J =
2.5 Hz, 1 H), 4.59-4.56 (m, 1 H), 4.02 (t, J = 6.6 Hz, 2H), 3.82 (d, J = 12.9 Hz, 2H), 3.65-3.56 (m, 4H), 3.48-3.46 (m, 2H), 3.17 (t, J = 6.6 Hz, 2H), 2.96 (s, 3H)1 1.27 (d, J = 6.2 Hz, 6H); 13C NMR (MeOH-d4) 156.8, 147.2, 139.3, 130.9, 129.6, 124.2, 120.6, 1 16.2, 111.9, 111.3, 70.1 , 53.0, 42.5, 31.2, 21.0.
B. 1-(2-r2-(4-Methylpiperazin-1-yl)-pyridin-3-vn-ethyl>-3-(4-oxazol-2- ylphenvπ-1,3-dihvdroim-idazol-2-one. Using 2-(4-bromophenyl)oxazole (see US 5,612,359), yield 8%: mp 135-1400C; NMR (CDCI3) 8.21 (dd, J = 4.6, 2.9 Hz, 1 H), 7.90 (AB quartet, Δu = 136.5, J = 9.1 Hz, 4H), 7.69 (s, 1 H), 7.45 (m, 1 H), 7.21 (s, 1 H), 6.91-6.88 (m, 1H), 6.53 (d, J = 2.9 Hz, 1H), 6.06 (d, J = 2.9 Hz, 1H), 3.96 (t, J = 7.1 Hz, 2H), 3.14 (br s, 4H), 3.02 (t, J = 7.1 Hz, 2H), 2.58 (br s, 4H), 2.33 (s, 3H); 13C NMR (CDCI3) 146.73, 138.93, 138.81 , 128.70, 127.56, 126.03, 124.73, 121.08, 119.00, 112.55, 108.50, 55.62, 50.80, 46.41 , 43.84, 31.28.
C. 1-(6-Methoxypyridin-3-yl)-3-{2-r2-(4-methylpiperazin-1-yl)pyridin-3- vnethyl>-1,3-dihvdroim-idazol-2-one. Using 5-bromo-2-methoxypyridine, yield 8.7%, HCI salt had: NMR (MeOH-d4) 8.42 (s, 1 H), 8.27 (d, J = 6.2 Hz, 1 H), 8.22 (d, J = 6.2 Hz, 1 H),
8.06 (dd, J = 9.1 , 2.5 Hz, 1 H), 7.51-7.48 (m, 1 H), 7.09 (d, J = 9.1 Hz, 1H), 6.87 (d, J = 2.9 Hz, 1 H), 6.79 (d, J = 2.9 Hz, 1 H), 4.04 (t, J = 7.1 Hz, 2H), 4.00 (s, 3H), 3.90-3.87 (m, 2H), 3.69- 3.66 (br s, 4H), 3.61-3.50 (m, 2H), 3.19 (t, J = 7.1 Hz, 2H), 3.00 (s, 3H); 13C NMR (MeOH-d4) 139.94, 133.40, 129.05, 120.32, 113.30, 112.49, 111.14, 109.82, 54.07, 53.24, 47.86, 43.04, 42.81 , 30.99. D. 1-(2-Mβthylbenzothiazol-5-yl)-3-(2-r2-(4-methylpiperazin-1-yl)pyridin-3- vnethyl}-1 ,3-dihydroimidazol-2-one. Using 5-bromo-2-methylbenzothiazole, yield 9.9%, HCI salt had: NMR (DMSO-d6) 8.29 (d, J = 2.1 Hz, 1 H), 8.18 (d, J = 3.3 Hz, 1 H), 7.90 (d, J = 8.7 Hz, 1 H), 7.77-7.72 (m, 2H), 7.14-7.11 (m, 1 H), 7.03 (d, J = 2.9 Hz, 1 H), 6.73 (d, J = 3.3 Hz, 1 H), 3.91 (t, J = 7.1 Hz, 2H), 3.47-3.38 (m, 4H), 3.30-3.18 (m, 4H), 2.97 (t, J = 7.5 Hz, 2H), 2.75 (br s, 6H); 13C NMR (DMSO-d6) 193.03, 167.78, 151.70, 136.58, 134.87, 122.71 , 120.30, 120.06, 114.36, 113.44, 109.90, 53.15, 47.82, 43.01 , 42.77, 30.96, 20.42.
E. 1-r4-(1-Methoxycvclobutyl)phenvn-3-{2-f2-(4-methylpiperazin-1- yl)pyridin-3-yllethyl}-1,3-dihvdroimidazol-2-one. Using PP55, yield 9.6%, yellow oil: NMR (CDCI3) 8.20-8.18 (m, 1 H), 7.50 (AB quartet, , Δu = 44.4 Hz, J = 8.7 Hz, 4H), 7.43-7.42 (m, 1 H) 6.88 (dd, J = 7.5, 4.6 Hz, 1 H), 6.46 (d, J = 3.3 Hz, 1 H), 6.04 (d, J = 3.3 Hz, 1 H), 3.95 (t, J = 7.1 Hz, 2H), 3.14 (t, J = 5.0 Hz, 4H), 3.01 (t, J = 7.1 Hz, 2H), 2.9 (s, 3H), 2.57 (br s, 4H), 2.36-2.34 (m, 4H), 2.32 (s, 3H), 1.93-1.86 (m, 1 H), 1.66-1.59 (m, 1 H). 13C NMR (CDCI3) 162.24, 151.81 , 146.66, 140.85, 138.94, 136.47, 127.43, 126.10, 121.48, 119.02, 111.92, 109.28, 81.33, 55.56, 50.72, 50.68, 46.32, 43.74, 33.08, 31.32, 13.08.
F. 1-(2-r2-(4-Methylpiperazin-1-yl)pyridin-3-yllethyl}-3-(4-oxazol-5- ylphenyl)-1 ,3-dihvdro-imidazol-2-one. Using 5-(4-bromophenyl)oxazole (see US 5,612,359), yield 12%, oil: NMR (CDCI3) 8.20 (d, 3.3 Hz, 1 H), 7.90 (s, 1 H), 7.68 (br s, 4H), 7.45 (d, J = 6.2 Hz, 1 H), 7.33 (s, 1 H), 6.93 (d, J = 2.1 Hz, 1 H), 6.50 (d, J = 2.9 Hz, 1 H), 6.08 (d, J = 2.9 Hz, 1 H), 3.94 (t, J = 7.1 Hz, 2H), 3.28 (br s, 4H), 3.00 (t, J = 7.1 Hz, 2H), 2.81 (br s, 4H), 2.47 (s, 3H).
G. 1 -F4-(1 -Hydroxy-vclopentyl)phenvn-3-{2-r2-(4-methylpiperazin-1 - yl)pyridin-3-yllethyl}-1,3-dihvdroimidazol-2-one. Using PP49, yield 3.8%, yellow oil: NMR (CDCI3) 8.20 (dd, J = 5.0, 1.6 Hz, 1 H), 7.51 (br s, 4H), 7.42 (dd, J = 7.5, 1.7 Hz, 1 H), 6.88 (dd, J = 7.5, 5.0 Hz, 1 H), 6.45 (d, J = 2.90 Hz, 1 H), 6.04 (d, J = 2.9 Hz, 1 H), 3.95 (t, J = 7.1 Hz, 2H), 3.14 (t, J = 4.56 Hz, 4H), 3.01 (t, J = 7.5 Hz, 2H), 2.57 (br s, 4H), 2.33 (s, 3H), 1.97 (br s, 6H), 1.82 (br s, 2H).
H. 1-f2-f2-(4-Methylpiperazin-1-yl)pyridin-3-vπethyl}-3-r4-(tetrahvdropyran- 4-yl)phenyll-1,3-di-hydroimidazol-2-one. Using 4-(4-bromophenyl)tetrahydropyran (see above), yield 8.3%: mp 152-154°C; NMR (CDCI3) 8.20 (dd, J = 5.6, 2.1 Hz, 1 H), 7.49 (d, J = 8.7 Hz, 2H), 7.43 (dd, J = 7.5, 1.7 Hz, 1 H), 7.24 (d, J = 8.7 Hz, 2H), 6.88 (dd, J = 7.5, 5.0 Hz, 1 H), 6.43 (d, J = 3.3 Hz, 1 H), 6.04 (d, J = 3.3 Hz, 1 H), 4.05 (m 2H), 3.96 (t, J = 7.1 Hz, 2H), 3.54-3.47 (m, 2H), 3.13 (t, J = 5.0 Hz, 4H), 3.01 (t, J = 7.5 Hz, 2H), 2.74 (m, 1 H), 2.56 ( br s, 4H), 2.33 (s, 3H), 1.80-1.74 (m, 4H); 13C NMR (CDCI3) 162.30, 151.84, 146.65, 143.68, 138.91 , 135.76, 127.69, 126.10, 121.99, 118.94, 111.74, 109.40, 68.55, 55.65, 50.79, 46.43, 43.67, 41.30, 34.13, 31.34. I. 1-r6-(1-Hvdroxy-1-methylethyl)pyridin-3-vn-3-{2-r2-(4-methylpiperazin-1 - yl)pyridin-3-vn-eth-yl>-1,3-dihydroimidazol-2-one. Using PP53, yield 8.8%: mp 133- 136°C; NMR (CDCI3) 8.60 (d, J = 2.5 Hz, 1 H), 8.20 (m, 1 H), 8.08 (dd, J = 8.3, 2.5 Hz, 1 H), 7.42 (d, J = 8.3 Hz, 1 H), 6.90 (m, 1 H), 6.48 (d, J = 2.9 Hz, 1 H), 6.10 (d, J = 2.9 H, 1 H), 4.69 (s, 1 H), 3.97 (t, J = 7.1 Hz, 2H), 3.14 (t, J = 4.6 Hz, 4H), 3.02 (t, J = 7.1 Hz, 2H), 2.57 (br s, 2H), 2.83 (s, 3H), 1.53 (s, 6H); 13C NMR (CDCI3) 146.78, 140.25, 138.91 , 132.79, 130.20, 125.86, 1 19.10, 119.00, 112.82, 112.50, 108.43, 72.04, 66.07, 55.62, 50.76, 46.41 , 43.79, 31.34, 30.86, 15.49.
J. 1-[4-(2-Hvdroxy-2-methylpropyl)phenvπ-3-{2-r2-(4-methylpiperazin-1- yl)pyridin-3-vnethylH,3-dihvdroimidazol-2-one. Using PP52, yield 6.9%: mp 117-1220C; NMR (CDCI3) 8.20 (dd, J = 5.0,1.7 Hz, 1 H), 7.43 (dd, J = 7.5, 1.7 Hz, 1 H), 7.37 (AB quartet, Δu = 104.5 Hz, J = 8.3 Hz, 4H), 6.88 (m, 1H), 6.44 (d, J = 2.9 Hz, 1 H), 6.04 (d, J = 3.3 1 H) 3.96 (t, J = 7.1 Hz, 2H), 3.13 (t, J = 5.0 Hz, 4H), 3.02 (t, J =7.5 Hz, 2H), 2.75 (s, 2H), 2.56 (br s, 4H), 2.32 (s, 3H), 1.21 (s, 6H); 13C NMR (CDCI3) 162.30, 151.80, 146.65, 138.92, 138.92, 136.09, 135.55, 131.37, 126.11 , 121.47, 118.95, 111.83, 109.30, 70.99, 55.66, 50.79, 49.34, 46.43, 31.34, 29.38, 15.49.
K. 1-r4-(2-Methoxy-2-methylpropyl)phenvn-3"f2-r2-(4-methylpiperazin-1- yl)pyridin-3-vnβthyl>-1,3-dihydroimidazol-2-one. Using PP56, yield 16%, yellow oil: NMR (CDCI3) 8.21-8.19 (m, 1 H), 7.47-7.42 (m 3H), 7.24-7.20 (m, 2H), 6.90-6.87 (m, 1 H), 6.44 (d, J = 2.9 Hz, 1 H), 6.02 (d, J = 2.9 Hz, 1 H), 3.95 (t, J = 7.1 Hz, 2H), 3.25 (s, 3H), 3.13 (t, J = 4.6 Hz, 3H), 3.01 (t, J = 7.1 Hz, 2H), 2.74 (s, 2H), 2.56 (br s, 4H), 2.31 (s, 3H), 1.10 (s, 6H); 13C NMR (CDCI3) 162.30, 151.78, 146.60, 138.89, 136.19, 135.69, 131.31 , 126.13, 121.14, 118.93, 1 11.69, 109.38, 75.38, 55.63, 50.79, 49.61 , 46.41 , 45.92, 43.68, 31.30, 24.83. L. 1-{2-f2-(4-Methylpiperazin-1-yl)pyridin-3-yl1ethyl}-3-(1-oxo-1 ,3- dihvdroisobenzofuran-5-yl)-1,3-dihydroimidazol-2-one. Using PP16, yield 11.4%: mp 170-175°C; NMR (CDCI3) 8.20 (dd, J = 4.6, 1.7 Hz, 1 H), 8.04 (s, 1 H), 7.92 (d, J = 8.3 Hz, 1 H), 7.60 (d, J = 8.3 Hz, 1 H), 7.42 (d, J = 6.2 Hz, 1 H), 6.90 (dd, J = 7.5, 5.0 Hz, 1 H), 6.55 (d, J = 3.3 Hz, 1 H), 6.11 (d, J = 2.9 Hz 1 H), 5.31 (s, 2H), 3.98 (t, J = 7.1 Hz, 2H), 3.17 (br s, 4H), 3.02 (t, J = 7.1 Hz, 2H), 2.61 (br S, 4H), 2.36 (s, 3H); 13C NMR (CDCI3) 151.64, 148.38, 146.85, 142.52, 138.97, 127.04, 125.04, 125.78, 122.46, 121.10, 119.13, 114.21 , 113.33, 108.22, 69.65, 55.40, 50.51 , 46.20, 43.86, 31.29.
M. 1-lsochroman-6-yl-3-f2-f2-(4-methylpiperazin-1-yl)pyridin-3-vn-ethyl>- 1.3-dihvdroimidazol-2-one. Using PP15, yield 23%, HCI salt had: NMR (CDCI3) 8.20 (dd, J = 4.6, 1.7 Hz, 1 H), 7.44 (d, J = 1.7 Hz, 1 H), 7.42 (d, J = 1.7 Hz, 1 H), 7.29 (dd, J = 8.3, 2.1 Hz, 1 H), 6.99 (d, J = 8.3 Hz, 1 H), 6.89 (dd, J = 7.5, 5.0 Hz, 1 H), 6.42 (d, J = 2.9 Hz, 1 H), 6.04 (d, J = 3.3 Hz, 1 H), 4.74 (s, 2H), 3.97-3.93 (m, 4H), 3.13 (t, J = 4.6 Hz, 4H), 3.01 (t, J = 7.1 Hz, 2H), 2.86 (t, J = 5.4 Hz, 2H), 2.56 (br s, 4H), 2.32 (s, 3H). N. 1 -r4-(1 -Hydroxy-1 -methylethyl)-phenvπ-3-f2-r2-(4-methylpiperazin-1 - yl)pyridin-3-yllethyl}-1,3-dihvdroimidazol-2-one. Using PP51 , yield 5.0%: mp 150-1520C; NMR (CDCI3) 8.20 (dd, J = 5.0, 1.7 Hz, 1H), 7.52 ( br s, 4H), 7.43 (dd, J = 7.5, 1.7 Hz, 1 H), 6.88 (m, 1 H), 6.45 (d, J = 2.9 Hz, 1 H), 6.04 (d, J = 2.9 Hz, 1 H), 3.96 (t, J = 7.1 Hz, 2H), 3.13 (t, J = 5.0 Hz, 4H), 3.02 (t, J = 7.1 Hz, 2H), 2.56 (br s, 4H), 2.32 (s, 3H), 1.56 (s, 6H); 13C NMR (CDCI3) 162.30, 151.83, 146.89, 146.65, 138.92, 136.06, 126.09, 125.52, 121.51 , 118.95, 111.82, 109.34, 72.56, 55.66, 50.79, 46.44, 43.44, 43.68, 32.01 , 31.33.
O. 1-r4-(5-Methviπ ,3,4loxadiazol-2-yl)-phenvn-3-{2-r2-(4-nnethylpiperazin-1- yl)pyridin-3-vπeth-yl}-1,3-dihvdroimidazol-2-one. Using PP18, yield 12%: mp 155-159°C; NMR (CDCI3) 8.20 (dd, J = 5.0, 2.1 Hz, 1H), 8.05 (d, J = 8.7 Hz, 2H), 7.78 (d, J = 8.7 Hz, 2H), 7.43 (dd, J = 7.5, 1.7 Hz, 1 H), 6.89 (m, 1H), 6.53 (d, J = 2.9 Hz, 1 H), 6.08 (d, J = 3.3 Hz, 1 H), 3.97 (t, J = 7.1 Hz, 2H), 3.13 (t, J = 5.0 Hz, 4H), 3.02 (t, J =7.1 Hz, 2H), 2.60 (s, 3H), 2.55 (br s, 4H), 2.32 (s, 3H); 13C NMR (CDCI3) 164.58, 163.82, 162.35, 151.65, 146.36, 140.21 , 138.92, 127.99, 125.96, 121.07, 120.99, 118.99, 112.85, 108.24, 55.65, 46.45, 43.85, 31.27, 11.36.
P. 1-f4-(1-Methoxy-1-methylethyl)-phenvn-3-f2-r2-(4-methylpiperazin-1- yl)pyridin-3-yllethyl>-1,3-dihvdroimidazol-2-one. Using PP54, yield 5.4%: mp 103-1060C; NMR (CDCI3) 8.20 (dd, J = 4.6, 1.7 Hz, 1 H), 7.48 (AB quartet, Δu = 41.9 Hz, J = 8.71 Hz, 4H), 7.42 (m, 1 H), 6.89 (dd, J = 7.5 , 5.0 Hz, 1 H), 6.45 (d, J = 3.3 Hz, 1 H), 6.04 (d, J = 3.3 Hz, 1 H), 3.97 (t, J = 7.1 Hz, 2H), 3.13 (t, J = 4.6 Hz, 4H), 3.05 (s, 3H), 3.01 (t, J = 7.1 2H), 2.56 (br s, 4H), 2.32 (s, 3H), 1.50 (s, 6H); 13C NMR (CDCI3) 162.31 , 151.84, 146.65, 143.70, 138.92, 136.22, 126.91 , 126.09, 121.45, 118.94, 111.84, 109.29, 76.73, 55.67, 50.89, 50.81 , 46.44, 43.69.31.34, 28.16.
Q. 1 -rβ-(1 -Methoxy-1 -methylethyl)pyridin-3-vπ-3-{2-r2-(4-methylpiperazin-1 - yl)pyridin-3-vn-ethyl)-1.3-dihvdroimidazol-2-one. Using PP20, yield 25%, tan oil: NMR (CDCI3) 8.65 (d, J = 2.1 Hz, 1 H), 8.21 (dd, J = 5.0,1.7 Hz, 1 H), 8.06 (dd, J = 8.7, 2.9 Hz, 1 H), 7.58 (d, J = 7.9 Hz, 1 H), 7.43 (dd, J = 7.5, 1.7 Hz, 1 H), 6.89 (dd, J = 7.1 , 4.6 Hz, 1 H), 6.47 (d, J = 3.3 Hz, 1 H), 6.08 (d, 3.32 Hz, 1 H), 3.97 (t, J = 6.6 Hz, 2H), 3.14 (s, 3H)1 3.13-3.11 (m, 4H), 3.02 (t, J = 7.5 Hz, 2H), 2.56 (br s, 4H), 2.32 (s, 3H), 1.54 (s, 6H); 13C NMR (CDCl3) 162.54, 162.29, 151.80, 146.72, 141.31 , 138.89, 132.60, 129.58, 125.90, 120.43, 118.96, 112.68, 108.50, 78.67, 55.62, 51.11 , 50.77, 46.40, 43.77, 31.29, 26.76.
R. 1-r4-(3-Methyl-ri,2.4loxadiazol-5-vnphenvn-3-f2-r2-(4-methyl-piperazin-1- yl)-Pyridin-3-yll-ethyl}-1.3-dihvdro-imidazol-2-one
Using PP19, yield 7.3%: mp 153-156°C; NMR (CDCI3) 8.21 (dd, J = 4.6,1.7 Hz, 1 H), 7.98 (AB quartet, Δu = 128.6 Hz, J = 9.1 Hz, 4H), 7.43 (dd, J = 7.5, 1.7 Hz, 1 H), 6.89 (dd, J =7.5, 5.0 Hz, 1 H), 6.54 (d, J = 3.3 Hz, 1 H), 6.07 (d, J = 3.3 Hz, 1 H), 3.97 (t, J = 7.1 Hz, 2H), 3.13 (t, J = 5.0 Hz, 4H), 3.02 (t, J = 7.5 Hz, 2H), 2.55 (br s, 4H), 2.45 (s, 3H), 2.32 (s, 3H); 13C NMR (CDCI3) 197.78, 175.00, 168.04, 162.34, 151.63, 146.78, 141.18, 138.93, 129.38, 125.94, 120.87, 119.01 , 113.05, 108.07, 55.63, 50.83, 46.43, 43.88, 31.25, 11.94.
S. 1 -rβ-(1 -Methoxy-cvclopentyl)-pyridin-3-yll-3-f2-r2-(4-methylpiperazin-1 - vnpyridin-3-yll-eth-yl>-1,3-dihvdroimidazol-2-one. Using PP21, yield 3.7%: NMR (CDCI3) 8.64 (d, J = 2.5 Hz, 1 H), 8.21 (dd, J = 5.0, 2.1 Hz, 1 H), 8.05 (dd, J = 8.3, 2.5 Hz, 1 H), 7.56 (d, J = 8.7 Hz, 1 H), 7.42 (dd, J = 7.5, 1.7 Hz, 1 H), 6.89 (dd, J = 7.5, 5.0 Hz, 1 H), 6.48 (d, J = 2.9 Hz, 1 H), 6.08 (d, J = 1.3 Hz, 1 H), 3.97 (t, J = 7.1 Hz, 2H), 3.13 (t, J = 4.6 Hz, 4H), 3.06 (s, 3H), 3.02 (t, J = 7.1 Hz, 2H), 2.56 (br s, 4H), 2.32 (s, 3H), 2.09-2.05 (m, 4H), 1.86-1.73 (m, 4H); 13C NMR (CDCI3) 162.31 , 160.76, 151.82, 146.76, 141.33, 138.91 , 132.65, 129.54, 125.91 , 121.48, 118.98, 112.69, 108.51 , 90.35, 55.65, 51.50, 50.80, 46.43, 43.78, 36.62, 31.33, 23.86.
EXAMPLE 6
Syntheses of the compounds below, using PP4B, are essentially the same procedure as described in Example 1 : A. 1 -r4-(1 -HydroxycvclopentvDphenvπ-S-fΣ-rS-^-methylpiperazirt-i -
Figure imgf000047_0001
Using PP49, yield 6%: NMR (CDCI3) 8.26 (dd, J = 4.9, 1.7Hz, 1 H), 7.50 (s, 4H), 7.33 (dd, J = 8.3, 1.7 Hz, 1 H), 7.10 (q, J = 4.6 Hz, 1 H), 6.4 (d, J = 2.9 Hz, 1 H), 6.13 (d, J = 2.9Hz, 1 H), 4.14 (t, J = 6.6 Hz, 2H), 3.22 (t, J = 6.6Hz, 2H), 2.85 (t, J = 5Hz, 4H), 2.8-2.5 (br s, 4H), 2.29 (s, 3H), 2.00-1.90 (br m, 6H), 1.80 (br m, 2H); 13C NMR (CDCI3) 163.82, 154.73, 151.96, 148.21 , 144.78, 144.25, 136.24, 127.71 , 126.17, 122.45, 121.48, 112.53, 112.50, 108.93, 83.38, 55.38, 52.28, 46.10, 43.15, 42.11 , 32.72, 29.91 , 24.03.
B. 1 -F4-(1 -Hydroxy-1 -methylethyl)-phenvn-3-(2-r3-(4-methylpiperazin-1 -yl)- pyridin-2-yllethylM.3-dihvdroimidazol-2-one. Using PP51 , yield 2.6%; oil: NMR (CDCI3) 8.28 (dd, J = 4.8, 1.6 Hz, 1 H), 7.36 (dd, J = 8.0, 1.5 Hz, 1 H), 7.52 (s, 4H), 7.12 (q, J = 4.8 Hz, 1 H), 6.4 (d, J = 2.9Hz, 1 H), 6.14 (d, J = 3.1 Hz, 1 H), 4.12 (t, J = 6.8 Hz, 2H), 3.41 (t, J = 6.8 Hz, 2H), 2.84 (br m, 4H), 2.70-2.60 (br m, 4H), 2.37 (s, 3H), 1.56 (s, 6H).
C. 1 -r4-(1 -Hvdroxycvclobutyl)phenvπ-3-f2-r3-(4-methylpiperazin-1 - yl)pyridin-2-vnethyl}-1,3-di-hvdroimidazol-2-one. Using PP50, yield 9.9%: mp 128-1320C; NMR (CDCI3) 8.28 (m, 1 H), 7.54 (AB quartet, Δu = 18.3 Hz, J = 8.7 Hz, 4H), 7.34 (dd, J = 7.9, 1.2 Hz, 1H), 7.11 (dd, J = 7.9, 4.6 Hz, 1H), 6.42 (d, J = 2.9 Hz, 1 H), 6.15 (d, J = 3.3 Hz, 1H), 4.15 (t, J = 7.1 Hz, 2H), 3.22 (t, J = 7.1 Hz, 2H), 2.85 (t, J = 4.6 Hz, 4H), 2.51 (br s, 4H), 2.36- 2.31 (m, 2H), 2.29 (s, 3H), 2.02-1.94 (m, 1 H), 1.69-1.62 (m, 1 H); 13C NMR (CDCI3) 154.73, 148.28, 144.13, 136.57, 127.61 , 126.11 , 122.41 , 121.49, 112.59, 108.77, 76.59, 55.41 , 52.33, 46.17, 43.06, 37.22, 32.67, 13.13.
D. 1 -f4-(1 -Methoxycvclobutyl)phenvn-3-f2-r3-(4-methylpiperazin-1 - vnpyridin-Σ-vnethylM .S-dihvdroimidazol-Σ-one. Using PP55, yield 8.3%; mp 115-1190C; NMR (CDCl3) 8.28 (dd, J = 4.6, 1.2 Hz, 1 H), 7.50 (AB quartet, Δu = 51.0 Hz, J = 8.7 Hz, 4H), 7.34 (dd, J = 8.3, 1.2 Hz, 1 H), 7.13-7.10 (m, 1 H), 6.43 (d, J = 2.9 Hz, 1 H), 6.15 (d, J = 2.9 Hz, 1 H), 4.16 (t, J = 7.1 Hz, 2H), 3.23 (t, J = 7.1 Hz, 2H), 2.90 (s, 3H), 2.85 (t, J = 4.6 Hz, 4H), 2.53 (br s, 4H), 2.36-2.32 (m, 4H), 2.29 (s, 3H), 1.92-1.83 (m, 1 H), 1.66-1.59 (m, 1 H); 13C NMR (CDCI3) 154.77, 151.91 , 148.30, 144.18, 140.58, 136.69, 127.57, 127.40, 122.40, 121.42, 112.61 , 108.77, 81.34, 55.47, 52.43, 50.72, 46.22, 43.09, 33.09, 32.72, 13.08.
E. 1-r4-(1-Methoxy-1-methylethyl)phenvn-3-(2-r3-(4-methvIpiperazin-1- yl)pyridin-2-yllethyl>-1.3-dihvdroimidazol-2-one. Using PP54, yield 3.2%, oil: NMR (CDCI3) 8.29 (dd, J = 4.5, 1.2 Hz, 1 H), 7.48 (AB quartet, Δu = 47.3 Hz, J = 8.7 Hz, 4H), 7.35 (dd, J = 7.9, 1.2 Hz, 1 H), 7.13 (dd, J = 7.9, 4.6 Hz, 1 H), 6.43 (d, J = 3.3 Hz, 1 H), 6.16 (d, J = 2.9 Hz, 1H), 4.17 (t, J = 7.1 Hz, 2H), 3.24 (t, J = 7.1 Hz, 2H), 3.05 (s, 3H), 2.87 (t, J = 4.6 Hz, 4H), 2.55 (br s, 4H), 2.31 (s, 3H), 1.51 (s, 6H); 13C NMR (CDCI3) 154.79, 151.93, 148.31 , 144.18, 143.45, 127.58, 126.89, 122.41 , 121.42, 112.56, 108.83, 76.75, 55.48, 52.44, 50.89, 46.24, 43.09, 32.78, 28.17. F. 1-r6-(1-IVlethoxy-1-methylethyl)-pyridin-3-vn-3-(2-r3-(4-methylpiperazin-1- yl)pyridin-2-vn-ethyl>-1 ,3-dihvdroimidazol-2-one. Using PP20, yield 15.7%: mp 120- 125°C; NMR (CDCI3) 8.65 (d, J = 2.5 Hz, 1 H), 8.27 (dd, J = 5.0, 1.7 Hz, 1 H), 8.07 (dd, J = 8.7, 2.5 Hz, 1 H), 7.57 (d, J = 8.7 Hz, 1 H), 7.34 (dd, J = 7.9, 1.2 Hz, 1 H), 7.12 (dd, J = 7.9, 4.6 Hz, 1 H), 6.45 (d, J = 3.3 Hz, 1 H), 6.22 (d, J = 2.9 Hz, 1 H), 4.16 (t, J = 7.1 Hz, 2H), 3.23 (t, J = 7.1 Hz, 2H), 3.13 (s, 3H), 2.86 (t, J = 4.6 Hz, 4H), 2.54 (br s, 4H), 2.30 (s, 3H), 1.53 (s, 6H); 13C NMR (CDCI3) 162.31 , 154.33, 151.92, 148.26, 144.18, 141.25, 132.80, 129.57, 127.61 , 122.48, 120.45, 113.44, 108.03, 78.68, 55.47, 52.40, 51.13, 46.23, 43.14, 32.64, 26.79.
EXAMPLE 7 Syntheses of the compounds below, using PP4C, are essentially the same procedure as described in Example 1 :
A. 1-r4-(1-Hvdroxycvclopentyl)phenvn-3-r2-(4-methyl-3,4,5,6-tetrahydro-2H- H ,2'lbipyrazinyl-3'-vD-ethvπ-1 ,3-dihydroimidazol-2-one. Using PP49, yield 38%: mp 126- 128°C; NMR (CDCI3) 8.10 (d, J = 2.5 Hz, 1 H), 8.07 (d, J = 2.5 Hz, 1 H), 7.51 (br s, 4H), 6.44 (d, J = 2.9 Hz, 1 H), 6.19 (d, J = 3.3 Hz, 1 H), 4.15 (t, J = 6.8 Hz, 2H), 3.20-3.14 (m, 6H), 2.60- 2.50 (m, 4H), 2.30 (s, 3H), 1.96 (br s, 6H), 1.81 (br s, 2H); 13C NMR (CDCI3) 158.12, 151.91 , 147.19, 144.81 , 139.86, 136.88, 136.15, 126.19, 121.45, 112.47, 109.17, 83.38, 55.09, 49.75, 46.27, 42.42, 42.14, 33.30, 24.03.
B. i-f4-(i-Methoxycvclobutyl)-phenvπ-3-r2-(4-methyl-3,4,5.6-tetrahvdro-2H- ri,2'1bipyrazinyl-3'-yl)-ethvπ-1,3-dihvdroimidazol-2-one. Using PP55, yield 10.9%, oil: NMR (CDCI3) 8.09 (d, J = 2.9 H, 1 H), 8.06 (d, J = 2.9 Hz, 1 H), 7.50 (AB quartet, Δu = 48.1 Hz, J = 8.3 Hz, 4H), 6.46 (d, J = 3.3 Hz, 1 H), 6.20 (d, J = 2.9 Hz, 1 H), 4.16 (t, J = 6.6 Hz, 2H), 3.19-3.15 (m, 6H), 2.90 (s, 3H), 2.53-2.48 (m, 4H), 2.36-2.32 (m, 4H), 2.29 (s, 3H), 1.91-1.89 (m, 1 H), 1.66-1.61 (m 1 H);13C NMR (CDCI3) 158.16, 151.92, 147.18, 140.75, 139.85, 136.85, 136.54, 127.42, 121.45, 1 12.54, 109.10, 81.33, 55.11 , 50.71 , 49.82, 49.13, 46.29, 42.44, 33.08, 12.08.
C. 1 -f4-(1 -Methoxy-1 -methylethyl)phenvn-3-r2-(4-methyl-3.4,5,6-tetrahvdro- 2H-H ,2'1bipyraz-inyl-3'-yl)ethvπ-1 ,3-dihvdroimidazol-2-one. Using PP54, yield 23%, yellow oil: NMR (CDCl3) 8.07 (d, J = 2.5 Hz, 1 H), 8.04 (d, J = 2.5 Hz, 1 H), 7.44 (AB quartet, Δu = 46.0 Hz, J = 9.1 Hz, 4H), 6.43 (d, J = 2.9 Hz, 1 H), 6.17 (d, J = 3.3 Hz, 1 H), 4.13 (t, J = 6.6 Hz, 2H), 3.16-3.12 (m, 6H), 3.01 (s, 3H), 2.51 (br s, 4H), 2.26 (s, 3H), 1.46 (s, 6H).
EXAMPLE 8 Synthesis of 1 -F4-(1 -Hydroxy-1 -methylethyl)phenyll-3-r2-(4-methylpiperazin-1 - yl)benzyll-imid-azolidin-2-one.
PP23B (0.166 g, 0.605 mmol), PP51 (0.20 g, 0.93 mmol), tris
(dibenzylideneacetone)dipalladium(O) (0.028g, 0.030 mmol), 9,9-dimethyl-4,5-bis (diphenyl- phosphino)xanthene (0.053 g, 0.092 mmol) and cesium carbonate (0.39 g, 1.20 mmol) in dioxane (2 ml_) were stirred for 24hrs at 80-900C. The reaction was diluted with EtOAc, filtered (Celite) and concentrated to yield an orange foam. Chromatography with 20% MeOH/
EtOAc and 20% MeOH/ EtOAc -2% NH4OH yielded 0.189 g (76%) of 1 -[4-(1 -hydroxy- 1- methylethyl)phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]imidazolidin-2-one as a tan solid: mp 157-1610C; NMR (CDCI3) 7.53 (d, J = 9.1 Hz, 2H), 7.44 (d, J = 8.7 Hz, 2H), 7.29-7.22 (m, 2H), 7.12 (d, J = 7.1 Hz, 1 H), 7.06 (dt, J = 7.3, 1.2 Hz, 1 H), 4.57 (s, 2H), 3.77 (dd, J = 9.5, 6.8
Hz, 2H), 3.33-3.29 (m, 2H), 3.00-2.90 (br m, 4H), 2.64 (br s, 4H), 2.36 (s, 3H), 1.55 (s, 6H).
EXAMPLE 9
Syntheses of the compounds below, substituting PP23A for PP23B, are essentially the same procedure as described in Example 8: A. 1 -f4-(1 -Hydroxy-1 -methylethyl)phenyll-3-{2-r2-(4-rnethylpiperazin-1 - yl)phenvπethyl}imid-azolidin-2-one. Yield 11 %. Maleate salt had: mp-137-140°C; NMR (MeOH-d4) 7.42 (s, 4H), 7.29-7.17 (m, 3H), 7.11 (dt, J = 7.5, 1.4 Hz, 1 H), 6.22 (s, 2H), 3.78 (dd, J = 9.9, 6.6 Hz, 2H), 3.55-3.38 (m, 8H), 3.17 (br s, 4H), 2.94-2.91 (m, 5H), 1.48 (s, 6H).
B. 1 -{2-r2-(4-Methylpiperazin-1 -yl)phenvπethyl)-3-(4- trifluorome.hylphenyl)imidazolidin-2-one. Using 4-bromobenzotrifluoride in place of PP51 ; yield 41 %. Maleate salt had: mp 154-155.5°C; NMR (DMSO-d6) 7.71 (d, J= 8.7, 2H), 7.61 (d, J = 8.7 Hz, 2H), 7.25 (dd, J = 7.5, 1.2 Hz, 1 H), 7.19 (dt, J = 7.9, 1.7 Hz, 1 H), 7.12 (d, J = 7.1 Hz, 1 H), 7.06 (dt, J = 7.5, 1.2 Hz, 1 H), 5.99 (s, 2H), 3.79 (t, J = 7.5 Hz, 2H), 3.52-3.43 (m, 4H), 3.29 (br s, 4H), 3.05 (br s, 4H), 2.85-2.80 (m, 5H). This compound was also prepared as follows: 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. K2CO3, the organics were then washed with brine, dried (MgSO4) and concentrated to yield 11 mg (84%) of the title compound as a white solid. The NMR spectrum of this mateπal was identical to that prepared above.
C. 1 -f4-(1 -HydroxycyclopentvDphenvn-S^^^-metriylpiperazin-i - yl)phenvπethyl)-innidaz-olidin-2-one. Using PP49 in place of PP51 ; yield 4%: mp 153- 154°C; NMR (CDCI3) 7.47 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 9.1 Hz, 2H), 7.23-7.15 (m, 2H), 7.11 (d, J = 7.9 Hz, 1H), 7.02 (dt, J =7.3, 1.4 Hz, 1 H), 3.74-3.69 (m, 2H), 3.54 (dd, J = 8.7, 6.9 Hz, 2H), 3.37 (dd, J = 7.9, 6.8 Hz, 2H), 2.93-2.88 (m, 6H), 2.58 (br s, 4H), 2.34 (s, 3H), 1.94 (br m, 6H), 1.92 (br m, 2H).
EXAMPLE 10 1 -r4-(1 -Hvdroxycvclopentyl)phenvn-3-r2-(4-methylpiperazin-1 -vO-pyridin-3- yllimidazolidin-2-one. PP22 (0.10 g, 0.383 mmol), PP49 (0.10 g, 0.41 mmol), copper (I) iodide (75 mg,
0.393 mmol), N, N'-dimethylethylenediamine (85μL, 0.80 mmol) and K3PO4 (0.17 g, 0.80 mmol) in dioxane (1mL) were combined, purged with N2 gas for 2 min. and heated to 110°C in a sealed tube for 24 hrs. After cooling, the mixture was diluted with EtOAc and water and filtered to remove insoluble materials. The organic phase was separated and washed with brine, dried (MgSO4) and concentrated to a tan solid (0.136 g). Chromatography with 20% MeOH/ EtOAc and 20% MeOH/ EtOAc +1 % NH4OH gave 0.067g (42%) of Example 10 as a white solid: mp 187-188°C; NMR (CDCI3) 8.14 (dd, J = 4.6, 1.9 Hz, 1 H), 7.68 (dd, J = 7.9, 1.7 Hz, 1H), 7.54 (d, J = 9.1 Hz, 2H), 6.90 (dd, J = 7.5, 4.8 Hz, 1H), 3.96-3.85 (sym.mult., 4H), 3.27 (br s, 4H), 2.50 (br s, 4H), 2.28 (s, 3H), 1.94 (br s, 6H), 1.77 (br s, 2H); 13C NMR (CDCI3) 197.97, 157.20, 156.25, 145.83, 142.02, 138.87, 136.76, 125.95, 117.78, 117.57, 83.20, 55.59, 48.47, 46.43, 43.10, 41.96, 41.34, 23.98.
EXAMPLE 11 1-r4-(1-Hvdroxycvclobutyl)phenvn-3-{2-r2-(4-methylpiperazin-1-yl)- phenyllethyl>tetrahvdro-pyrimidin-2-one. Example 11 was prepared using essentially the same procedure described in
Example 10, substituting PP23C for PP22, and PP50 for PP49, and K2CO3 for K3PO4. Yield 8.8%: NMR (CDCI3) 7.44 (dd, J= 6.6, 1.7 Hz, 2H), 7.26 (dd, J = 6.7, 2.1 Hz, 2H), 7.23 (m, 2H), 7.04-7.02 (m, 1 H), 3.65-3.57 (m, 4H), 3.28 (t, J = 5.8 Hz, 2H), 2.97-2.93 (m, 6H), 2.56-2.49 (m, 6H), 2.34 (s, 3H), 2.04-1.99 (m, 5H), 1.64-1.61 (m, 1H); 13C NMR (CDCI3) 155.02, 151.98, 143.55, 142.84, 135.35, 131.05, 127.45, 125.55, 125.49, 124.52, 120.75, 56.09, 53.12, 49.84, 48.77, 46.96, 46.46, 37.02, 29.70, 22.96, 13.08.
EXAMPLE 12 1-r4-(1-Hvdroxy-1-methylethyl)phenvπ-3-{2-r2-(4-methyl-piperazin-1-vπphenyllethyl|-
1 ,3-dihvdrobenzoimidazol-2-one.
PP27 (0.052 g, 0.155 mmol), PP33 (0.05Og, 0.305 mmol), triethylamine (0.065 ml_,
0.466 mmol) and copper (ll)acetate (0.056 g, 0.4308 mmol) in CH2CI2 (2mL) were stirred for 4 days at rt. The mixture was concentrated, EtOAc and aq. K2CO3 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 (MgSO4) 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
(MeOH-d4) 7.66 (d, J = 8.7 Hz, 2H), 7.36 (d, J= 8.3 Hz, 2H), 7.24-7.00 (m, 8H), 6.23 (s, 2H), 4.24 (t, J = 7.3 Hz, 2H), 3.48-3.42 (m, 2H), 7.24-7.00 (m, 8H), 6.23 (s, 2H), 4.24 (t, J= 7.3 Hz,
2H), 3.48-3.42 (m, 2H), 3.32-3.20 (m, 2H), 3.15-3.11 (m, 4H), 3.07-2.98 (m, 2H), 2.89 (s, 3H),
1.55 (s, 6H).
EXAMPLE 13
1 -f4-(1 -Hydroxycvclopentyl)-phenvn-3-{2-r2-(4-methylpiperazin-1 -yl)phenyllethyl}-1 ,3- dihydrobenzoimidazol-2-one.
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 μL, 0.61 mmol), K2CO3 (0.094 g, 0.713 mmol) and toluene (1 mL) were degassed with N2 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 (MgSO4) and concentrated to give a yellow oil (153 mg). Chromatography using 10% MeOH/CH2CI2 yielded 88.8 mg (60%) of Example 13: mp 150- 152°C; NMR (CDCI3) 7.62 (d, J = 8.7 Hz, 2H), 7.45 (d, J = 8.7 Hz, 2H), 7.25-7.20 (m, 2H), 7.15 (d, J = 7.9 Hz, 1 H), 7.1 1-7.00 (m, 5H), 4.15 (t, J = 7.9 Hz, 2H), 3.40-2.70 (br m, 9H), 2.52 (br s, 4H), 2.10-1.95 (m, 6H), 1.86-1.82 (m 2H); 13C NMR (CDCI3) 153.35, 152.18, 146.85, 134.41 , 133.42, 130.90, 129.73, 129.56, 128.13, 126.54, 125.72, 124.96, 121.93, 121.44, 121.25, 108.90, 108,41 , 83.78, 55.79, 53.08, 46.34, 42.58, 42.27, 30.52, 24.14.
EXAMPLE 14
Syntheses of the compounds below are essentially the same procedure as described in Example 13: A. 1-{2-r2-(4-Methylpiperazin-1-yl)phenvnethyl}-3-(4-oxazol-4°yl-phenyl)-
1,3-dihvdro-benzoimidazol-2-one. Using 4-(4-bromophenyl)oxazole (see U.S. 5,612,359) in place of PP49, yield 37%:mp 165-1700C (decomposes); NMR (CDCI3) 7.98 (s, 1 H), 7.94 (s, 1 H), 7.87 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 7.24-7.17 (m, 3H), 7.14-6.97 (m, 5H), 3.12 (t, J = 7.7 Hz, 2H), 2.90 (t, J = 4.6 Hz, 4H), 2.58 (br s, 4H), 2.35 (s, 3H); 13C NMR (CDCI3)154, 145.28, 151.67, 134.82, 134.41 , 134.24, 130.87, 129.80, 128.10, 126.82, 126.22, 124.89, 122.06, 121.48, 121.20, 108.87, 108.49, 55.88, 53.25, 46.45, 42.63, 30.47. B. 1-{2-r2-(4-Methylpiperazin-1-yl)phenvnethyl}-3-(4-oxazol-2-yl-phenyl)- 1 ,3-dihydro-benzoimidazol-2-one. Using 2-(4-bromophenyl)oxazole (see US Patent 5,612,359) in place of PP49, yield 51 %: mp 133-136°C; NMR (CDCI3) 8.20 (d, J = 8.7 Hz, 2H), 7.74 (s, 1 H), 7.68 (d, J = 8.3 Hz, 2H), 7.26-7.21 (m, 3H), 7.16-7.04 (m, 6H), 4.18 (t, J = 7.5 Hz, 2H), 3.14 (t, J = 7.7 Hz, 2H), 2.92 (t, J = 4.4 Hz, 4H), 2.61 (br s, 4H), 2.37 (s, 3H); 13C NMR (CDCI3) 161.50, 153.02, 152.28, 139.09, 136.90, 134.37, 130.89, 129.88, 128.90,
128.85, 128.16, 127.69, 126.43, 125.96, 124.93, 122.33, 121.59, 121.22, 109.97, 108.63, 55.88, 53.25, 46.45, 42.69, 30.47.
C. 1-{2-r2-(4-Methylpiperazin-1-vnphenvπethyl}-3-(3-oxo-1.3- dihvdroisobenzofuran-5-yl)-1,3-dihydrobenzoimidazol-2-one. Using PP17 in place of PP49, yield 46%: mp 113-115°C; NMR (CDCI3) 8.07 (s, 1 H), 7.92 (dd, J = 7.9, 1.5 Hz, 1 H), 7.65 (d, J = 7.9 Hz, 1 H), 7.25-7.20 (m, 2H), 7.15-7.03 (m, 6H), 5,38 (s, 2H), 4.17 (t, J = 7.5 Hz, 2H), 3.14 (t, J = 7.5 Hz, 2H), 2.91 (br s, 4H), 2.60 (br s, 4H), 2.37 (s, 3H); 13C NMR (CDCI3) 170.35, 153.02, 152.26, 145.24, 136.34, 134.23, 132.04, 130.87, 129.83, 128.69, 128.22, 127.36, 124.94, 123.66, 122.66, 122.51 , 121.78, 121.28, 108.80, 108.68, 69.89, 55.85, 53.20, 46.42, 42.68, 30.46.
D. 1-(6-Methoxypyridin-3-yl)-3-f2-r2-(4-methylpiperazin-1-yl)phenvnethyl)- 1 ,3-dihydro-benzo-imidazol-2-one. Using 5-bromo-2-methoxypyridine in place of PP49, yield 46%: NMR (CDCI3) 8.31 (d, J = 2.5 Hz, 1 H), 7.71 (dd, J = 8.7, 2.9 Hz, 1 H), 7.26-7.21 (m, 2H), 7.17-7.15 (m, 1 H), 7.14-7.03 (m, 4H), 6.98 (d, J = 7.9 Hz, 1 H), 6.89 (d, J = 9.1 Hz, 1 H), 4.17 (t, J= 7.7 Hz, 2H), 3.98 (s, 3H), 3.14 9t, J = 7.5 Hz, 2H), 2.93 (t, J = 4.8 Hz, 4H), 2.61 (br s, 4H), 2.38 (s, 3H); 13C NMR (CDCI3) 163.33, 153.41 , 152.27, 144.66, 137.09, 134.29,
130.86, 129.78, 129.66, 128.16, 125.50, 124.90, 122.15, 121.61 , 121.26, 11 1.88, 108.59, 108.44, 55.88, 54.09, 53.24, 46.47, 42.59, 30.47. E. 1-r4-(2-Methyloxazol-4-yl)phenyll-3-(2-r2-(4-methylpiperazin-1-yl)- phenyllethyl}-1,3-dihvdro-benzoimidazol-2-one. Using 4-(4-bromophenyl)-2- methyloxazole (see US Patent 5,612,359) in place of PP49, yield 25%: NMR (CDCI3) 7.84- 7.81 (m, 3H), 7.55 (d, J = 7.6 Hz, 2H), 7.24-7.18 (m, 3H), 7.15-7.00 (m, 5H), 4.15 (t, J = 7.5 Hz, 2H), 3.11 (t, J = 7.5 Hz, 2H), 2.90 (t, J = 4.8 Hz, 4H), 2.60 (br s, 4H), 2.51 (s, 3H), 2.36 (s, 3H); 13C NMR (CDCI3) 153.19, 152.28, 151.67, 139.98, 134.82, 134.41 , 134.24, 130.87, 130.04, 129.80, 129.29, 128.10, 126.82, 126.27, 124.89, 122.06, 121.48, 108.87, 108.49, 55.88, 53.25, 46.45, 42.63, 30.47.
F. 1 -F4-(1 -Methoxycvclobutyl)phenvn-3-f 2-r2-(4-methylpiperazin-1 - yl)phenvπethyl}-1,3-dihvd-robenzoimidazol-2-one. Using PP55 in place of PP49, yield 78%: NMR (CDCI3) 7.54 (AB quartet, Δu = 18.3 Hz, J = 8.7 Hz, 4H), 7.24-7.19 (m, 2H), 7.15- 7.01 (m, 6H), 4.16 (t, J = 7.7 Hz, 2H), 3.13 (t, J = 7.7 Hz, 2H), 2.98 (s, 3H), 2.91 (t, J = 4.6 Hz, 4H), 2.59 (br s, 4H), 2.43-2.35 (m, 7H), 1.97-1.93 (sym.mult, 1 H), 1.73-1.65 (sym.mult, 1 H); 13C NMR (CDCI3) 153.31 , 152.29, 142.69, 134.44, 133.94, 130.88, 129.77, 129.47, 128.09, 127.61 , 125.76, 124.88, 121.95, 121.39, 121.22, 109.83, 108.43, 81.46, 55.89, 53.28, 50.88, 46.46, 42.57, 33.10, 30.47, 13.13.
G. 1-r4-(2-Methoxy-2-methylpropyl)phenvn-3-{2-f2-(4-methylpiperazin-1- yl)phenvπethyl}-1,3-dihydrobenzoimidazol-2-one. Using PP56 in place of PP49, yield
67%: NMR (CDCI3) 7.41 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 7.24-7.19 (m, 2H), 7.13
(d, J = 7.1 Hz, 1 H), 7.09-6.99 (m, 5H), 4.15 (t, J = 7.7 Hz, 2H), 3.28 (s, 3H), 3.12 (t, J= 7.7 Hz,
2H), 2.91 (t, J = 4.6 Hz, 4H), 2.81 (s, 2H), 2.59 (br s, 4H), 2.36 (s, 3H), 1.16 (s, 6H); 13C NMR
(CDCI3) 197.80, 153.33, 152.28, 138.04, 134.48, 133.03, 131.64, 130.88, 129.74, 129.47, 128.06, 125.46, 124.88, 121.80, 121.33, 121.19, 108.90, 108.34, 75.43, 55.89, 53.27, 49.66,
46.45, 46.11 , 42.56, 30.46, 24.93.
H. 1 -F4-(1 -Hvdroxycvclopentyl)phΘnvn-3-f2-[2-(4-methylpiperazin-1 - yl)phenyllethyl}-1 ,3-di-hvdroimidazor4,5-blpyridin-2-one. Using PP28A in place of PP27, yield 22%: NMR (CDCI3) 8.06-8.05 (m, 1 H), 7.61 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.41-7.14 (m, 3H), 7.10 (d, J = 7.1 Hz, 1 H), 7.00-6.92 (m, 2H), 4.33 (t, J = 7.7 Hz, 2H), 3.20 (t, J = 7.5 Hz, 2H), 2.95 (t, J = 4.6 Hz, 4H), 2.57 (br s, 4H), 2.32 (s, 3H), 1.99 (br s, 6H), 1.84 (br S, 2H); 13C NMR (CDCI3) 152.77, 152.42, 147.02, 143.85, 141.40, 134.21 , 132.73, 130.83, 127.86, 126.66, 125.31 , 124.42, 123.92, 121.01 , 117.13, 1 14.50, 83.42, 55.83, 53.08, 46.43, 42.32, 40.99, 30.23, 24.11. I. 1 -r4-(1 -Hvdroxycvclopentyl)phenvn-3-{2-[3-(4-methylpiperazin-1 - yl)pyridin-2-vπethyl>-1,3-dihvdroimidazor4,5-b1pyridin-2-one. Using PP28B in place of PP27, yield 36%: mp 50-570C; NMR (CDCI3) 8.21 (dd, J = 4.6, 1.5 Hz, 1 H), 8.02 (dd, J = 5.4, 1.2 Hz, 1 H), 7.59 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.28 (dd, J = 8.3, 1.5 Hz, 1 H), 7.21 (dd, J = 7.5, 1.2 Hz, 1 H), 7.05 (dd, J = 8.3, 4.8 Hz, 1 H), 6.91 (dd, J = 7.5, 5.2 Hz, 1 H), 4.48 (t, J = 7.3 Hz, 2H), 3.35 (t, J = 7.3 Hz, 2H), 2.83 (t, J = 4.6 Hz, 4H), 2.42 (br s, 4H), 2.24 (s, 3H), 1.97 (br s, 6H), 1.81 (br s, 2H); 13C NMR (CDCI3) 155.06, 152.71 , 148.01 , 147.11, 144.38, 143.88, 141.43, 132.70, 127.42, 126.67, 125.17, 123.97, 122.35, 117.07, 114.50, 83.26, 55.49, 52.46, 46.26, 42.29, 39.84, 31.95, 24.11.
J. 1-r4-(1-Hvdroxy-1-methylethyl)phenvπ-3-{2-r3-(4-methylpiperazin-1- yl)pyridin-2-vHethyl}-1,3-dihvdroimidazor4,5-b1pyridin-2-one. Using PP28B in place of PP27 and PP51 in place of PP49, yield 58%: NMR (CDCI3) 8.19 (dd, J= 4.6, 1.5 Hz, 1 H), 8.01 (d, J = 5.0, 1.2 Hz, 1 H), 7.58 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.3 Hz1 2H), 7.27 (dd, J = 7.8, 1.7 Hz, 1 H), 7.20 (dd, J = 7.5, 1.5 Hz, 1 H), 7.04 (dd, J = 7.9, 4.8 Hz, 1 H), 6.90 (dd, J = 7.5, 5.2 Hz, 1 H), 4.46 (t, J = 7.5 Hz, 2H), 3.34 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 4.8 Hz, 4H), 2.42 (br s, 4H), 2.22 (s, 3H), 1.55 (s, 6H); 13C NMR (CDCI3) 154.98, 152.71 , 149.2, 148.01 , 144.35, 143.83, 141.41 , 132.57, 127.50, 126.09, 125.19, 123.98, 122.39, 1 17.10, 114.56, 72.32,
55.46, 52.42, 46.23, 39.85, 32.05, 31.94. K. 1-r4-(1-Hvdroxy-1-methylethyl)-phenyll-3-{2-r2-f4-methylpiperazin-1- yl)phenyllethyl)-1.3-di-hvdroimidazof4,5-blpyridin-2-one. Using PP28A in place of PP27 and PP51 in place of PP49, yield 67%: mp 60-650C; NMR (CDCI3) 8.02 (dd, J=1.7, 4.1 Hz, 1 H), 7.60 (d, J= 8.7Hz, 1 H), 7.37 (d, J = 8.3Hz, 2H), 7.20-7.06 (m,4H), 6.98-6.88 (m, 2H), 4.60 (t, J = 7.5Hz, 2H), 3.40 (t, J = 7.0 Hz, 2H), 2.80 (m, 4H), 2.51 (br s, 4H), 2.28 (s, 3H), 1.56 (s, 6H); ); 13C NMR (CDCI3) 152.75, 152.36, 149.34, 143.76, 134.16, 132.51 , 130.82, 127.93, 126.10, 125.24, 124.40, 123.91 , 120.96, 117.14, 114.53, 72.18, 66.03, 55.77, 52.95, 52.67, 46.40, 40.96, 32.07, 30.20, 15.48.
L. 1-r6-(1-Hvdroxy-1-methylethyl)pyridin-3-yll-3-f2-f2-(4-methylpiperazin-1- yl)phenyll-ethylM ,3-dihvdroimidazor4,5-b1pyridin-2-one. Using PP28A in place of PP27 and PP53 in place of PP49, yield 11%: NMR (CDCI3) 8.65 (d, J=4.8Hz, 1 H), 8.13 (dd, J= 1.6, 4.8 Hz, 1 H), 7.85 (dd, J = 2.9, 8.4 Hz, 1 H), 7.56 (d, J = 9.6 Hz, 1 H), 7.28 (dd, J= 1.2, 8.0 Hz, 1 H), 7.22-7.12 (m, 3H), 7.04-6.98 (m, 2H), 4.40 (t, J = 7.5Hz, 2H), 3.12 (t, J = 7.0Hz, 2H), 2.97 (m, 4H), 2.35 (s, 3H), 1.59 (s, 6H); 13C NMR (CDCI3) 165.56, 152.44, 14424, 142.04, 134.15, 134.03, 130.83, 129.79, 127.99, 124.46, 123.28, 121.10, 199.74, 117.37, 114.43, 72.37, 55.82, 53.09, 46.41 , 41.12, 30.87, 30.27.
M. 1-r6-(1-Methoxy-1-methylethyl)pyridin-3-vn-3-{2-r2-(4-methylpiperazin-1- yl)phenyllethylM ,3-dihvdroimidazor4,5-b1pyridin-2-one. Using PP28A in place of PP27 and PP20 in place of PP49, yield 75%: NMR (CDCI3) 8.64 (d, J = 2.5 Hz, 1 H), 8.07 (dd, J = 1.3, 9.1 Hz, 1 H), 7.80 (dd, J = 2.5, 8.7 Hz, 1 H), 7.66 (d, J= 8.3 Hz, 1 H), 7.25 (dd, J=1.2, 7.9 Hz, 1H), 7.18-7.06 (m, 3H), 6.98-6.93 (m, 2H), 4.32 (t, J = 7.5 Hz, 2H), 3.18 (m, 3H), 2.92 (m, 2H), 2.54 (br s, 4H), 2.30 (s, 3H), 1.55 (s, 6H); 13C NMR (CDCI3)164.80, 152.57, 152.43, 145.09, 143.89, 141.89, 134.04, 133.49, 130.79, 129.59, 127.93, 124.39, 123.31 , 121.02, 120.87, 117.27, 114.41 , 78.87, 55.80, 53.10, 52.85, 51.21 , 46.42, 41.07, 30.21 , 26.75. N. 1 -F4-(1 -Methoxy-1 -methylethyl)phenvπ-3-(2-r2-(4-methylpiperazin-1 - yl)phenvπethyl}-1.3-dihvdroimidazor4,5-bipyridin-2-one. Using PP28A in place of PP27 and PP54 in place of PP49, yield 73%: NMR (CDCI3) 8.05 (dd, J = 1.7,5.0 Hz, 1 H), 7.52 (d, J = 7 Hz, 2H), 7.4 (d, J= 7 Hz, 2H), 7.25 (dd, J = 1.2, 7.9 Hz, 1 H), 7.2-7.12 (m 2H), 7.10 (d, J = 5.0 Hz, 1 H), 6.99-6.92 (m, 2H), 4.32 (t, J = 7.5 Hz, 2H), 3.20 (t, J = 7.5Hz, 2H), 3.08 (s, 3H), 2.94 (m, 4H), 2.56 (br s, 4H); 2.30 (s, 3H), 1.52 (s, 6H); 13C NMR (CDCl3)125.73, 152.43, 145.93, 143.83, 141.39, 134.21 , 132.88, 130.81 , 128.31 , 127.84, 127.25, 125.27, 125.22, 124.40, 124.34, 123.84, 120.99, 117.08, 114.53, 55.83, 53.12, 52.84, 50.99, 46.42, 40.97, 30.23, 28.16.
O. 3-f2-r2-(4-Methylpiperazin-1-yl)phenvnethyl>-1-r4-(tetrahydropyran-4- yl)phenyll-1,3-dihv-droimidazor4,5-bipyridin-2-one. Using PP28A in place of PP27 and 4- (4-bromophenyl)tetrahydropyran in place of PP49, yield 78%: mp 58-610C; NMR (CDCI3) 8.06 (dd, J = 1.3,5.4 Hz, 1 H), 7.40-7.30 (m, 4H), 7.22 (dd, J = 1.2, 7.9 Hz, 1 H), 7.20-7.14 (m, 2H), 7.10 (d, J = 7.8 Hz, 1 H), 6.96-6.92 (m, 2H), 4.33 (t, 7.5 Hz, 2H), 4.07 (m, 2H), 3.50 (m, 2H), 3.20 (t, J = 7.9 Hz, 2H), 2.95 (m, 4H), 2.80 (m, 1 H), 2.50 (br s, 4H), 2.32 (s, 3H), 1.80 (m, 4H); 13C NMR (CDCI3) 152.77, 152.42, 145.67, 143.82, 141.36, 134.22, 132.34, 130.81 , 128.15, 127.84, 125.74, 124.39, 123.95, 120.00, 117.07, 114.44, 68.49, 55.83, 53.11 , 52.84, 46.42, 41.49, 40.96, 34.06, 30.23.
P. 3-f 2-r2-(4-Methylpiperazin-1 -vDphenyllethyl'M -(3-oxo-1 ,3- dihvdroisobenzofuran-5-yl)-1,3-dihydroinrιidazor4,5-blpyridin-2-one. Using PP28A in place of PP27 and PP17 in place of PP49, yield 70%: mp 76-810C (decomposed); NMR (CDCI3) 8.13 (dd, J = 1.2, 6.0 Hz, 1 H), 8.02 (d, J = 9.2 Hz, 1 H), 7.70 (s, 1 H), 7.64 (d, J=10.4 Hz, 1 H), 7.36 (dd, J = 1.0, 7.2 Hz, 1 H), 7.04-6.94 (m, 3H), 5.35 (s, 2H), 4.34 (t, J = 8.8 Hz, 2H), 3.20 (t, J = 8.8 Hz, 2H), 2.94 (m, 4H), 2.50 (br s, 4H), 2.32 (s, 3H); 13C NMR (CDCI3) 170.22, 152.45, 152.26, 148.33, 143.88, 142.34, 139.81 , 133.98, 130.79, 127.97, 125.37, 124.45, 122.76, 121.07, 119.03, 117.41 , 114.93, 69.63, 60.59, 55.81 , 53.13, 52.87, 46.44, 41.17, 30. 19, 21.27, 14.42. Q. 1 -(4-tert-Butylphenyl)-3-f 2-F2-(4-methylpiperazin-1 -yl)phenyllethyl)-1 ,3- dihydroimid-azor4,5-blpyridin-2-one. Using PP28A in place of PP27 and 4- bromobenzotrifluoride in place of PP49, yield 67%: NMR (CDCI3) 8.06 (d, J = 4.0 Hz, 1 H), 7.50 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.8Hz, 2H), 7.28-7.09 (m, 4H), 7.02-6.90 (m, 2H), 4.34 (m, 2H), 3.23 (m, 2H), 2.97(m, 4H), 2.59 (br s, 4H), 2.34 (s, 3H), 1.35 (s, 9H); 13C NMR (CDCI3)152.81 , 152.43, 150.93, 143.82, 141.27, 134.24, 131.53, 130.84, 127.84, 126.77, 125.19, 124.40, 124.05, 120.98, 117.07, 114.49, 55.84, 53.14, 46.44, 40.97, 34.94, 31.56, 30.25.
EXAMPLE 15 3-(2-r2-(4-Methylpiperazin-1-yl)-phenvnethyl>-6-phenyl-1H-quinazoline-2,4-dione. PP34 (0.10 g, 20.226 mmol), phenylboronic acid (0.033 g, 0.271 mmol), tetrakis(triphenylphosphine) palladium(O) (5 mg, 0.005 mmol) and K2CO3 (CIOg , 0.724 mmol) were refluxed in EtOH (10 mL)/water (1 mL) for 1.5 hrs. The reaction was concentrated, extracted into EtOAc and washed with water and brine, dried (MgSO4) and concentrated to a dirty white solid. Chromatography with first 20% MeOH/EtOAc then 20% MeOH/EtOAc with 1 % NH4OH gave 67 mg (67%) of Example 15 as a white solid. The maleate salt had: mp 80- 850C; NMR (DMSO-d6) 8.12 (s, 1 H), 7.97 (d, J = 8.3 Hz, 1 H), 7.63 (d, J = 7.5 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1 H), 7.26-7.05 (m, 5H), 6.06 (s, 2H), 4.14 (t, J = 7.7 Hz, 2H), 3.48 (br s, 2H), 3.40-3.05 (m, 4H), 3.05-2.85 (m, 4H), 2.85 (s, 3H).
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-Mθthylpiperazin-1-yl)phenvπethyl}-7-phenyl-1 H-quinazoline- 2,4-dione. Using PP35 in place of PP34, yield 30%. Maleate salt had: mp 80-850C (foams); NMR (DMSO-d6) 11.52 (s, 1 H), 7.97 (d, J = 8.3 Hz, 1 H), 7.63 (d, J = 7.1 Hz, 2H), 7.52-7.41 (m, 4H), 7.36 (d, J = 1.3 Hz, 1 H), 7.23-7.19 (m, 2H), 7.13-7.05 (m, 2H), 6.06 (s, 2H), 4.13 (t, J = 7.9 Hz, 2H), 3.60-3.10 (br m, 6H), 3.10-2.80 (br m, 4H), 2.86 (s, 3H).
B. 1-Methyl-3-{2-f2-(4-methylpiperazin-1-yl)phenvnethyl)-7-phenyl-1H- quinazoline-2,4-dione. Using PP36 in place of PP34, yield 50%, maleate salt had: mp 175- 176°C; NMR (DMSO-d6) 8.09 (d, J= 7.9 Hz, 1 H), 7.80 (d, J = 7.1 Hz, 2H), 7.61-7.57 (m, 2H), 7.51 (t, J = 7.3 Hz, 2H), 7.44 (t, J = 7.1 Hz, 1 H), 7.23-7.19 (m, 2H), 7.51 (t, J = 7.3 Hz, 2H), 7.44 (t, J = 7.1 Hz, 2H), 7.23-7.19 (m, 2H), 7.13 (d, J = 7.1 Hz, 1 H), 7.10-7.05 (m, 1 H), 5.97 (s, 2H), 4.20-4.15 (sym. mult., 2H), 3.62 (s, 3H), 3.57-2.92 (br m, 8H), 2.92-2.88 (sym. mult., 2H), 2.85 (s, 3H).
C. 1-Methyl-3-{2-r2-(4-methylpiperazin-1-yl)phenvnethyl)-7-(4- trifluoromethylphenyl)-1 H-quinazoline-2,4-dione. Using PP36 in place of PP34 and 4- trifluorobenzene boronic acid in place of phenyl boronic acid, yield 32%, maleate salt had: mp 95-97°C; NMR (MeOH-d4) 8.24 (d, J = 8.3 Hz, 1 H), 7.87 (AB quartet, Δu = 56.4 Hz, J = 8.3 Hz, 4H), 7.65-7.60 (m, 2H), 7.30-7.11 (m, 4H), 4.31-4.26 (m, 2H), 3.69 (s, 3H), 3.58 (br s, 4H), 3.48-3.43 (m, 1 H), 3.27 (br s, 3H), 3.13 (br s, 2H), 3.06 (s, 3H).
D. 7-f4-(1 -Hvdroxy-1 -methylethyl)phenyll-1 -methyl -3-(2-F2-(4- methylpiperazin-1 -yl)phenyll-ethyl}-1 H-quinazoline-2,4-dione. Using PP36 in place of PP34 and PP33 in place of phenyl boronic acid, yield 56%: mp 182-185°C; NMR (CDCI3) 8.23 (d, J= 8.3 Hz, 1 H), 7.60 (br s, 4H), 7.45-7.43 (m, 1 H), 7.31 (m, 2H), 7.29-7.23 (m, 1 H), 7.20- 7.11 (m, 1 H), 7.09-7.01 (m, 1 H), 4.36-4.32 (m, 2H), 3.63 (s, 3H), 3.05-3.01 (m, 2H), 3.00-2.97 (m, 4H), 2.65 (br s, 4H), 2.38 (s, 3H), 1.61 (s, 6H). EXAMPLE 17
S-fΣ-fΣ^-Mθthylpiperazin-i-vDphenvnethvD-β-dnorpholine^-carbonvD-IH-quinazoline-
2,4-dione.
PP34 (0.167 g, 0.377 mmol), morpholine (2 mL), and dichlorobis(triphenylphosphine)- palladium (II) (0.015 g, 0.0.21 mmol) were stirred under a carbon monoxide atmosphere at 125°C for 2hrs. The reaction was diluted with water and extracted into EtOAc. The extracts was washed with brine, dried (MgSO4) and concentrated to afford a yellow oil (0.11 g). Chromatography with first 20% MeOH/EtOAc then 20% MeOH/EtOAc with 1-2.5% NH4OH gave 0.13 g (72%) of Example 17 as a white foam, the maleate salt of which had: mp 90- 12O0C (foams and melts); NMR (DMSO-d6) 11.65 (s, 1H), 7.92 (d, J = 2.1 Hz, 1 H), 6.69 (dd, J = 8.3, 2.1 Hz, 1 H), 7.23-7.18 (m, 3H), 7.12 (d, J = 7.5 Hz, 1 H), 7.07 (dt, J = 7.3, 0.8 Hz, 1 H), 6.00 (s, 2H), 4.10 (dd, J = 10.4, 6.4 Hz, 2H), 3.70-2.93 (m, 16 H), 2.90-2.86 (m, 2H), 2.85 (s, 3H). EXAMPLE 18 5-tert-Butyl-2-{2-r2-(4-methylpiperazin-1-yl)phenvπethyl>isoindole-1,3-dione.
PP5 (0.10 g, 0.455 mmol) and 4-t-butylphthalic anhydride (0.094 g, 0.460 mmol) were stirred vigorously in CH2CI2 (6 ml_)/ THF (4 ml_) for 3 days. The reaction was concentrated and the residual solid was triturated with EtOAc to give 108 mg (56%) of a 1 :1 mixture of regioisomeric acids, 4-tert-butyl-N-{2-[2-(4-methylpiperazin-1 -yl)phenyl]-ethyl}-phthalamic acid and 5-tert-butyl-N-{2-[2-(4-methylpiperazin-1-yl)phenyl]-ethyl}-phthalamic acid. This mixture was refluxed in glacial HOAc (3 ml.) for 4 hrs, cooled and concentrated to give 70 mg of orange oil. Chromatography with 10% MeOH/ EtOAc gave 33mg (35%) of Example 18 as an oil, the HCI salt of which had: mp 153-157°C; NMR (MeOH-d4) 7.85-7.82 (m, 2H), 7.72 (d, J =
7.9 Hz, 1 H), 7.21-7.19 (m, 3H), 7.05 (m, 1 H), 3.89, (t, J = 7.5 Hz, 2H), 3.59-3.56 (m, 2H),
3.48-3.42 (m, 3H), 3.28-3.14 (m, 3H), 3.01 (s, 3H), 2.99-2.95 (m, 2H) 1.36 (s, 9H).
EXAMPLE 19
Syntheses of the compounds below are essentially the same procedure as described in Example 18 with the noted changes:
A. 2-{2-r2-(4-Methylpiperazin-1-yl)phenyllethyl>benzorflisoindole-1,3- dione. Using naphtho-[2,3-c]furan-1 ,3-dione in place of 4-t-butylphthalic anhydride, yield 15%: mp ~ 165C; NMR (CDCI3) 8.29 (s, 2H), 8.02 (dd, J = 6.2, 3.3 Hz, 2H), 7.67 (dd, J = 6.2, 3.3 Hz, 2H), 7.21-7.12 (m, 3H), 7.04-6.96 (m, 1 H), 4.01 (t, J = 7.5 Hz, 2H), 3.02 (t, J = 7.5 Hz, 2H), 2.83 (br s, 8 H), 2.51 (s, 3H).
B. 5-Methyl-2-(2-r2-(4-methylpiperazin-1-yl)phenyllethyl}isoindole-1 ,3- dione. Using 4-methyIphthalic anhydride in place of 4-t-butylphthalic anhydride, yield 65%. HCI salt had: mp ~57°C; NMR (MeOH-d4) 7.67 (d, J = 7.9 Hz, 1 H), 7.62 (s, 1 H), 7.57 (d, J = 7.9 Hz, 1 H), 7.21-7.16 (m, 3H), 7.07-7.05 (m, 1 H), 3.88 (t, J = 7.5 Hz, 2H), 3.60-3.58 (m, 2H), 3.56-3.43 (m, 2H), 3.30-3.11 (m, 4H), 3.00 (s, 3H), 2.97 (t, J = 7.9 Hz, 2H), 2.48 (s, 3H).
C. 2-{2-r2-(4-Methylpiperazin-1-yl)phenyllethyl}-5-nitro-isoindole-1 ,3-dione. Using 4-nitro-phthalic anhydride in place of 4-t-butylphthalic anhydride, yield 60%. HCI salt had: mp 252-259°C; NMR (MeOH-d4) 8.63 (dd, J = 7.9, 2.1 Hz, 1 H), 8.57 (d, J = 0.8 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1 H) 7.25-7.19 (m, 3H), 7.08-7.04 (m, 1 H), 3.96 (t, J = 7.5 Hz, 2H), 3.62- 3.59 (m, 2H), 3.52-3.43 (m, 2H) 3.31-3.24 (m, 2H), 3.19-3.09 (m, 2H), 3.02 (s, 3H), 3.01 (t, J = 7.5 Hz, 2H); 13C NMR (MeOH-d4) 166.6, 166.4, 150.3, 136.6, 134.1 , 133.6, 131.0, 129.4, 128.2, 125.8, 124.2, 121.3, 117.9, 54.3, 50.1 , 42.6, 38.8, 30.6.
D. 5-Fluoro-2-{2-r2-(4-methylpiperazin-1-yl)phenvnethyl)isoindole-1 ,3- dione. Using 4-fluorophthalic anhydride in place of 4-t-butylphthalic anhydride, yield 54%. HCI salt had: mp 238-2440C; NMR (DMSO-d4) 7.91-7.87 (m, 1 H), 7.73 (dd, J = 7.5, 2.1 Hz, 1 H), 7.64-7.59 (m, 1 H), 7.20-7.08 (m, 3H), 7.01-6.99 (m, 1 H), 3.82 (t, J = 7.5 Hz, 2H), 3.45 (br s, 2H), 3.20-3.11 (m, 2H), 3.07-3.05 (m, 4H), 2.90 (t, J = 7.9 Hz, 2H), 2.81-2.80 (m, 3H); 13C NMR (DMSO-d6) 167.5, 150.9, 134.1 , 131.2, 128.5, 128.4, 126.5, 126.4, 125.6, 122.0, 121.8, 121.4, 11.8, 11.6, 53.8, 49.9, 42.9, 38.8, 30.5.
E. 5-Chloro-2-{2-r2-(4-methylpiperazin-1-yl)phenyllethyl}isoindole-1 ,3- dione. Using 4-chlorophthalic anhydride in place of 4-t-butylphthalic anhydride, yield 59%. HCI salt had: mp 25-=255°C; NMR (DMSO-d6) 7.91 (s, 1 H), 7.84-8.82 (m, 2H), 7.21-7.09 (m, 3H), 7.05-6.99 (m, 1 H), 3.82 (t, J= 7.8 Hz, 2H), 3.46-3.43 (m, 2H), 3.19-3.14 (m, 2H), 3.07- 3.06 (m, 4H), 2.90 (t, J = 7.8 Hz, 2H), 2.80 (d, J= 4.6 Hz, 3H); 13C NMR (DMSO-d6) 167.6, 167.2, 150.9, 139.9, 134.9, 134.2, 134.1 , 131.2, 130.7, 128.6, 125.6, 125.5, 123.9, 121.5, 53.8, 49.9, 42.9, 38.8, 30.4. F. 2-{2-f2-(4-Methylpiperazin-1-yl)phenvnethyl)isoindole-1,3-dione. Using phthalic anhydride in place of 4-t-butylphthalic anhydride, yield 85%. HCI salt had: mp ~235°C; NMR (MeOH-d4) 7.82-7.75 (m, 4H), 7.21-7.18 (m, 3H), 7.07-7.03 (m, 1 H), 3.91 (t, J = 7.5 Hz, 2H), 3.60-3.57 (m, 2H), 3.28-3.15 (m, 4H), 3.01 (s, 3H), 2.99-2.96 (m, 2H); 13C NMR (DMSO-d6) 168.4, 150.9, 135.1 , 134.2, 132.2, 131.2, 128.5, 125.6, 123.7, 121.4, 53.7, 49.8, 42.9, 38.6, 30.5.
G. 5-Methoxy-2-(2-f2-(4-methylpiperazin-1-yl)phenvπethyl)-isoindole-1 ,3- dione. Using 4-methoxyphthalic anhydride in place of 4-t-butylphthalic anhydride, yield 49%. HCI salt had: mp 95-1050C; NMR (DMSO-d4) 7.73 (d, J = 8.3 Hz, 1 H), 7.32 (d, J = 2.5 Hz, 1 H), 7.26 (m, 1 H), 7.20-6.99 (m, 5H), 3.87 (s, 3H), 3.80 (t, J = 7.1 Hz, 2H), 3.40-3.32 (m, 2H), 3.16-3.03 (m, 6H), 2.87 (t, J = 7.5 Hz, 2H), 2.78 (d, J = 5.0 Hz, 3H); 13C NMR (DMSO-d4) 168.10, 165.03, 150.95,134.83, 134.22, 131.25, 128.50, 125.58, 123.93, 121.42, 120.36, 108.95, 65.57, 56.97, 53.73, 49.84, 42.86, 38.60, 30.57, 15.83.
EXAMPLE 20 2-f2-r2-(4-Methylpiperazin-1-yl)phenvnethyl>-5-phenylisoindole-1,3-dione. Step 1 : 4-Bromo-phthalic acid (1.00 g, 4.08 mmol), phenylboronic acid (0.52 g, 4.26 mmol), tetrakis(triphenylphosphine)palladium (0) and K2CO3 in EtOH/ water (40 mL/4 ml.) were refluxed for 3 hrs then concentrated. The residue was dissolved in water and washed with EtOAc (2x50 mL). The aqueous phase was acidified with 1 N HCI and extracted with EtOAC (2x200 mL). The extracts were washed with water and brine, dried (MgSO4) 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 CH2CI2 (30 mL) for 1.5 hrs. After concentration, the reaction was dissolved in EtOAc and washed with water and brine, dried (MgSO4) and concentrated to give 2.36 g of a mixture of amide esters 4-{2- ^-(^methyl-piperazin-i-ylJ-phenyll-ethylcarbannoylJ-biphenyl-S-carboxylic acid ethyl ester and 4-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethylcarbamoyl}-biphenyl-4-carboxylic acid ethyl ester as a sticky yellow foam. This mixture was dissolved in EtOH (20 ml_) and LiOH-H2O (50 mg) was added and the mixture was stirred at rt for 60 hrs. After concentration, the reaction was dissolved in EtOAc and washed with water and brine, dried (MgSO4) and concentrated to a light yellow oil. Chromatography with 20% MeOH/ EtOAc gave 1.08 g (59%) of 2-{2-[2-(4- methylpiperazin-1-yl)-phenyl]ethyl}-5-phenyl-isoindole-1 ,3-dione as a yellow oil, the fumarate salt of which had: mp 184-186°C; NMR (DMSO-d6) 8.07-8.04 (m, 2H), 7.86 (d, J = 7.5 Hz, 1 H), 7.77 (d, J= 7.1 Hz, 2H), 7.50-7.40 (m, 3H), 7.16-7.12 (m, 2H), 7.05 (d, J = 7.5 Hz, 1 H), 6.97 (t, J = 7.3 Hz, 1 H), 6.55 (s, 2H), 3.84 (t, J = 7.3 Hz, 2H), 2.92 (t, J= 7.3 Hz, 2H), 2.82- 2.79 (m, 4H), 2.64 (br s, 4H), 2.35 (s, 3H); 13C NMR (DMSO-d6) 168.12, 167.04, 152.18, 146.82, 138.89, 134.89, 134.27, 133.33, 133.14, 131.11 , 130.90, 129.89, 129.54, 128.30, 127.34, 124.88, 124.29, 121.62, 121.12, 55.13, 52.24, 45.53, 38.98, 30.38.
EXAMPLE 21 2-(2-r2-(4-Methylpiperazin-1-yl)phenyllethyl>-5-morpholin-4-yl-isoindole-1,3-dione.
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 (MgSO4) and concentrated to afford a yellow-orange oil (58mg). Chromatography with 10-20% MeOH/ EtOAc yielded 32 mg ((32%) of Example 21 as a yellow oil, the maleate salt of which had: mp 192-193°C; NMR (MeOH- d4) 7.61 (d, J = 8.3 Hz, 1 H), 7.30 (d, J = 2.5 Hz, 1 H), 7.23-7.13 (m, 4H), 7.06 (dt, J = 7.5, 1.7 Hz, 1 H), 6.22 (s, 2H), 3.87-3.79 (m, 6H), 3.51 (br s, 4H), 3.35 (t, J = 4.8 Hz, 4H), 3.16 (br s, 4H), 3.00 (s, 3H), 2.96 (t, J = 7.7 Hz, 2H). EXAMPLE 22
5-r4-(1 -Hvdroxy-1 -methylethyl)phenyll-2-{2-r2-(4-methylpiperazin-1 - yl)phenyllethyl}isoindole-1 ,3-dione.
PP40 (0.200 g, 0.313 mmol), PP51 (0.074 g, 0.344 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.011 g, 0.016 mmol), Et3N (0.21 mL, 1.49 mmol), LiCI (0.041 g, 0.97 mmol), and BHT (3 crystals) in DMF (6 mL) were heated at 115°C for 3.5 hrs.1 N LiCI (50 mL) was added and the mixture was extracted twice with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated to give 171 mg of crude product. Chromatography with 10-20% MeOH/ EtOAc followed by concentration and ether trituration yielded 20 mg (13%) of Example 22: mp 162-166°C; NMR (CDCI3) 8.02 (d, J = 0.8 Hz, 1 H), 7.91-7.84 (m, 2H), 7.60 (br s, 4H), 7.24-7.15 (m, 3H), 7.08-7.04 (m, 1 H), 3.93 (t, J = 7.5 Hz, 2H), 3.11-2.99 (br s, 8H), 2,97 (t, J = 7.9 Hz, 2H), 2.64 (s, 3H), 1.61 (s, 6H).
EXAMPLE 23 Syntheses of the compounds below are essentially the same procedure as described in Example 22, using the identified agent in place of PP51 :
A. 5-r4-(1-Hvdroxycvclopentyl)phenvn-2-{2-r2-(4-methylpiperazin-1- yl)phenyllethyl}isoindole-1 ,3-dione. Using PP49, yield 19%: mp 174-1770C; NMR (CDCI3) 8.01 (d, J = 0.8 Hz, 1 H), 7.90-7.83 (m, 2H), 7.60 (br s, 4H), 7.21-7.14 (m, 3H), 7.07-6.97 (m, 1 H), 3.94 (t, J = 7.5 Hz, 2H), 3.07-2.93 (br s, 8H), 2.98 (t, J = 7.5 Hz, 2H), 2.57 (br s, 3H), 2.01 (br s, 6H), 1.86 (br s, 2H); 13C NMR (CDCI3) 173.3, 168.5, 148.3, 147.4, 137.5, 133.8, 133.2, 132.6, 131.2, 120.6, 129.4, 128.5, 127.3, 126.2, 125.7, 123.9, 121.9, 83.5, 66.1 , 54.7, 51.1 , 42.4, 39.0, 31.4, 24.1 , 15.5. B. 5-r6-(1-Hvdroxy-1-methylethyl)pyridin-3-vn-2-{2-r2-(4-methylpiperazin-1- yl)phenvπethyl}-isoindole-1 ,3-dione. Using PP53, yield 24%: mp146-149°C; NMR (CDCI3) 8.76 (m, 1 H), 7.99 (m, 1 H), 7.92 (dd, J = 8.3, 2.5 Hz, 1 H), 7.88-7.87 (m, 2H), 7.50 (dd, J = 8.3, 0.8 Hz, 1 H), 7.19-7.15 (m, 2H), 7.11-7.08 (m, 1 H), 7.01-6.97 (m, 1 H), 3.98 (t, J = 7.5 Hz, 2H), 3.01 (t, J = 7.5 Hz, 2H), 2.92 (t, J = 4.6 Hz, 4H), 2.62 (br s, 4H), 2.38 (s, 3H), 1.57 (s, 6H).
C. 2-{2-r2-(4-Methylpiperazin-1-yl)phenvnethyl}-5-(4- trifluoromethylphenyl)isoindole-1,3-dione. Using 4-bromobenzotrifluoride, yield 25%, HCI salt had: mp 80-850C; NMR (DMSO-d6) 8.19, (s, 1 H), 8.18 (d, J = 7.5 Hz, 1 H), 7.97 (d, J = 8.3 Hz, 1 H) 7.96 (AB quartet, Δu = 70.5 Hz, J = 8.3 Hz, 4H), 7.24-7.13 (m, 3H), 7.07-7.03 (m, 1 H), 3.90, (t, J = 7.1 Hz, 2H), 3.50-3.48 (m, 2H), 3.22 (br s, 2H), 3.12 (br s, 4H), 2.96 (t, J = 7.1 Hz, 2H), 2.85 (d, J = 4.6 Hz, 3H).
D. 2-{2-r2-(4-Methylpiperazin-1-yl)phenvnethyl>-5-pyridin-2-ylisoindole-1,3- dione. Using 2-bromopyridine, yield 13%; mp 146-148°C; NMR (CDCI3) 8.73-8.71 (m, 1 H), 8.40-8.37 (m, 2H), 7.88 (d, J = 7.9 Hz, 1 H), 7.83-7.78 (m, 2H), 7.33-7.31 (m, 1 H), 7.31-7.17 (m, 2H), 7.13-7.11 (m, 1 H), 7.03-6.99 (m, 1 H), 3.96 (t, J = 7.5 Hz, 2H), 3.00 (br s, 6H), 2.77 (br s, 4H), 2.48 (s, 3H); 13C NMR (CDCI3) 168.2, 168.1 , 155.3, 150.3, 150.3, 145.4, 137.4, 134.0, 133.1 , 132.6, 132.2, 131.0, 128.2, 124.9, 123.8, 123.7, 121.7, 121.3, 121.2, 55.4, 52.5, 45.9, 39.0, 30.9.
E. 2-f2-r2-(4-Methyl-piperazin-1-yl)phenvnethyl}-5-pyridin-3-yl-isoindole- 1.3-dione. Using 3-bromopyridine, yield 19%: mp 117-1220C; NMR (CDCI3) 8.86 (d, J = 2.1
Hz, 1 H), 8.66 (dd, J = 4.6, 1.7 Hz, 1 H), 8.00 (s, 1 H), 7.92-7.86 (m, 3H), 7.43-7.40 (m, 1 H), 7.20-7.16 (m, 2H), 7.13-7.10 (m, 1 H), 7.03-7.01 (m, 1 H), 3.97 (t, J = 7.5 Hz, 2H), 3.00 (t, J = 7.5 Hz, 2H), 3.00-2.97 (br s, 4H), 2.72 (br s, 4H), 2.44 (s, 3H) ; 13C NMR (CDCI3) 173.4, 168.0, 152.0, 150.2, 148.5, 144.1 , 135.0, 134.8, 133.9, 133.5, 132.7, 131.6, 130.9, 128.1 , 124.8, 124.1 , 124.0, 122.0, 121.3, 55.6, 52.7, 46.1 , 39.1 , 30.8.
F. 5-(4-tert-Butylphenyl)-2-{2-r2-(4-methylpiperazin-1- yl)phenyriethyl}isoindole-1,3-dione. Using 1-bromo-4-t-butylbenzene, yield 24%, HCI salt had: mp 111-118°C; NMR (MeOH-d4) 8.03-8.00 (m, 2H), 7.84 (d, J= 7.9 Hz, 1 H), 7.59 (AB quartet, Δu = 41.5 Hz, J = 8.3 Hz, 4H), 7.22-7.17 (m, 3H), 7.09-7.07 (m, 1 H), 3.93 (t, J = 7.5 Hz, 2H), 3.61-3.56 (m, 2H), 3.51-3.44 (m, 2H), 3.28-3.22 (m, 2H), 3.17-3.14 (m, 2H), 3.02 (s, 3H), 3.01-2.98 (m, 2H), 1.34 (s, 9H); 13C NMR (MeOH-d4) 168.4, 152.2, 150.2, 147.5, 136.1 , 134.3, 133.1 , 132.3, 131.1 , 130.3, 128.1 , 126.8, 126.1 , 125.8, 123.4, 121.1 , 120.9, 112.5, 54.3, 50.1 , 42.6, 38.4, 34.3, 30.7, 30.4.
EXAMPLE 24
5-Amino-2-{2-r2-(4-methylpipera2in-1-yl)phenvnethyl}isoindole-1,3-dione. 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 Celite™ and concentrated. Aqueous K2CO3 was added and the mixture was extracted with EtOAc. The extract was washed with brine, dried (MgSO4) and concentrated to a yellow oil. Stirring with ether gave a 121 mg (75%) of Example 24 as a yellow solid: mp-57-66°C; NMR (CDCI3) 7.54 (d, J = 7.9 Hz1 1 H), 7.20-7.15 (m, 2H), 7.10-7.09 (m, 1 H), 7.02-6.96 (m, 2H), 6.77 (dd, J = 8.3, 2.1 Hz, 1 H), 4.29 (br s, 2H), 3.88 (t, J = 7.9 Hz, 2H), 2.98-2.93 (m, 6H), 2.65 (br s, 4H), 2.40 (s, 3H); 13C NMR (CDCI3) 173.3, 168.6, 152.1 , 135.2, 134.3, 130.9, 127.9, 125.1 , 124.6, 121.1 , 121.0, 118.0, 108.6, 55.6, 52.8, 46.2, 38.7, 30.7.
EXAMPLE 25 2-r2-(4-Methylpiperazin-1-yl)benzvn-7-phenyl-3,4-dihvdro-2H-isoquinolin-1-one. BINAP (16 mg, 0.027 mmol) was dissolved in toluene (2-3 mL) with heating. After cooling to rt, palladium acetate (5 mg, 0.022 mmol) was added to give an orange solution. PP41 (0.100g, 0.254 mmol), 1-methylpiperazine (0.15 mL, 1.39 mmol), toluene (4 mL) and sodium t-butoxide (33 mg, 0.31 mmol) were next added to give a dark red solution. This mixture was refluxed (2 hrs), cooled and concentrated to a brown oil which was dissolved in EtOAc and washed with water and brine, dried (MgSO4) and concentrated onto silica gel. Chromatography, first flushing with 10-20% MeOH/ EtOAC and then eluting with 20% MeOH/ EtOAC +1% NH4OH afforded 30 mg (29%) of Example 25 as a light brown solid : mp 140- 142°C;NMR (DMSO-d6) 8.35 (d, J = 2.1 Hz, 1 H), 7.65 (dd, J = 7.9, 2.1 Hz, 1 H), 7.61 (d, J = 7.1 Hz, 2H), 7.43 (t, J = 7.7 Hz, 2H), 7.36-7.20 (m, 5H), 7.13 (t, J = 6.8 Hz, 1 H), 4.88 (s, 2H), 3.39 (t, J = 6.6 Hz, 2H), 3.34-2.95 (br m, 8H), 2.90 (t, J = 6.4 Hz, 2H); 13C NMR (DMSO-d6) 164.67, 140.48, 137.11 , 132.09, 130.62, 130.38, 129.92, 129.19, 129.13, 127.87, 127.18, 126.93, 125.58, 121.60, 54.62, 50.56, 46.44, 44.98, 44.15, 27.96.
EXAMPLE 26 2-f2-(4-Methylpiperazin-1-yl)benzvn-7-nriorpholin-4-yl-3,4-dihvdro-2H-isoquinolin-1-one. This material was prepared following the same general procedure described in
Example 25: Using PP42 in place of PP41 , yield 7%, HCI salt had: mp -150-1900C (amorphous); NMR (DMSO-d6) 10.48 (br s, 1 H), 7.46 (s, 1 H), 7.23 (t, J = 8.3 Hz, 1 H), 7.14- 7.12 (m, 4H), 7.07 (t, J = 7.3 Hz, 1 H), 4.74 (s, 2H), 3.72 (t, J = 4.8 Hz, 4H), 3.43-3.31 (m, 4H), 3.20-3.00 (m, 10H), 2.82-2.76 (m, 5H).
EXAMPLE 27
2-r2-(4-Methylpiperazin-1-yl)benzvn-7-morpholin-4-yl-1 ,2,3,4-tetrahydroisoquinoline. PP43 (0.090 g, 0.41 mmol), PP57 (0.10 g, 0.49 mmol) and sodium triacetoxyborohydride (0.11 g, 0.52 mmol) were stirred in DCE (5 mL) at rt for 16 hrs. After concentration, the residue was dissolved in EtOAc and washed with aq. K2CO3 and brine, dried (MgSO4) and reconcentrated to a thick yellow oil (0.17 g). Chromatography with 10% MeOH/ EtOAc gave 0.109 g (65%) of Example 27 as a light orange tinted oil, the HCI salt had: mp -190-220 0C (amorphous); NMR (DMSO-d6) 11.13 (br s, 1 H), 10.92 (br s, 1 H), 7.79 (dd, J = 7.5, 1.5 Hz, 1 H), 7.44 (t, J = 8.3 Hz, 1 H), 7.28-7.20 (m, 2H), 7.10 (d, J = 8.3 Hz, 1 H), 7.00 (br d, J = 7.1 Hz, 1 H), 6.87 (s, 1 H), 4.36 (d, J= 5.4 Hz, 2H), 4.33-4.22 (m, 1 H), 4.15 (d, J = 15.8 Hz, 1 H), 3.73-3.70 (m, 4H), 3.54-3.50 (m, 1 H), 3.45-3.30 (m, 4H), 3.22-3.00 (m, 10H), 2.90 (br d, J = 17.0 Hz, 1 H), 2.70 (d, J= 5.0 Hz, 3H). EXAMPLE 28
2-f2-r2-(4-Methylpiperazin-1-yl)phenvπethyl}-7-morpholin-4-yl-1 ,2,3,4- tetrahydroisoquinoline.
Example 28 was prepared following the same general procedure described in Example 27: Using PP44 in place of PP57, yield 36%, HCI salt had: mp -185-2100C (amorphous); NMR (DMSO-d6) 11.57 (br s, 1 H), 11.57 (br s, 1 H), 10.73 (br s, 1 H), 7.26-7.23 (m, 2H), 7.18-7.05 (m, 3H), 6.95 (d, J = 8.3 Hz, 1 H), 6.78 (s, 1 H), 4.47 (br d, J = 16.2 Hz, 1 H), 4.34-4.20 (m, 1 H), 3.72-3.66 (m, 4H), 3.53-3.00 (m, 19H), 2.87 (br d, J = 16.2 Hz, 1 H), 2.45- 2.42 (m, 3H).
EXAMPLE 29 2-(2-r2-(4-Methylpiperazin-1-vnphenyllethyl>-5-phenyl-2,3-dihvdroisoindol-1-one.
Example 29 was prepared following the same general procedure described in Example 15: Substituting PP45 for PP34, yield 64%, HCI salt ahd: mp 135-1400C; NMR (DMSO-d6) 7.83 (s, 1 H), 7.73-7.67 (m, 4H), 7.46 (t, J = 7.5 Hz, 2H), 7.40-7.35 (m, 1 H)1 7.25 (dd, J = 7.5, 1.7 Hz, 1 H), 7.22-7.17 (m, 1 H), 7.10 (d, J = 7.1 Hz, 1 H), 7.04 (dt, J = 7.3, 1.1 Hz, 1 H), 4.49 (s, 2H), 3.79 (t, J = 7.7 Hz, 2H), 3.42 (br d, J = 11.2 Hz, 2H), 3.22 (br pent., J = 8.7 Hz, 2H), 3.13-3.08 (m, 4H), 2.93 (t, J = 7.7 Hz, 2H), 2.81-2.79 (m, 3H).
EXAMPLE 30 2-{2-r2-(4-Methyl-piperazin-1-yl)-phenvn-ethyl)-5-(morpholin-4-yl)-2.3-dihvdro-isoindol-
1-one. Example 30 was prepared following the same general procedure described in
Example 21 : Substituting PP45 for PP39, yield 53%, HCI salt had: mp 145-1500C; NMR (DMSO-d6) 10.76 (br s, 1 H), 7.43 (d, J = 8.7 Hz, 1 H), 7.24-7.16 (m, 2H), 7.09 (d, J = 7.1 Hz, 1 H), 7.05-6.98 (m, 3H), 4.30 (s, 2H), 3.72-3.68 (m, 6H), 3.41 (br d, J = 11.6 Hz, 2H), 3.20- 3.16 (m, 6H), 3.08-3.05 (m, 4H), 2.88 (t, J = 7.5 Hz, 2H), 2.80-2.78 (m, 3H).
EXAMPLE 31
2"f2-r2-(4-Methylpiperazin-1-yl)phenyllethyl}-5-(morpholine-4-carbonyl)-2,3- dihydroisoindol-1-one.
Example 31 was prepared following the same genera! procedure described in Example 17:
Substituting PP45 for PP34, yield 38%, HCI salt had: mp 125-13O0C; NMR (DMSO- d6) 10.61 (br s, 1 H), 7.66 (d, J = 7.9Hz, 1 H), 7.59 (s, 1 H), 7.44 (d, J = 7.9 Hz, 1 H), 7.25-7.17 (m, 2H), 7.10 (d, J = 7.1 z, 1H), 7.04 (dt, J = 8.3, 1.0 Hz, 1 H), 4.48 (s, 2H), 3.78 (t, J = 7.7 Hz, 2H), 3.75-3.17 (br m, 12H), 3.15-3.02 (m, 4H), 2.91 (t, J = 7.7 Hz, 2H), 2.81-2.80 (m, 3H).
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. K2CO3. The organics were washed with brine dried (MgSO4) and concentrated to give an orange oil Chromatography using 20 % MeOH/ EtOAc + 1-5% NH4OH yielded 0.167 g (54%) of 4-bromo-2-(2-{2-[2-(4-methylpiperazin-1-yl)-phenyl]ethylamino}- ethyl)benzonitrile as an orange oil : NMR (CDCI3) 7.89 (br d, J = 8.3 Hz, 1 H), 7.40 (dd, J = 8.3, 2.1 Hz, 1 H), 7.26-7.25 (m, 1 H), 7.20-7.12 (m, 3H), 7.01 (dt, J = 7.3, 1.7 Hz, 1 H), 3.72 (t, J = 7.5 Hz, 2H), 3.27 (t, J= 6.2 Hz, 2H), 2.98 (t, J = 7.7 Hz, 2H), 2.92 (t, J = 4.8 Hz, 4H), 2.73 (t, J = 6.2 Hz, 2H), 2.58 (br s, 4H), 2.35 (s, 3H). Step 2: This material was refluxed with LiOH. H2O in MeOH/ water (10mL/5 mL) for
2.5 hrs. The reaction was concentrated to remove MeOH, diluted with water and extracted with EtOAc. The extract was washed with brine, dried (MgSO4) and concentrated to a yellow oil (0.139 g). Chromatography with 10-20% MeOH/ EtOAc then 20% MeOH/ EtOAc +1 % NH4OH gave pure Example 32 as a waxy yellow solid: mp 109-1100C; NMR (CDCI3) 7.89 (d, J = 8.3 Hz, 1 H)1 7.42 (dd, J = 8.3, 2.1 Hz, 1 H), 7.26 (d, J = 1.7 Hz, 1 H), 7.20-7.15 (m, 2H), 7.10 (d, J = 6.6 Hz, 1 H), 6.99 (dd, J = 7.3, 1.4 Hz, 1 H), 3.77 (t, J = 7.5 Hz, 2H), 3.36 (t, J = 6.6 Hz, 2H), 2.96 (t, J = 7.3 Hz, 2H), 2.91 (t, J = 4.6 Hz, 4H), 2.77 (t, J = 6.4 Hz, 2H), 2.55 (br s, 4H), 2.33 (s, 3H); 13C NMR (CDCI3) 163.62, 151.98, 140.10, 134.78, 130.91 , 130.47, 130.12, 129.94, 128.81 , 127.77, 126.23, 124.60, 120.89, 55.95, 53.04, 49.1 1 , 46.87, 46.36, 29.90, 28.05.
EXAMPLE 33 These materials were prepared following the same general procedure described in Example 15 with the noted changes:
A. 2-f2-r2-(4-Methylpiperazin-1 -yl)phenyllethylV6-phenyl-3,4-dihydro-2H- isoquinolin-1-one. Substituting Example 32 for PP34, yield 73%, HCI salt had: mp ~260°C (dec); NMR (DMSO-d6) 10.47 (br s, 1 H), 7.90 (d, J = 8.3 Hz, 1 H), 7.66 (d, J = 7.1 Hz, 2H), 7.60 (dd, J = 7.9, 1.9 Hz, 1 H), 7.56 (s, 1 H), 7.45 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.3 Hz, 1 H), 7.26-7.17 (m, 2H), 7.11 (d, J = 7.1 Hz, 1 H), 7.06 (t, J = 7.5 Hz, 1 H), 3.71 (t, J = 7.7 Hz, 2H), 3.55-3.40 (m, 4H), 3.26-3.03 (m, 6H), 2.95-2.86 (m, 4H), 2.82 (d, J = 4.6 Hz, 3H).
B. 2-{2-r2-(4-Methylpipera2in-1 -yl)phenvnethyl>-6-pyridin-4-yl-3,4-dihydro- 2H-isoquinolin-1-one. Substituting Example 32 for PP34 and 4-pyridine boronic acid for phenyl boronic acid, yield 72%, HCI salt had: mp 235-237X; NMR (DMSO-d6) 11.19 (br s, 1 H), 8.97 (d, J = 6.6 Hz, 2H), 8.39 (d, J = 6.6 Hz, 2H), 8.02 (d, J = 8.7 Hz, 1 H), 7.95-7.94 (m, 2H), 7.25-7.17 (m, 2H), 7.10 (d, J = 7.9 Hz, 1 H), 7.04 (dt, J = 7.1 , 0.8 Hz, 1 H), 3.73 (t, J = 7.7 Hz, 2H), 3.56 (t, J= 6.6 Hz, 2H), 3.42 (br d, J = 11.2 Hz, 2H), 3.40-3.00 (m, 6H), 2.98 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 7.5 Hz, 2H), 2.78 (d, J= 4.6 Hz, 3H).
EXAMPLE 34 2-f2-F2-(4-Methylpiperazin-1-vπphenvnethyl>-6-pyridin-3-yl-3,4-dihydro-2H-isoquinolin-
1-one.
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 (MgSO4) and concentrated to an orange oil. Chromatography with 20% MeOH/ EtOAc then 20% MeOH/ EtOAc +0.5% NH4OH gave 0.223 g (75%) of Example 34 as a thick orange oil, the HCI salt had: mp 160-1700C; NMR (DMSO-d6) 11.17 (br s, 1 H), 9.25 (d, J = 1.7 Hz, 1 H), 8.88-8.83
(m, 2H), 8.08 (dd, J = 8.3, 5.6 Hz, 1 H), 7.98 (d, J = 8.7 Hz, 1 H), 7.85-7.81 (m, 2H), 7.25-7.17
(m, 2H), 7.10 (d, J = 7.1 Hz, 1 H), 7.05 (t, J = 7.5 Hz, 1 H), 3.72 (t, J = 7.7 Hz, 2H), 3.55 (t, J =
6.4 Hz, 2H), 3.42 (br d, J = 11.6 Hz, 2H), 3.24-3.00 (m, 6H), 2.96 (t, J = 6.4 Hz, 2H), 2.89 (t, J = 7.7 Hz, 2H), 2.78 (d, J= 4.6 Hz, 3H).
EXAMPLE 35 2-f2-r2-(4-Methylpiperazin-1-yl)phenvnethyl>-6-morpholin-4-yl-3,4-dihvdro-2H- isoquinolin-1-one.
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
(foams); NMR (DMSO-d6) 10.79 (br s, 1 H), 7.66 (d, J = 8.7 Hz, 1 H), 7.22-7.16 (m, 2H), 7.09- 7.01 (m, 2H), 6.84 (dd, J = 8.7, 2.1 Hz, 1 H), 6.72 (s, 1 H), 3.69-3.60 (m, 6H), 3.44-3.37 (m, 6H), 3.25-3.00 (m, 6H), 2.85-2.75 (m, 5H).
EXAMPLE 36
2-{2-r2-(4-Methylpiperazin-1-yl)phenvnethyl}-6-(morpholine-4-carbonyl)-3,4-dihvdro-2H- iso-quinolin-1-one.
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;
NMR (DMSO-d6) 10.85 (br s, 1 H), 7.86 (d, J = 7.9 Hz, 1 H), 7.32-7.27 (m, 2H), 7.23-7.16 (m,
2H), 7.09 (d, J = 7.5 Hz, 1 H), 7.04 (t, J = 7.5 Hz, 1 H), 3.69 (t, J = 7.7 Hz, 2H), 3.58-3.08 (m, 18H), 2.90-2.84 (m, 4H), 2.80-2.77 (m, 3H).
EXAMPLE 37 2-f2-r2-(4-Methylpiperazin-1-yl)phenyllethyl>-6-phenyl-1,2,3,4-tetrahydroisoquinoline.
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.
Na2SO4, filtered (Celite) and concentrated to yield 0.166 g (100%) of Example 37 as a waxy yellow solid, the HCI salt of which had: mp -170-190 0C; NMR (DMSO-d6) 11.76 (s, 1 H),
10.72 (s, 1 H), 7.63 (d, J = 7.5 Hz, 2H), 7.54-7.52 (m, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.34 (t, J =
7.5 Hz, 1 H), 7.29-7.24 (m, 3H), 7.17 (d, J= 7.1 Hz, 1 H), 7.12 (dt, J = 7.1 , 1.0 Hz, 1 H), 4.62 (br d, J = 15.4 Hz, 1 H), 4.34 (dd, J = 15.8, 8.3 Hz, 1 H), 3.75 (d, J= 7.5 Hz, 1 H), 3.60-3.00 (m,
15H), 2.80-2.78 (m, 3H).
EXAMPLE 38 2-f2-r2-(4-Methylpiperazin-1-yl)phenvnethyl>-5-phenyl-2,3-dihvdro-1H-isoindole.
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.
Na2SO4, filtered (Celite™) and concentrated to give a purple tinted oil. Chromatography with
10-20% MeOH/EtOAc yielded 0.101 g (41%) of Example 38 as a light red-brown oil, the dimaleate salt of which had: mp 50-600C (amorphous); NMR (DMSO-d6) 7.69 (d, J = 10.8 Hz, 1 H), 7.65-7.62 (m, 3H), 7.50-7.43 (m, 3H), 7.40-7.34 (m, 1 H), 7.31-7.25 (m, 2H), 7.20 (d, J =
7.1 Hz, 1 H), 7.15 (t, J = 7.5 Hz, 1 H), 6.01 (s, 4H), 3.63-2.90 (br M, 16H), 2.85 (s, 3H). EXAM PLE 39 2-f2-r2-(4-Methylpiperazin-1-yl)phenyllethyl>-2,3-dihvdro-1H-isoindol-5-ylamine.
This material was prepared following the same general procedure described in Example 38: Substituting Example 24 for Example 20, yield 24%: NMR (CDCl3) 7.24-7.22 (m, 1 H), 7.19-7.10 (m, 2H), 7.05-7.03 (m, 1 H), 7.01-6.96 (m, 1 H), 6.54-6.51 (m, 2H), 3.95 (d, J = 3.3 Hz, 4H), 3.59 (br s, 2H), 2.95-2.91 (m, 8H), 2.59 (br s, 4H), 2.35 (s, 3H).
PREPARATION 1 1 -{2-r2-(4-Methylpiperazin-1 -yl)phenyllethyl}-1 ,3-dihydroimidazol-2-one. A solution of PP5 (3.37 g, 15.36 mmol) and Et3N (4.3 mL, 30.9 mmol) in 50 mL
CH2CI2 was added dropwise over 30 min to a O0C solution of diphosgene (0.95 mL, 7.70 mmol) in 50 mL CH2CI2. After stirring 30 min, aminoacetaldehyde dimethyl acetal (1.7 mL, 15.6 mmol) in 20 mL CH2CI2 was added and stirring was continued for an additional 1.5hrs. The reaction was washed with water and brine, dried (MgSO4) and concentrated to afford 4.45g (83%) of 1-(2,2-dimethoxyethyl)-3-{2-[2-(4-methylpiperazin-1-yl)phenyl]ethyl}-urea as a thick orange oil. 1N HCI (20 mL) was added and the mixture was stirred for 2h at ambient temperature. NaHCO3 was carefully added until the solution was basic. After concentration to dryness, MeOH was added. Drying over Na2SO4 and re-concentration removed most of the inorganic salts. Chromatography with 20:80:1 and 10:40:1 MeOH/EtOAc/NH4OH gave PP1 as a light orange oil: NMR (CDCI3) 9.57 (br s, 1 H) 7.21-7.09 (m, 3H), 7.02 (dt, J = 7.3, 1.2 Hz, 1 H), 6.16 (t, J = 2.5 Hz, 1 H), 5.92 (t, J = 2.5 Hz, 1 H), 3.85 (t, J= 7.5 Hz, 2H), 2.99 (t, J = 7.3 Hz, 2H), 2.95-2.90 (m, 4H), 2.63 (br s, 4H), 2.36 (s, 3H); 13C NMR (CDCI3) 154.88, 152.13, 134.18, 130.59, 127.90, 124.69, 121.03, 111.85, 107.94, 55.90, 52.97, 46.31 , 44.29, 31.46; MS- PH+ 287.2. PREPARATION 2
1-{2-r2-(4-Methylpiperazin-1-yl)pyridin-3-vπethyl>1.3-dihvdroimidazol-2-one.
Essentially the same procedure as described in Preparation 1 was used in the synthesis of PP2: Using PP6B, yield 88%: NMR (MeOH-d4) 8.19 (m, 1 H), 7.64 (m, 1 H), 7.08 (m, 1 H), 6.27 (d, J = 2.9 Hz, 1 H), 6.20 (d, J = 2.9 Hz, 1 H), 3.89 (t, J = 7.3 Hz, 2H), 3.65-3.10 (m, 8H), 3.00 (t, J= 7.1 Hz, 2H), 2.96 (s, 3H).
PREPARATION 3
1 -( 1 -Methyl-2-r2-(4-methylpiperazin-1 -yl)phenyl1ethyl}-1 ,3-dihydroimidazol-2- one. PP12 (0.31 g, 2.36mmol) in CH2Cl2 (5 mL) was added to a solution of PP6A (0.53g, 2.27 mmol) in CH2CI2 (15 mL) and stirred overnight. Following concentration, the intermediate urea was stirred for 4hrs with 1 N HCI (25 mL). The mixture was concentrated, then redissolved in
MeOH and re-concentrated to remove residual HCI. Excess NH4OH was added and the mixture was concentrated again and loaded onto silica gel. Chromatography using 20% MeOH/ CH2CI2 gave a yellow semi-solid material which was dissolved in CH2CI2 and filtered (Celite™) to remove inorganic impurities. Concentration gave 0.37g, 54% of PP3 as a yellow foam: NMR (CDCl3) 9.80 (s, 1 H), 7.21-7.15 (m, 1 H), 7.12-7.09 (m, 2H), 7.05-7.00 (m, 1 H), 6.55 (t, J= 2.5 Hz, 1 H), 6.27 (t, J= 2.5 Hz, 1 H), 4.55-4.50 (sym. mult., 1 H), 3.18-3.08 (m, 3H), 3.08-2.95 (m, 2H), 2.95-2.85 (m, 1 H), 2.80-2.70 (m, 5H), 1.15 (d, J = 7.1 Hz, 3H); ); 13C NMR (CDCI3) 153.63, 151.03, 134.96, 131.56, 128.24, 125.49, 121.65, 109.10, 108.09, 55.62, 53.76, 49.93 (broad), 48.02,43.02, 38.55, 20.52.
PREPARATION 4
Syntheses of the compounds below use the indicated compound in essentially the same procedure as described in Preparation 3:
A. 4-Methyl-1 -{2-r2-(4-methyl-piperazin-1 -vD-phenyli-ethylM ,3-dihvdro- imidazol-2-one. Using PP13 in place of PP12; yield 64%: NMR (MeOH-d4) 7.25-7.10 (m, 4H), 5.89 (d, J = 1.2 Hz, 1 H), 3.78 (t, J = 7.1 Hz, 2H), 3.38 (br s, 4H), 3.07 (t, J = 5.0 Hz, 4H), 2.96 (t, J = 7.5 Hz, 2H), 2.91 (s, 3H), 1.93 (d, J= 1.3 Hz, 3H).
B. 1-(2-r3-(4-Methylpiperazin-1-yl)pyridin-2-vnethyl}-1,3-dihvdroimidazol-2- one. Using PP6C, yield 32%: NMR (MeOH-d4) 8.3 (dd, J=1.7,5.0 Hz, 1 H), 7.62,(dd, J = 1.2, 7.9 Hz, 1 H), 7.28(dd, J = 8.0, 5.0 Hz, 1 H), 6.40 (d, J = 2.9 Hz, 1 H), 6.10 (d, J = 2.5 Hz, 1 H), 3.98 (t, J = 7.0 Hz, 2H), 3.5-3.4 (m, 4H), 3.28 (m, 2H), 3.20 (t, J = 7.6 Hz, 2H), 3.11 (t, J = 5.2Hz, 2H), 2.95 (s, 3H).
C. 1-r2-(4-Methyl-3.4.5.6-tetrahvdro-2H-ri.2'1bipyrazinyl-3'-yl)ethvn-1.3- dihvdroimidazol-2-one. Using PP7, yield 48%: NMR (DMSO-d6) 9.86 (s, 1 H), 8.21 (d, J = 2.5 Hz, 1 H), 8.15 (d, J = 2.5 Hz, 1 H), 6.28 (t, J = 2.5 Hz, 1 H), 6.23 (t, J = 2.5 Hz, 1 H), 3.87 (t, J = 7.5 Hz, 2H), 3.40-3.00 (mult with t (J = 2.7 Hz) @ 3.03, 10H total), 2.66 (br s, 3H); 13C NMR (DMSO-d6) 154.06, 147.92, 140.23, 138.33, 112.33, 107.92, 53.40, 47.50, 41.26, 33.39.
PREPARATION 5 2-r2-(4-methylpiperazin-1-yl)phenvπethylamine.
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 Na2SO4 was added to dry the mixture. Filtration through Celite™ with EtOAc rinse and concentration gave 9.72 g (quant) of PP5 as an orange oil: NMR
(CDCI3) 7.20-7.11 (m, 3H), 7.03 (dt, J = 7.3, 1.4 Hz, 1 H), 2.97 (t, J = 7.1 Hz, 2H), 2.90 (t, J =
4.8 Hz, 4H), 2.80 (t, J= 6.8 Hz, 2H), 2.55 (br s, 4H), 2.33 (s, 3H), 1.89 (br s, 2H); 13C NMR (CDCI3) 152.07, 135.41 , 130.25, 127.38, 124.46, 120.87, 55.90, 52.95, 46.37, 43.07, 35.24.
PREPARATION 6
Syntheses of the compounds below use the indicated compound in essentially the same procedure as described in Preparation 5:
A. 1 -Methyl-2-r2-(4-methylpiperazin-1 -vOphenyliethylamine. Using PP9, yield 60%, yellow oil: NMR (CDCI3) 7.20-7.10 (m, 3H), 7.03 (t, J = 7.5 Hz, 1 H), 3.24-3.19 (m,
1 H), 2.94-2.84 (m, 4H), 2.73(dd, J = 12.9, 5.4 Hz, 1 H), 2.65-2.40 (m, 5H), 2.33 (s, 3H), 1.08 (d, J= 6.6 Hz, 3H); 13C NMR (CDCI3) 152.29, 135.85, 130.80, 127.36, 124.47, 121.09, 55.97, 52.98, 48.27, 46.43, 42.17, 24.09.
B. 2-r2-(4-Methylpiperazin-1-yl)pyridin-3-yllethylamine. Using PP11A, yield 50%, yellow oil: NMR (CDCI3) 8.13-8.11 (m, 1 H), 7.39-7.37 (dd, J = 7.5, 2.1 Hz, 1 H), 6.84
(dd, J = 7.5, 2.5 Hz, 1 H), 3.11-3.07 (m, 4H), 2.94 (t, J = 7.1 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 2.50 (br S, 4H), 2.28 (s, 3H); 13C NMR (CDCI3) 162.2, 145.9, 138.0, 127.3, 118.5, 55.5, 50.6, 46.4, 42.1 , 35.1.
C. 2-r3-(4-Methylpiperazin-1-yl)pyridin-2-vπethylamine. Using PP11 B, orange oil, yield 56%: NMR (CDCI3) 8.24 (dd, J = 4.5, 1.2 Hz, 1 H), 7.34 (dd, J = 8.3, 1.7 Hz,
1 H), 7.08 (dd, J = 7.9, 4.6 Hz, 1 H), 3.45 (s, 2H), 3.13 (t, J= 6.6 Hz, 2H), 2.97 (t, J= 6.6 Hz, 2H), 2.90 (t, J = 4.8 Hz, 4H), 2.57 (br s, 4H), 2.34 (s, 3H).
PREPARATION 7 2-(4-Methyl-3.4,5,6-tetrahvdro-2H-π,2'1bipyrazinyl-3'-yl)ethylamine. NaBH4 (0.069g, 1.82 mmol) dissolved in EtOH (-10 mL) was added dropwise over 1 min to a rapidly stirring solution of PP10 (0.91 g, 3.65 mmol) in 100 mL EtOH. After 5 min., water was added and the reaction was concentrated to dryness. The residue was dissolved in CH2CI2 and loaded onto silica gel. Chromatography with 5-10% MeOH/ CH2CI2 gave 0.58 g (63%) of 4-methyl-3'-(2-nitroethyl)-3,4,5,6-tetrahydro-2H-[1 ,2I]bipyrazinyl as a red oil which slowly solidified to a waxy red solid: NMR (CDCI3) 8.09 (d, J= 2.5 Hz, 1 H), 8.04 (d, J = 2.5 Hz, 1 H), 4.88 (t, J = 6.6 Hz, 2H), 3.44 (t, J = 6.6 Hz, 2H), 3.21 (t, J = 5.0 Hz, 4H), 2.58 (t, J = 4.6 Hz, 4H), 2.35 (s, 3H). 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 CH2CI2 and filtered through Celite™ to remove residual inorganic impurities. Re-concentration gave 0.4Og (79%) of PP7 as an orange oil : NMR (CDCI3) 8.07-8.05 (m, 2H), 3.21-3.17 (m, 6H), 2.93 (t, J = 6.5 Hz, 2H), 2.55 (br s, 4H), 2.40- 2.20 (singlet @2.34 overlapping a multiplet, 5H total); 13C NMR (CDCI3) 157.94, 148.78, 139.60, 136.80, 55.25, 49.74, 46.39, 40.36, 36.13.
PREPARATION 8
1-Methyl-4-r2-(2-nitrovinyl)phenyllpiperazine. PP57 (10.0 g, 48.96 mmol), ammonium acetate (1.53 g, 19.85 mmol) and nitromethane (8.0 mL, 147.7 mmol) in acetic acid (40 mL) were refluxed for 2hrs and concentrated. Water and EtOAc were added and the mixture was carefully neutralized with portion wise addition of K2CO3. The mixture was extracted into EtOAc (3x125 mL) and the combined extracts were washed with brine, dried (MgSO4) and concentrated to yield 10.69 g (88%) of PP8 as a thick orange oil which solidified upon evacuation: NMR (CDCI3) 8.34 (d, J = 13.7 Hz, 1 H), 7.65 (d, J = 13.7 Hz, 1 H), 7.47-7.39 (m, 2H), 7.12-7.05 (m, 2H), 2.99 (t, J = 4.8 Hz, 4H), 2.63 (br s, 4H), 2.37 (s, 3H); 13C NMR (CDCI3) 154.01 , 137.21 , 136.72, 133.10, 124.56, 123.71 , 120.03, 55.34, 53.15, 46.13.
PREPARATION 9 1-Methyl-4-r2-(2-nitropropenyl)phenyllpiperazine.
PP9 was prepared using essentially the same procedure described in Preparation 8 using nitroethane instead of nitromethane, yield 85%. A portion recrystallized from ether had: mp 90.5-91.50C; NMR (CDCI3) 8.25 (s, 1 H), 7.36 (dt, J = 7.7, 1.4Hz, 1 H), 7.29 (d, J = 8.3 Hz, 1 H), 7.8-7.04 (m, 2H), 2.97 (t, J= 4.8 Hz, 4H), 2.58 (br s, 4H), 2.42 (d, J = 0.8 Hz, 3H), 2.35 (s, 3H); 13C NMR (CDCI3) 153.26, 146.97, 132.16, 131.21 , 130.29, 126.34, 122.59, 118.88, 55.50, 52.83, 46.23, 14.41.
PREPARATION 10
4-Methyl-3'-(2-nitrovinyl)-3,4,5,6-tetrahvdro-2H-ri .2'1bipyrazinyl.
Potassium t-butoxide (0.11g, 0.98 mmol) was added to an ice cold mixture of PP14 (3.34g, 16.19 mmol), THF (10 mL), nitromethane (1.4 mL, 25.85 mmol) and t-butanol (9.75 mL, 101.9 mmol) . After stirring overnight at rt, the reaction was concentrated and partitioned between water and EtOAc. The organics were washed with brine, dried (MgSO4) and concentrated to give 3.67 g of -80% pure 1-(4-methyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-
3'-yl)-2-nitroethanol which was used without purification: NMR (CDCI3) 8.26 (d, J = 2.5 Hz, 1 H), 8.17 (d, J = 2.5 Hz, 1 H), 5.61 (dd, J= 8.3, 3.3 Hz, 1 H), 4.95 (dd, J= 12.4, 3.3 Hz, 1 H),
4.59 (dd, J = 12.4, 8.3 Hz, 1 H), 3.38-3.32 (m, 2H), 3.19-3.14 (m, 2H), 2.65-2.52 (m, 4H), 2.34
(s, 3H). This material was dissolved in CH2CI2 (70 mL), treated with acetic anhydride (1.45 mL, 15.37 mmol) and DMAP (0.084 g, 0.69 mmol) and stirred overnight at rt. The reaction was concentrated, made basic with sat. NaHCO3 and extracted into EtOAc (4x150 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated to a dark red oil (3.2 g). Chromatography with 5-10% MeOH/CH2CI2 gave a red oil which was redissolved in ether and filtered (Celite™) to remove a dark brown particulate. Concentration of the filtrate gave 2.37 g (59%) of PP10 as a waxy red solid: mp 74-77°C; NMR (CDCI3) 8.17 (d, J = 2.5
Hz, 1H), 8.11 (d, J= 2.5 Hz, 1 H), 7.94 (AB quartet, Δu = 19.1 Hz, J = 13.0 Hz, 2H), 3.36 (t, J =
5.0 Hz, 2H), 2.57 (t, J = 4.8 Hz, 2H), 2.33 (s, 3H); 13C NMR (CDCI3) 158.09, 143.80, 140.72, 137.43, 135.34, 133.98, 54.91 , 50.54, 46.21.
PREPARATION 11
The following compounds were prepared in essentially the same manner as described in Preparation 10:
A. 1-Methyl-4-r3-(2-nitro-vinyl)-pyridin-2-vn-piperazine. Using 2-(4- methylpiperazin-1-yl)pyridine-3-carbaldehyde, a yield of 84% obtained: NMR (CDCI3) 8.34-
8.32 (m, 1 H), 8.06 (d, J = 13.7 Hz, 1 H), 7.67-7.65 (dd, J = 7.9, 2.1 Hz, 1 H), 7.60 (d, J= 13.7 Hz, 1 H), 6.92 (dd, J= 7.5, 5.0 Hz, 1 H), 3.30 (br s, 4H), 2.60 (br s, 4H), 2.36 (s, 3H).
B. 1-Methyl-4-r2-(2-nitrovinyl)pyridin-3-yl1piperazine. Using PP58, yield: 92%: NMR (CDCI3) 8.33-8.27 (m, 3H), 8.01 (d, J= 12.9 Hz, 1 H), 7.42 (dd, J= 8.3, 1.7 Hz, 1 H), 7.30 (dd, J = 8.3, 4.6 Hz, 1 H), 3.01 (t, J = 4.8 Hz, 4H), 2.66 (br s, 4H), 2.38 (s, 3H).
PREPARATION 12
Aminoacetaldehyde dimethyl acetal isocyanate.
Aminoacetaldehyde dimethyl acetal (4.12 g, 39.2 mmol) and triethylamine (11.5 mL,
82.5 mmol) in CH2CI2 (100 mL) were added dropwise over 10 min to an ice cold solution of triphosgene (3.95g, 13.3 mmol) in CH2CI2 (100 mL). After stirring at rt for 20 min, the mixture was refluxed for 20 min, cooled and stirred again for 3.5 hr at rt. The reaction mixture was washed with water and dried (Na2SO4). Concentration gave a mixture of oil and solid which was rinsed with ether. The rinse was concentrated to give 3.0 g (58%) of PP12 as a tan oil:
MS - 132.0 (PH+) ; NMR (CDCI3) 4.45 (t, J = 5.4 Hz, 1 H), 3.38 (s, 6H), 3.28 (d, J = 5.4 Hz, 2H).
PREPARATION 13
1 ,1 -Dimethyloxy-2-propanamine isocvanate.
PP13 was prepared using the same procedure described in Preparation 12, substituting 1 ,1-dimethyloxy-2-propanamine for aminoacetaldehyde dimethyl acetal: Yield following Kugelrohr distillation - 38.8%: NMR (CDCI3) 4.13 (d, J = 5.8 Hz, 1 H), 3.64-3.55 (m, 1 H), 3.41 (s, 3H), 3.40 (s, 3H), 1.19 (d, J = 7.1 Hz, 3H).
PREPARATION 14 4-Methyl-3,4,5,6-tetrahvdro-2H-π,2'lbipyrazinyl-3'-carbaldehvde.
S-Chloro-pyrazine^-carb-aldehyde (Turck, et al., Synthesis 1988, 881-4) (6.01 g, -40 mmol), N-methylpiperazine (6.6 mL, 59.4 mmol) and K2CO3 (8.3g, 60.0 mmol) were refluxed for 1h in dioxane (250 mL). After cooling, the mixture was filtered and concentrated to an orange oil. This was dissolved in EtOAc (500 mL) and washed with water (4x150 mL) and brine, dried (MgSO4) and concentrated. Chromatography with 5% MeOH/ CH2CI2 gave 3.34 g (40%) of PP14 as a dark red oil : NMR (CDCI3) 9.94 (s, 1 H), 8.18 (d, J= 2.1 Hz, 1 H), 8.08 (d, J = 2.1 Hz, 1 H), 3.59 (t, J= 5.2 Hz, 4H), 2.53 (t, J = 5.0 Hz, 4H), 2.32 (s, 3H).
PREPARATION 15 6-Bromoisochroman.
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 (Celite™) and concentrated. The residue was dissolved in EtOAc and washed with sat. NaHCO3 and brine, dried (MgSO4) and concentrated to yield 2.24 g (87%) of isochroman-6-ylamine as a crystalline pink tinted solid: NMR (CDCI3) 6.75 (d, J = 7.9 Hz, 1 H), 6.50 (dd, J = 7.9, 2.5 Hz, 1 H), 6.44 (d, J = 2.5 Hz, 1 H), 4.66 (s, 2H), 3.91 (t, J = 5.8 Hz, 2H), 3.51 (br s, 2H), 2.74 (t, J= 5.8 Hz, 2H); 13C NMR (CDCI3) 144.91 , 134.34, 125.53, 125.26, 115.19, 113.67, 68.03, 65.56, 28.67.
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
5 min. and the mixture was stirred 15 additional minutes to give a yellow solution. This solution was pipetted over -10 min to an ice cold solution of copper (I) bromide in 48% HBr
(10 mL). The resulting dark brown mixture was stirred for 30 min and then diluted with water
(10OmL), producing an orange precipitate. This was filtered off and treated with sat. NaHCO3 and extracted into EtOAc. The extract was washed with brine, dried (MgSO4) and concentrated to an orange oil (2.6 g). Chromatography using 10% EtOAC/hexanes yielded
2.37 g (77%) of PP15 as a light yellow oil: NMR (CDCI3) 7.26-7.23 (m, 2H), 6.83 (d, J = 8.7
Hz, 1 H), 4.68 (s, 2H), 3.92 (t, J = 5.5 Hz, 2H), 2.81 (t, J = 5.6 Hz, 2H); 13C NMR (CDCI3)
135.73, 134.05, 131.88, 129.29, 126.32, 120.12, 67.80, 65.18, 28.29. PREPARATION 16
5-Bromo-3H-isobenzof uran-1 -one.
PP16 was prepared from 5-amino-3H-isobenzofuran-1-one (Tetrahedron, 54 (1998), 7485-96) following the general procedure described in Step 2 of Preparation 15, yield 63%: mp 156-157.5°C; NMR (CDCI3) 7.76 (d, J = 8.7 Hz, 1 H), 7.67-7.64 (m, 2H), 5.28 (s, 2H); 13C NMR (CDCI3) 170.23, 148.42, 132.96, 129.53, 127.29, 125.80, 124.97.
PREPARATION 17 6-Bromo-3H-isobenzof uran-1 -one. Prepared using the same general procedure described in Preparation 15 using 6- amino-3H-isobenzofuran-1-one in place of 5-amino-3H-isobenzofuran-1-one, yield 91 %: mp 93-94°C; NMR (CDCI3) 8.03 (d, J = 1.2 Hz, 1 H), 7.77 (dd, J = 8.3., 1.7 Hz, 1 H), 7.36 (dd, J = 8.3, 0.8 Hz, 1 H), 5.26 (s, 2H). PREPARATION 18
2-(4-Bromo-phenyl)-5-methyl-ri,3,41oxadiazole.
5-(4-Bromo-phenyl)-1 H-tetrazole (0.50 g, 2.22 mmol) and acetic anhydride (2.5 mL) were refluxed for 16 hrs and concentrated. The residue was triturated with hexanes to yield
0.245 g (47%) of PP18 as white crystals: NMR (DMSO-d6) 7.67 (AB quartet, Δu = 39.0 Hz, J = 8.7 Hz, 4H), 2.52 (s, 3H); 13C NMR (DMSO-d6) 164.8, 163.9, 133.2, 128.9, 126.0, 123.4,
1 1.3.
PREPARATION 19
5-(4-lodophenyl)-3-methyl-H ,2,41oxadiazole.
4-lodobenzoyl chloride (1.1 g, 4.14 mmol) was added portion wise to a solution of N- hydroxyacetamidine (see EP 0283162B1 , 0.18 g, 2.43 mmol) in pyridine (1 mL) and the mixture was refluxed for 16 hrs and cooled. The reaction was dissolved in CH2CI2 and washed with water and brine, dried (MgSO4) and concentrated to give an orange solid (1.0 g). Chromatography with 10% EtOAc/ hexanes yielded 0.412 g (59%) of PP19 as white crystals: NMR (MeOH-d4) 7.94 (d, J= 8.7 Hz, 2H), 7.81 (d, J = 8.7 Hz, 2H), 2.40 (s, 3H). PREPARATION 20
5-Bromo-2-(1 -methoxy-1 ■me.hylethvDpyridine.
Sodium hydride (0.467g, 11.68 mmol) was added portion wise to a solution of 2-(5- bromopyridin-2-yl)-propan-2-ol (0.84 g, 3.89 mmol) and methyl iodide (0.72 mL, 11.68 mmol) in THF (20 mL). After stirring overnight at rt, water was carefully added and the mixture extracted into EtOAc. The extract was washed with brine, dried (MgSO4) and concentrated to yield 1.07 g of an orange oil. Chromatography with 10% EtOAc/ hexanes gave 0.68 g (76%) of PP20: NMR (CDCI3) 8.41 (d, J= 2.5 Hz, 1 H), 7.60 (dd, J = 8.7, 2.5 Hz, 1 H), 7.28 (m, 1 H), 2.98 (S, 3H), 1.35 (s, 6H); 13C NMR (CDCI3) 164.09, 149.68, 139.01 , 121.51 , 118.93, 78.55, 50.88, 26.48. PREPARATION 21
5-Bromo-2-(1-methoxycvclopentyl)pyridine.
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 (CDCI3)
8.53 (d, J= 2.5 Hz, 1 H), 7.73 (dd, J = 8.7, 2.5 Hz, 1 H), 7.37-7.35 (m, 1 H), 3.01 (s, 3H), 2.02- 1.99 (m, 4H), 1.81-1.68 (m, 4H); 13C NMR (CDCI3) 162.26, 149.85, 139.09, 122.67, 119.08,
90.27, 51.46, 36.62, 23.89.
PREPARATION 22 1-r2-(4-Methylpiperazin-1-yl)pyridin-3-vnimidazolidin-2-one.
PP24 (0.35 g, 1.82 mmol) and 2-chloroethyl isocyanate (0.16 ml_, 1.87 mmol) were stirred in THF (20 mL) at rt for 72 hrs. The crude urea was concentrated, redissolved in DMF (3ml_) and treated with 60% sodium hydride (0.08Og, 2.00 mmol). The initially purple solution turned dark green. After 30 min. stirring at rt, the reaction was concentrated and loaded onto silica gel. Chromatography using first 20% MeOH/ EtOAc then 20% MeOH/ EtOAc with 1 % NH4OH gave 0.33 g (69%) of PP22 as a light orange solid: NMR (DMSO-d6) 8.05 (dd, J= 4.6, 1.7 Hz, 1 H), 7.53 (dd, J = 7.9, 1.9 Hz, 1 H), 6.93 (dd, J = 7.9, 4.8 Hz, 1 H), 6.79 (s, 1 H), 3.67 (t, J =7.1 Hz, 2H), 3.37 (t, J= 7.9 Hz, 2H), 3.19 (br s, 4H), 2.62 (br s, 4H), 2.31 (s, 3H); 13C NMR (DMSO-d6) 160.67, 156.72, 145.14, 136.99, 127.02, 1 17.95, 55.59, 54.82, 47.58, 45.58, 44.66, 38.44.
PREPARATION 23
The following materials were prepared according to the general procedure described in Preparation 22, with the noted changes: A. 1-(2-f2-(4-Methylpiperazin-1-yl)phenvnethyl>imidazolidin-2-one. Using
PP5 in place of PP24. The urea intermediate was prepared in CH2CI2 instead of THF, then cyclized using t-BuOK in place of sodium hydride in THF instead of DMF. Yield 27%: MS (AP/CI) 289.3 (MH+); NMR (CDCI3) 7.21-7.00 (m, 4H); 3.50-3.40 (m, 2H), 3.50-3.25 (m, 2H), 2.97-2.91 (m, 4H), 2.90-2.80 (m, 4H), 2.60 (br s, 4H), 2.37-2.34 (m, 3H). B. 1-r2-(4-Me.hylpiperazin-1-yl)benzyllimidazolidin-2-one. Using PP25 in place of PP24. The urea intermediate was prepared in toluene, concentrated and cyclized with NaH in THF, yield 26%, yellow oil: MS (AP/CI) 275.2 (MH+); NMR (CDCI3) 7.26-7.19 (m, 2H), 7.10-7.03 (m, 2H), 4.81 (s, 1 H), 4.45 (s, 2H), 3.40-3.35 (m, 2H), 3.29-3.24 (m, 2H), 2.90 (t, J= 4.8 Hz, 4H), 2.56 (br s, 4H), 2.33 (s, 3H). C. 1-{2-r2-(4-Methylpiperazin-1-yl)phenyllethyl}tetrahvdropyrimidin-2-one.
The urea inter-mediate was prepared using PP5 in place of PP24, 3-chloropropyl isocyanate in place of 2-chloroethyl isocyanate in CH2CI2 instead of THF, then cyclized using t-BuOK in place of sodium hydride. Yield 39%, yellow solid: NMR (CDCI3) 7.23-7.01 (m, 4H), 4.63 (br s, 1 H), 3.55-3.51 (m, 2H), 3.25-3.21 (m, 2H), 3.14 (t, J = 5.8 Hz, 2H), 2.93-2.86 (m, 6H), 2.57 (br s, 4H), 2.34 (s, 3H), 1.83 (t, J = 5.4 Hz, 2H); 13C NMR (CDCI3) 156.20, 152.02, 135.25, 130.93, 127.44, 124.41 , 120.71 , 56.02, 53.08, 49.05, 46.44, 46.22, 40.75, 29.85, 22.53.
PREPARATION 24
2-(4-Methylpiperazin-1-vQpyridin-3-ylamine. PP26 (0.50 g, 2.25 mmol), ammonium formate (1.00 g, 15.85 mmol) and 10% Pd on carbon (0.050 g) in MeOH (20 mL) were stirred for 1 h at rt, then filtered (Celite™) and concentrated. The residue was dissolved in EtOAc and washed with aq. K2CO3 and brine, dried (MgSO4) and concentrated to yield 0.35 g (81 %) of PP24 as a purple oil that was used without purification: NMR (CDCI3) 7.77 (dd, J = 4.6, 1.7 Hz, 1 H), 6.90 (dd, J = 7.5, 1.7 Hz, 1 H), 6.79 (dd, J = 7.9, 5.0 Hz, 1 H), 3.71 (br s, 2H), 3.15 (br s, 4H), 2.57 (br s, 4H), 2.34 (s, 3H).
PREPARATION 25 2-(4-Methylpiperazin-1-yl)benzylamine.
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.
Concentration gave the crude oxime which was slurried in THF (20 mL) and added to a stirred slurry of LAH (0.19 g, 5.01 mmol) in 10 mL THF. The mixture was refluxed for 3 hrs, cooled and carefully quenched with excess sodium sulfate decahydrate. Following quenching, this mixture was dried over anh. Na2SO4 , filtered (Celite™) and concentrated to yield 0.47 g,
(93%) of PP25 as a yellow oil: NMR (CDCI3) 7.27-7.19 (m, 2H), 7.12 (dd, J = 7.9, 1.2 Hz, 1 H),
7.06 (dt, J = 7.5, 1.2 Hz, 1 H), 3.87 (s, 2H), 2.93 (t, J = 4.8 Hz, 2H), 2.57 (br s, 4H), 2.33 (s,
3H), 2.16 (br s, 2H). PREPARATION 26
1 -Methyl -4-(3-nitropyridin-2-yl)piperazine.
2-Chloro-3-nitropyridine (2.Og, 12.6 mmol), 1-methylpiperazine (2.1 mL, 18.9 mmol) and K2CO3 (3.5 g, 25.3 mmol) were refluxed overnight in water (50 mL). Following cooling, the mixture was extracted with EtOAc (2x75 mL). The extracts were washed with brine, dried (MgSO4) and concentrated to yield 2.63 g, 94%) of PP26 as an orange oil: MS (AP/CI) 223.0 (MH+); NMR (CDCI3) 8.29 (dd, J = 4.6, 1.7 Hz, 1 H), 8.08 (dd, J = 7.9, 1.7 Hz, 1 H), 6.70 (dd, J = 7.9, 4.6 Hz, 1 H), 3.45 (t, J = 5.2 Hz, 4H), 2.48 (t, J = 5.0 Hz, 4H), 2.31 (s, 3H); 13C NMR (CDCI3) 152.96, 151.96, 135.82, 133.17, 113.53, 54.92, 48.13, 46.36.
PREPARATION 27 1-{2-r2-(4-Methylpiperazin-1-yl)phenyllethyl>-1 ,3-dihydrobenzoimidazol-2-one.
Triphosgene (0.065 g, 0.219 mmol) in 5 mL CH2CI2 was added over 1 min. to an ice cold solution of PP29 (0.197 g, 0.635 mmol) and triethylamine (0.18 mL, 1.29 mmol) in
CH2CI2 (10 mL). The bath was removed and the mixture was stirred for 1 hr at rt and then concentrated. The residue was dissolved in EtOAc and washed with aq. K2CO3 and brine, dried (MgSO4) and concentrated to a sticky red foam. Chromatography using 10-30% MeOH/
EtOAc gave 0.113 g (53%) of PP27 as a light pink solid: mp 172.5-173.5°C; NMR (CDCI3)
9.21 (br s, 1 H), 7.28-7.19 (m, 2H), 7.12 (d, J = 7.1 Hz, 1 H), 7.09-7.00 (m, 4H), 6.97-6.94 (m,
1 H), 4.12-4.08 (sym. mult., 2H), 3.09 (t, J = 7.7 Hz, 2H), 2.95-2.85 (m, 4H), 2.66 (br s, 4H),
2.39 (s, 3H); 13C NMR (CDCI3) 155.18, 152.08, 134.35, 130.84, 130.67, 128.08, 127.85, 124.94, 121.48, 121.37, 121.16, 112.50, 109.44, 108.36, 55.65, 52.93, 46.16, 42.27, 30.53.
PREPARATION 28 The following materials were prepared according to the general procedure described in Preparation 27, with the noted changes:
A. 3-f2-r2-(4-Methylpiperazin-1-yl)phenvnethyl}-1 ,3-dihvdroimidazof4,5- blpyridin-2-one. Using PP30A instead of PP29. Yield 61 %, tan foam: NMR (CDCI3) 9.91 (br s, 1 H), 8.02 (dd, J = 8.7, 1.2 Hz, 1 H), 7.24-7.20 (m, 2H), 7.16-7.11 (m, 1 H), 7.07 (dd, J= 7.9, 1.2 Hz, 1 H), 7.01-6.93 (m, 2H), 4.28-4.24 (sym. mult., 2H), 3.16 (t, J= 7.7 Hz, 2H), 2.94 (t, J = 4.8 Hz, 4H), 2.59 (br s, 4H), 2.33 (s, 3H).
B. 3-{2-r3-(4-Methyl-piperazin-1 -yl)-pyridin-2-vn-ethyl}-1,3-dihvdro- imidazor4,5-blpyridin-2-one Using PP30B in place of PP29. Yield 65%: NMR (CDCI3) 9.95 (br s, 1 H), 8.26 (dd, J
= 4.4, 1.6 Hz, 1 H), 8.00 (dd, J = 4.4, 1.5 Hz, 1 H), 7.26 (dd, J= 7.6, 1.4 Hz, 1 H), 7.25-7.21 (m, 1 H), 7.06 (dd, J = 6.0, 4.8 Hz, 1 H), 6.94 (dd, J = 8.0, 5.2 Hz, 1 H), 4.43 (t, J = 7.6 Hz, 2H), 3.34 (t, J = 7.6 Hz, 2H), 2.83 (m, 4H), 2.70-2.61 (m, 2H), 2.44 (br s, 4H), 2.59 (s, 3H).
PREPARATION 29 N-{2-r2-(4-Methylpiperazin-1-yl)phenyllethyl}benzene-1,2-diamine.
PP31 (0.236 g, 0.693 mmol) and 10% Pd on carbon (25 mg) in EtOH (10 mL) were pressurized to 47 psi with hydrogen gas and shaken for 3hrs at rt. Filtration (Celite™) and concentration gave 0.197 g (92%) of PP29 as a red oil: NMR (CDCI3) 7.26-7.15 (m, 3H), 7.08 (dt, J = 7.3, 1.5 Hz, 1 H), 6.84 (dt, J = 7.5, 1.5 Hz, 1 H), 6.79 (dd, J = 7.9, 1.3 Hz, 1 H), 6.72- 6.65 (m, 2H), 3.39 (t, J = 7.3 Hz, 2H), 3.26 (br s, 1 H), 3.02 (t, J = 7.3 Hz, 2H), 2.96 (t, J = 4.8 Hz, 4H), 2.60 (br s, 4H), 2.38 (s, 3H).
PREPARATION 30
The following materials were prepared according the general procedure described in Preparation 29, with the noted changes: A. N-{2-r2-(4-Methylpiperazin-1-yl)phenyllethyl}pyridine-2,3-diamine. Using
PP32A instead of PP31 , Raney nickel instead of Pd on C and MeOH instead of EtOH. Yield 97%, purple foam: NMR (CDCI3) 7.72 (dd, J= 5.4, 1.5 Hz, 1 H), 7.21 (d, J = 7.9 Hz, 1 H), 7.18- 7.15 (m, 1 H), 7.14 (dd, J = 7.1 , 1.5 Hz, 1 H), 7.09 (dd, J = 7.9, 1.2 Hz, 1 H), 7.02 (dt, J = 7.3, 1.2 Hz, 1 H), 6.76 (dd, J = 7.5, 1.3 Hz, 1 H), 6.46 (dd, J = 7.5, 5.2 Hz, 1 H), 4.25 (br t, J = 5.2 Hz, 1 H), 3.71-3.65 (sym. mult, 2H), 3.03 (br s, 2H), 3.00 (t, J = 6.8 Hz, 2H), 2.90 (t, J = 4.8 Hz, 4H), 2.50 (br s, 4H), 2.30 (s, 3H); 13C NMR (CDCI3) 152.20, 150.60, 139.38, 135.55, 130.45, 128.52, 127.43, 124.42, 121.86, 120.44, 113.30, 55.86, 53.12, 52.48, 46.37, 43.10, 30.71.
B. N-{2-r3-(4-Methylpiperazin-1-yl)pyridin-2-yllethyl>pyridine-2,3-diamine. Using PP32B instead of PP31 , Raney nickel instead of Pd on C and MeOH instead of EtOH. Yield 99%, grey foam: NMR (CDCI3) 8.23 (dd, J = 4.6, 1.7 Hz, 1 H), 7.69 (dd, J = 5.0, 1.5 Hz, 1 H), 7.33 (dd, J = 8.0, 1.5 Hz, 1 H), 7.10 (dd, J= 7.9, 5.0 Hz, 1 H), 6.77 (dd, J = 7.5, 1.2 Hz, 1 H), 6.46 (dd, J = 8.0, 5.0 Hz, 1 H), 3.83 (t, J = 6.2 Hz, 2H), 3.28 (br s, 2H), 3.19 (t, J= 6.2 Hz, 2H), 2.90 (t, J= 4.8 Hz, 4H), 2.54 (br s, 4H), 2.33 (s, 3H).
PREPARATION 31
{2-r2-(4-Methylpiperazin-1-yl)phenvnethyl}(2-nitrophenyl)amine. PP5 (0.10 g, 0.456 mmol), 2-fluoro-1 -nitrobenzene (0.05 mL, 0.474 mmol) and K2CO3
(0.13 g, 0.94 mmol) were refluxed in water (5 mL) for 30 min, cooled and extracted with EtOAc (2x40 mL). The extracts were washed with brine, dried (MgSO4) and concentrated to an orange solid. Chromatography with EtOAc then 15% and 25% MeOH/EtOAc yielded 99 mg (64%) of PP31 as an orange solid: NMR (CDCI3) 8.12 (dd, J = 8.7, 1.7 Hz, 1 H), 8.08 (br s, 1 H), 7.42 (dt, J = 7.7, 1.2 Hz, 1 H), 7.24-7.16 (m, 3H), 7.08 (dt, J = 7.1 , 1.7 Hz, 1 H), 6.93 (d, J = 8.3 Hz, 1 H), 6.61 (sym. mult, 1 H), 3.53 (dd, J = 12.0, 7.3 Hz, 2H), 3.10-2.95 (m, 6H), 2.76 (br s, 4H), 2.47 (s, 3H).
PREPARATION 32
The following materials were prepared according to the general procedure described in Preparation 31 , with the noted changes:
A. f2-[2-(4-Methylpiperazin-1-yl)phenvnethyl}(3-nitropyridin-2-yl)amine. Using 2-chloro-3-nitropyridine in place of 2-fluoro-1 -nitrobenzene. Yield 63%, orange, waxy solid: NMR (CDCI3) 8.39-8.31 (m, 2H), 8.20 (br s, 1 H), 7.22-7.14 (m, 2H), 7.10 (d, J = 7.9 Hz, 1 H), 7.02 (dt, J = 7.3, 1.1 Hz, 1H), 6.59-6.55 (m, 1 H), 3.88-3.83 (m, 2H), 3.02 (t, J = 6.8 Hz, 2H), 2.91 (t, J = 4.6 Hz, 4H), 2.53 (br s, 4H), 2.30 (s, 3H); 13C NMR (CDCI3) 155.93, 152.88, 152.21 , 135.40, 134.59, 130.37, 127.79, 124.66, 124.55, 120.75, 11 1.69, 55.89, 53.11 , 46.39, 42.77, 30.56.
B. f2-r3-(4-Methylpiperazin-1-yl)pyridin-2-vπethylK3-nitro-pyridin-2- vOamine. Using 2-chloro-3-nitropyridine in place of 2-fluoro-1 -nitrobenzene and PP6C in place of PP5. Yield 69%, brown-orange oil: NMR (CDCI3) 8.81 (br s, 1 H), 8.40-8.30 (m, 3H), 7.35 (dd, J = 8.3, 1.5 Hz, 1 H), 7.12 (dd, J = 7.9, 4.6 Hz, 1 H), 6.57 (dd, J = 8.3, 4.6 Hz, 1 H), 4.08-4.03 (m, 2H), 3.20 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 4.8 Hz, 4H), 2.53 (br s, 4H), 2.32 (s, 3H).
PREPARATION 33 2-(4-phenylboronic acid)propan-2-ol. n-BuLi (2.5 M in hexanes, 1.00 mL, 2.5 mmol) was added to a -78°C solution of PP51 (0.50 g, 2.33 mmol) in THF (20 mL). After 1.5 hrs, an additional 0.95 mL n-BuLi (2.38 mmol) was added and the mixture was stirred for 2 additional hrs. Triisopropyl borate (1.08 mL, 4.66 mmol) was added and the reaction was warmed to rt and stirred for 3 days. 1 N HCI was added and the mixture was extracted 3x with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated to give 0.29 g of crude product. Chromatography, first flushing with 50% EtOAc/ hexanes and then eluting with 10% MeOH/EtOAc, gave partially pure material which was then triturated with ether to yield 51 mg (13%) of PP33 as a white solid: NMR (MeOH-d4) 7.67 (d, J = 8.3 Hz, 1 H), 7.54 (d, J = 7.88 Hz, 1 H), 7.45-7.40 (m, 2H), 1.97 (s, 6H).
PREPARATION 34 6-Bromo-3-{2-r2-(4-methylpiperazin-1-yl)phenyllethyl>-1H-quinazoline-2,4-dione.
Triphosgene (0.090 g, 0.303 mmol) in CH2CI2 (3 ml_) was added over 2 min. to an ice cold solution of 2-amino-5-bromo-benzoic acid methyl ester and Et3N in CH2CI2 (10 mL). The resulting slurry was stirred for 2 hrs and PP5 (0.20 g, 0.912 mmol) in CH2CI2 (2 mL) was added. The cooling bath was removed and the reaction was stirred overnight at rt. The mixture was concentrated and the residue was dissolved in EtOAC and washed with water and brine, dried (MgSO4) and concentrated to give 0.402 g of 5-bromo-2-(3-{2-[2-(4-methyl- piperazin-1-yl)-phenyi]-ethyl}-ureido)-benzoic acid methyl ester as a colorless oil: NMR (CDCI3) 10.14 (s, 1 H), 8.43 (d, J = 9.1 Hz, 1 H), 8.04 (d, J = 2.5 Hz, 1 H), 7.51 (dd, J = 9.1 , 2.5 Hz, 1 H), 7.21-7.14 (m 3H), 7.06 (dt, J = 7.3, 1.2 Hz, 1 H), 3.85 (s, 3H), 3.503.46 (m, 2H), 3.01 (t, J = 4.6 Hz, 4H), 2.90 (t, J = 6.2 Hz, 2H), 2.67 (br s, 4H), 2.37 (s, 3H). This material was refluxed in MeOH (13 mL) with LiOH-H2O (60 mg) for 2hrs. and then concentrated. The residue was acidified with 1 N HCI then treated with saturated aqueous NaHCO3 until basic. The resulting white solid was filtered, rinsed well with water and air dried to yield 0.27 g (71 %) of PP34: MS (AP/CI+) 445.2, 443.2 (MH+); NMR (MeOH-d4) 8.07 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.7, 2.1 Hz, 1 H), 7.21 (dd, J= 7.5, 1.7 Hz, 1 H), 7.17-6.98 (m, 4H), 4.25-4.20 (m, 2H), 3.00 (t, J = 7.7 Hz, 2H), 2.94 (t, J = 5.1 Hz, 4H), 2.76 (br s, 4H), 2.44 (s, 3H).
PREPARATION 35 7-Bromo-3-{2-r2-(4-methylpiperazin-1-yl)phenvnethyl}-1H-quinazoline-2.4-dione.
This material was prepared according to the general procedure described in Preparation 34, using PP37 in place of 2-amino-5-bromobenzoic acid methyl ester, yield 50%:
NMR (CDCI3) 7.95 (d, J = 8.7 Hz, 1 H), 7.31 (dd, J = 8.7, 1.7 Hz, 1H), 7.26-7.20 (m, 2H), 7.14-
7.07 (m, 2H), 7.02 (dt, J = 7.3, 1.2 Hz, 1 H), 4.32 (t, J = 7.5 Hz, 2H), 3.05 (t, J = 7.5 Hz, 2H),
2.95 (t, J = 4.8 Hz, 4H), 2.60 (br as, 4H), 2.32 (s, 3H).
PREPARATION 36 7-Bromo-1 -methyl-3-f 2-r2-(4-methylpiperazin-1 -yl)phenyllethyl}-1 H-quinazoline-2,4- dione.
PP5 (0.46 g, 2.10 mmol), PP38 (0.434 g, 1.89 mmol), BOP reagent (0.93 g, 2.10 mmol) and diisopropylethyl amine (1.65 mL, 9.47 mmol) in CH2CI2 (15 mL) were stirred at rt overnight. After concentration, the mixture was dissolved in EtOAc and washed with water and brine, dried (MgSO4) and concentrated to give an orange oil. Chromatography with 5- 10% MeOH/ CH2CI2 gave 1.09 g of partially purified 4-bromo-2-methylamino-N-{2-[2-(4- methylpiperazin-1-y|)-phenyl]ethyl}-benzamide (Rf = 0.85 on SiO2 in 20% MeOH/ CH2CI2) which was suitable for the next step. This intermediate amide (0.83 g, 1.92 mmol) was refluxed with methylchloroformate (5 mL) for 30 min and then concentrated. To this was added 10 mL of a solution of KOH/EtOH/water (2g/20mL/10ml_).The resulting mixture was stirred for 20 min at it EtOH was removed by rotary evaporation, EtOAc was added and this was washed with water and brine, dried (MgSO4) and reconcentrated to a solid. Trituration with ether yielded 0.515 g (59%) of PP36 as a dirty white solid: MS (AP/CI+) 457.2, 459.2 (MH+); NMR (CDCI3) 8.04 (d, J = 9.1 Hz, 1 H), 7.40 -7.38 (m, 2H), 7.31 (d, J = 7.5 Hz, 1 H), 7.26-7.11 (m, 3H), 4.22-4.18 (sym.mult, 2H), 3.62-3.10 (br m, 9H), 3.05 (s, 3H), 2.97-2.88 (sym.mult., 2H). PREPARATION 37
2-Amino-4-bromobenzoic acid methyl ester.
2-Amino-4-bromobenzoic acid (Boojamra et al., Journal of Organic Chemistry (1997), 62(5), 1240-1256) (0.60 g, 2.78 mmol) in MeOH (20 mL) was saturated with HCI gas, allowed to cool back to rt and saturated again. The mixture was stirred 24hrs, concentrated and partitioned between EtOAc and sat. aq. NaHCO3. The organics were washed with brine, dried (MgSO4) and concentrated to yield 0.54 g (85%) of PP37 as a waxy brown solid: NMR (CDCI3) 7.66 (d, J = 8.7 Hz, 1 H), 6.82 (d, J= 2.1 Hz, 1 H), 6.73 (dd, J= 8.7, 2.1 Hz, 1 H), 3.83 (s, 3H).
PREPARATION 38 4-Bromo-2-methylaminobenzoic acid.
2-Amino-4-bromobenzoic acid (Boojamra et al.,) (1.03 g, 4.78 mmol) was dissolved in 1 N NaOH (10 mL) with gentle heating. When the solution was at rt, dimethylsulfate (0.46 mL, 4.86 mmol) was added over 2-3 min. and the resulting mixture was stirred vigorously for 1 h. TLC (20% EtOAc/ hex) showed only a small amount of product, so an additional 0.5 mL of dimethylsulfate was added. Within 10 min a light tan solid precipitated. After 1 hour additional stirring, an additional 0.2 mL dimethylsulfate was added and the reaction stirred overnight. The solid was collected and rinsed well with water. The solid was dissolved in EtOAC and washed with water and brine, dried (MgSO4) and concentrated to a light tan solid which NMR showed to be a 3:1 mixture of 4-bromo-2-methyIamino-benzoic acid and starting material. Chromatography with 10% EtOAc/ hex gave the pure material as a white solid: NMR (CDCI3) 7.62 (d, J = 8.3 Hz, 1 H), 6.78 (d, J = 2.1 Hz, 1 H), 6.65 (dd, J = 8.7, 2.0 Hz, 1 H), 3.29 (br s, 2H), 2.78 (s, 3H). PREPARATION 39 5-Bromo-2-{2-r2-(4-methylpiperazin-1-yl)phenyll-ethyl}isoindole-1,3-dione.
PP5 (0.20 g, 0.912 mmol) and 4-bromophthaIic anhydride (0.21 g, 0.925 mmol) were refluxed in xylenes (5 mL) for 2hrs at which point a brown gooey solid formed. The mixture was concentrated and partitioned between EtOAc and water. The organics were washed with brine, dried (MgSO4) and concentrated to an oil. Chromatography using 20% MeOH/EtOAC gave 0.203 g (52%) of PP39: NMR (CDCI3) 7.95 (d, J= 1.7 Hz, 1 H), 7.84 (dd, J = 7.9, 1.7 Hz,
1 H), 7.68 (d, J = 7.9 Hz, 1 H), 7.25-7.14 (m, 3H), 7.05 (t, J = 7.3 Hz, 1 H), 3.95 (t, J= 7.7 Hz,
2H), 3.20-2.95 (m, 6H), 2.85 (br s, 4H), 2.55 (br s, 3H). This material was also prepared in 71 % yield using the same reagents according to the general procedure described in Example
18.
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.
The mixture was concentrated and purified by chromatography, first flushing with EtOAc to remove organotin impurities and then eluting with 10% MeOH/ EtOAc to yield 0.21 g (54%) of
PP40 as a light tan oil: NMR (CDCI3) 7.89 (s, 1 H), 7.77 (d, J = 6.7 Hz, 1 H), 7.69 (dd, J = 7.1 ,
0.8 Hz, 1 H), 7.22-7.16 (m, 2H), 7.10 (dd, J = 7.9, 1.2 Hz, 1 H), 7.01 (dt, J = 7.5, 1.2 Hz, 1 H), 3.94-3.90 (sym.mult., 2H), 3.01-2.92 (m, 6H), 2.72 (br s, 4H), 2.45 (s, 3H), 1.54-1.46 (m, 6H),
1.34-1.27 (m, 6H), 1.17-1.00 (m, 6H), 0.85 (t, J = 7.3 Hz, 9H).
PREPARATION 41
2-(2-Bromobenzyl)-7-phenyl-3,4-dihydro-2H-isoquinolin-1-one. Step 1 : 2-Biphenyl-4-yl-ethylamine (0.20 g, 1.01 mmol) and 2-bromobenzaldehyde (0.12 mL, 1.01 mmol) were stirred in EtOH (5 mL) at rt for 2 hrs. NaBH4 (50 mg, 1.32 mmol) was added and stirring was continued for 10 hrs. The mixture was concentrated, redissolved in EtOAc and washed with water and brine, dried (MgSO4) and concentrated to yield 0.397 g of crude (2-biphenyl-4-yl-ethyl)-(2-bromo-benzyl)-amine as a colorless oil. This material was used without purification. Step 2: The crude (2-biphenyl-4-yl-ethyl)(2-bromobenzyl)amine (0.326 g) and Et3N
(0.14 mL, 1.00 mmol) in ether (8 mL) was cooled in ice and methyl chloroform ate (0.075 mL, 0.98 mmol) in ether (2 mL) was added dropwise to give a white slurry. After 30 min, the mixture was concentrated, dissolved in EtOAc and washed with water and brine, dried (MgSO4) and reconcentrated to a yield (0.33 g) of (2-biphenyl-4-ylethyl)-(2- bromobenzyl)carbamic acid methyl ester as a colorless oil (0.33 g) which was used without purification. 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. HaHCO3 and brine, dried (MgSO4) and concentrated to a purple oil (0.32 g). NMR showed this to be a mixture of the desired 2-(2-bromo-benzyl)-7-phenyl-3,4-dihydro-2H-isoquinolin-1-one and the debrominated material 2-benzyl-7-phenyl-3,4-dihydro-2H-isoquinolin-1-one (-2:1 ratio). Chromatography with 10%EtOAc/hexanes afforded 0.176 g (75%) of the clean PP41 as a white solid: MS(AP/CI+) 394.1 , 392.1 (MH+); NMR (CDCI3) 8.38 (d, J= 2.1 Hz, 1 H), 7.67-7.60 (m, 3H), 7.55 (dd, J = 7.9, 1.2 Hz, 1 H), 7.42 (t, J = 7.0 Hz, 1 H), 7.37-7.22 (m, 5H), 7.1 1 (dt, J = 7.7, 1.5 Hz, 1 H), 4.92 (s, 2H), 3.56 (t, J = 6.6 Hz, 2H), 3.01 (t, J = 6.6 Hz, 2H).
PREPARATION 42
2-(2-Bromobenzyl)-7-morpholin-4-yl-3,4-clihvdro-2H-isoquinolin-1-one.
7-Morpholin-4-yl-3,4-dihydro-2H-isoquinolin-1-one (J. Med. Chem, 1996, 39, 4583) (0.10 g, 0.43 mmol) was added to a slurry of NaH (0.021 g, 0.53 mmol) in DMF (3 ml_). After the solids dissolved and gas evolution ceased, 2-bromobenzyl bromide (0.12 g, 0.48 mmol) was added and the mixture was stirred overnight at rt. The reaction was diluted with water (30 ml_) and extracted with EtOAc (50 mL). The extract was washed with brine, dried (MgSO4) and concentrated. Chromatography with 50% EtOAc/ hexanes yielded 0.142 g (82%) of PP42 as a white foam: NMR (CDCI3) 7.67 (d, J = 2.0 Hz, 1 H), 7.53 (dd, J = 7.9, 1.2 Hz, 1 H), 7.31
(dd, J = 7.9, 1.7 Hz, 1 H), 7.26-7.21 (m, 1H), 7.12-7.06 (m, 2H), 7.01 (br s, 1 H), 4.87 (s, 2H),
3.85 (t, J= 4.3 Hz, 4H), 3.50 (t, J= 6.6 Hz, 2H), 3.18 (t, J = 4.8 Hz, 4H), 2.88 (t, J= 6.6 Hz, 2H).
PREPARATION 43
7-Morpholin-4-yl-1.2.3,4-tetrahvdroisoquinoline. 7-Morpholin-4-yl-3,4-dihydro-2H-isoquinol-in-1-one (J. Med. Chem., 1996, 39, 4583)
(0.20 g, 0.86 mmol) in THF (10 mL) was added over 1 min to a slurry of LAH (0.075 g, 1.98 mmol) in THF (10 mL). This mixture was refluxed 3hrs, cooled and quenched with excess sodium sulfate decahydrate and then dried over anhydrous Na2SO4. Filtering (Celite™) and concentration yielded 0.183 g (96%) of PP43 as a waxy white solid : NMR (CDCI3) 6.98 (d, J = 8.7 Hz, 1 H), 6.72 (dd, J = 8.3, 2.5 Hz, 1 H), 6.53 (d, J = 2.5 Hz, 1 H), 3.98 (s, 2H), 3.82 (t, J = 4.8 Hz, 4H), 3.12 (t, J = 6.0 Hz, 2H), 3.07 (t, J = 4.8 Hz, 4H), 2.72 (t, J = 5.8 Hz, 2H). PREPARATION 44 F2-(4-Methylpiperazin-1-yl)phenyllacetaldehyde.
Potassium t-butoxide was added to a ~-10°C solution of (methoxymethyl)triphenylphosphonium chloride (7.4 g, 21.5 mmol) in THF (60 mL), and stirred for 15 min giving a red solution. PP57 (2.0Og, 9.79 mmol) in THF (40 mL) was added and the mixture was stirred overnight at rt. After concentration, 1 N HCI (150 mL) was added and this was stirred for 2.5 days. The reaction mixture was extracted with EtOAc (2x150 mL), then carefully made basic with K2CO3. This aqueous phase was then extracted with EtOAc (3X100 mL). These extracts were washed with brine, dried (MgSO4) and concentrated to yield 2.13 g (99%) of PP44 as an orange oil: NMR (CDCI3) 9.53 (t, J = 2.5 Hz, 1 H), 7.28 (dt, J = 7.7, 1.5 Hz, 1 H), 7.20-7.17 (m, 2H), 7.10 (dt, J = 7.3, 1.2 Hz, 1 H), 3.57 (d, J = 2.5 Hz, 2H), 2.90-2.88 (m, 4H), 2.51 (br s, 4H), 2.32 (s, 3H).
PREPARATION 45 5-Bromo-2-{2-r2-(4-methylpiperazin-1-yl)phenvnethyl>-2,3-dihydroisoindol-1-one. PP46 (0.61 g, 1.98 mmol) in THF (10 mL) was added over 3 min to a solution of PP5
(0.433 g, 1.97 mmol), and Et3N (0.55 mL, 3.95 mmol) in THF (10 mL). After stirring overnight at rt, the reaction was concentrated, dissolved in EtOAc and washed with water and brine, dried (MgSO4) and concentrated to an orange oil. Chromatography with 15-20% MeOH/ EtOAc yielded 0.42 g (51 %) of PP45 as a yellow oil : NMR (CDCI3) 7.65 (d, J = 7.9 Hz, 1 H), 7.54 (dd, J = 7.9, 1.7 Hz, 1 H), 7.50 (d, J = 0.9 Hz, 1 H), 7.20-7.12 (m, 2H), 7.11-7.08 (m, 1 H), 7.00 (dt, J = 7.2, 1.1 Hz, 1 H), 4.14 (s, 2H), 3.86 (t, J = 7.3 Hz, 2H), 2.99 (t, J = 7.3 Hz, 2H), 2.90-2.87 (m, 4H), 2.58 (br s, 4H), 2.36 (s, 3H).
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. NaHCO3 and brine, dried (MgSO4) and concentrated to a brown oil (20.5 g). Kugelrohr distillation (-0.3 torr, 80- 1000C) yielded 19.6 g (90%) of 4-bromo-2-methyl-benzoic acid methyl ester as a colorless oil: NMR (CDCI3) 7.75 (d, J = 8.3 Hz, 1 H), 7.38 (s, 1 H), 7.34 (dd, J = 8.3, 2.1 Hz, 1 H), 3.85 (s, 3H), 2.54 (s, 3H).
The ester (1.00 g, 4.37 mmol), N-bromosuccinimide (0.86 g, 4.83 mmol) and benzoylperoxide (0.10 g, 0.41 mmol) were refluxed in benzene (10 mL) for 4hrs, then cooled and concentrated. The residue was dissolved in ether and washed with water and brine, dried (MgSO4) and concentrated to a yellow-orange oil (1.42 g). NMR showed -70-75 % pure PP46 which was used without purification: NMR (CDCI3) 7.81 (d, J = 8.7 Hz, 1 H), 7.60 (d, J = 2.1 Hz, 1 H), 7.48 (dd, J = 8.3, 2.1 Hz, 1 H), 4.86 (s, 2H), 3.91 (s, 3H). PREPARATION 47 4-Bromo-2-(2-oxoethyl)benzonitrile.
Step 1 : 4-Bromo-2-methylbenzonitrile (5.00 g, 25.50 mmol) and t- butoxybis(dimethylamino)methane were heated to 1400C with vigorous stirring. After ~ 2hrs, the bubbling of the distilling t-butanol ceased and the reaction was cooled, slurried with hexanes (30 mL) and filtered to obtain 4.6 g, (72%) of 4-bromo-2-(2- dimethylaminovinyl)benzonitrile as an orange solid: NMR (CDCI3) 7.46 (d, J = 1.7 Hz, 1 H), 7.27 (d, J = 9.1 Hz, 1 H), 7.02-6.97 (m,2H), 7.28 (d, J = 13.3 Hz, 1H), 2.92 (s, 6H).
Step 2: 4-Bromo-2-(2-dimethylaminovinyl)benzonitrile (2.77 g, 11.03 mmol) was stirred vigorously with 4N HOAc (50 mL) at rt for 2 hrs. The light yellow solid was collected, rinsed well with water and air dried to yield 2.2 g (89%) of PP47: NMR (CDCI3) 9.80 (t, J = 1.0 Hz, 1H), 7.53 (AB quartet, Δu = 3.3 Hz, J = 1.6 Hz, 2H), 7.48 (d, J = 1.7 Hz, 1 H), 3.97 (s, 2H).
PREPARATION 48 1 -(4-Bromophenyl)cyclohexanol. 4-Bromo-1-iodobenzene (5g, 17.7 mmol) in tetrahydrofuran (20 mL) at -4O0C 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. Saturated aqueous ammonium chloride solution was added and the mixture was then diluted with EtOAc. The aqueous and organic layers were separated and the organic layer was washed with water (1x) and brine (1x). The combined aqueous layers were extracted with EtOAc (3 x 10 mL), the combined organic layers were dried over magnesium sulfate, were filtered, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (20:1 hexanes-EtOAc) to afford 3g (67% yield) of PP48. 13C NMR (100 MHz, CDCI3) 5148.8, 131.4, 126.8, 120.8, 73.2, 38.9, 25.6, 22.3.
PREPARATION 49 1 -(4-Bromophenyl)cvclopentanol.
PP49 was prepared using the procedure detailed for Preparation 48 with cyclopentanone in place of cyclohexanone. 1 H NMR (CDCI3) δ 7.44 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 1.9 (m, 6H), 1.8 (m, 2H), 1.75 (s, 1 H); 13C NMR (100 MHz, CDCI3) d 146.4,131.4, 127.2, 120.8, 83.4, 42.2, 24.1.
PREPARATION 50 1 -(4-BromophenvOcvclobutanol.
PP50 was prepared using the procedure detailed for Preparation 48 with cyclobutanone in place of cyclohexanone. 13C NMR (CDCI3) δ 145.5, 131.7, 127.1 , 121.3, 76.8, 37.2, 13.2; MS (AP/CI) 209.0, 211.0 (M+H-H2O)+.
PREPARATION 51 2-(4-Bromophenyl)propan-2-ol
A solution of methyl p-bromobenzoate (3g, 13.2 mmol) in tetrahydrofuran (14 ml.) cooled to -3O0C was treated dropwise with methyl magnesium bromide (1 M in diethyl ether,
105.5 mmol, 105.5 mL). Upon completion of addition, the resulting suspension was allowed to warm to rt and was stirred for 5 hours. Saturated aqueous ammonium chloride (100 mL) was added slowly and the mixture was diluted with EtOAc (100 mL). The organic and aqueous layers were separated and the aqueous layer was extracted with EtOAc (3 x 50 mL).
The combined organic layers were dried over magnesium sulfate, were filtered, and the solvent was removed in vacuo. Purification by silica gel chromatography (10:1 hexanes - EtOAc) gave 2.2 g (79% yield) of PP51. 13C NMR (100 MHz, CDCI3) d 148.4, 131.4, 126.6,
120.8, 72.5, 31.9; MS (AP/CI) 197.1 , 199.1 (M+H)+.
PREPARATION 52
1-(4-Bromophenyl)-2-methylpropan-2-ol.
PP52 was prepared using methyl-4-bromophenyl acetate and the procedure detailed for Preparation 51. 13C NMR (100 MHz, CDCI3) d 137.1 , 132.4, 131.4, 120.7, 70.9, 49.3, 29.4; MS (AP/CI) 211.0, 213.0 (M+H-H2O)+.
PREPARATION 53 2-(5-Bromopyridin-2-yl)propan-2-ol.
PP53 was prepared using ethyl-5-bromo-2-carboxypyridine, but otherwise followed the general procedure for Preparation 51. 13C NMR (100 MHz, CDCI3) d 165.1, 148.9, 139.7, 120.4, 118.9, 72.2, 30.7; MS (AP/CI) 216.0, 218.1 (M+H)+.
PREPARATION 54
1 -Bromo-4-(1 -methoxy-1 -methylethvDbenzene.
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, CDCI3) δ 145.4, 131.5, 127.9, 121.0, 76.7, 50.9, 28.1 ;
MS (AP/CI) 197.0, 199.0 (M+H-OMe)+.
PREPARATION 55
1 -Bromo-4-(1 -methoxycyclobutyDbenzene.
PP55 was prepared using the procedure detailed for Preparation 54 on the corresponding hydroxy! compound prepared above. 13C NMR (100 MHz, CDCI3) δ 142.5, 131.6, 128.4, 121.4, 81.3, 50.8, 33.0, 13.1 ; MS (AP/CI) 209.1 , 211.1 (M+H-OMe)+.
PREPARATION 56 1-Bromo-4-(2-methoxy-2-methylpropyl)benzene.
PP56 was prepared using the procedure detailed for Preparation 54 on the corresponding hydroxyl compound prepared above. 13C NMR (100 MHz, CDCI3) δ 137.6, 132.4, 131.1 , 120.3, 75.2, 49.7, 45.9, 24.9; MS (AP/CI) 211.1 , 213.1 (M+H-OMe)+. PREPARATION 57
2-(4-Methylpiperazin-1-v0benzaldehyde.
2-Fluorobenzaldehyde (20.0 mL, 189.9 mmol), 1-methylpiperazine (33.0 mL, 297.7 mmol) and potassium carbonate (40.0 g, 289.4 mmol) in water (200 mL) were refluxed for 18h. After cooling, the mixture was extracted with EtOAc (2X 150 mL). These extracts were washed with brine, dried over MgSO4 and concentrated to give PP57 (38.6 g, 100%) as an orange oil which had: NMR (CDCI3) δ 10.10 (s, 1 H), 7.77 (dd, J = 7.9, 1.7 Hz, 1 H), 7.51-7.48 (sym. mult., 1 H), 7.10-7.06 (m, 2H), 3.11 (t, J = 4.6 Hz, 4H), 2.63 (br s, 4H), 2.36 (s, 3H).
PREPARATION 58
3-(4-Methylpiperazin-1-vQpyridine-2-carbaldehvde. A solution of 1-methylpiperazine (54.2 mL, 0.48 moles), potassium carbonate (60 g,
0.43 moles), and 3-fluoro-pyridine-2-carbaldehyde (36.2 g, 0.28 moles) in water (340 mL) and 1 ,4-dioxane (150 mL) was heated at reflux for 2 h. The solution was cooled to rt, poured into water (1000 mL) and extracted with methylene chloride (2 x 700 mL). The combined organic layers were washed with water (2 x 900 mL). The organic layer was dried (MgSO4), filtered, and the solvent was removed in vacuo to afford 58.5 g of an oil. MS (AP/CI) 206.3 (M+1 ). 13C NMR (100 MHz, CDCI3) δ 46.3, 52.4, 55.1 , 126.7, 128.0, 142.9, 143.7, 150.2, 191.9.

Claims

1. A compound of the formula
Figure imgf000085_0001
wherein R1 is a group of the formula G1, G2, G3, G4, G5, G6, G7, G8, or G9 depicted below,
Figure imgf000085_0002
G1
Figure imgf000085_0003
G9
R2 is hydrogen,
Figure imgf000085_0004
and (C1 -C6)alkyl-phenyl;
R3 is independently selected from hydrogen, (C-rCβJalkyl, (CrCβJalkyl-phenyl, and (CrCβJalkyl-naphthyl, wherein phenyl and naphthyl may optionally be substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6JaIkOXy, trifluoromethyl, chloro, fluoro, bromo, iodo, cyano, -SO1(C1 -C6)alkyl, NH(C1-C6)alkyl, N((C1-C6)alkyl)2,
NHCO^rCeJalkyl, CONH(CrC6)alkyl, and CON((CrC6)alkyl)2; t is zero to two; R4 is hydrogen, R9, or R10;
R5 is independently selected from hydrogen, (CrC^alkyl, phenyKCrCβJalky!-, and naphthyl-(C1-C6)alkyl-, wherein phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from (C^C^alkyl, (CrC6)alkoxy, trifluoromethyl, chloro, fluoro, bromo, iodo, cyano, and -SOt(CrC6)alkyl; R6 and R7 are independently selected from hydrogen, (CrC6)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, (CτC6)alkyl, (CrCsJalkoxy, trifluoromethoxy, (CVC^perfluoroalkyl, (CrCeJhydroxyalkyl-, (C1-C6)alkoxy-(C1-C6)alkyl-, pheny](CrC6)alkyl-, naphthyl(CrC6)alkyl-, and -SCMCrCe^lkyl; or
R6 and R7, 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 R6 and R7 are attached, wherein the heteroalkyl ring may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, cyano, (CrC6)alkyl, (C1- C6)alkoxy, trifluoromethoxy, (CrC6)perfluoroalkyl, (CrC6)hydroxyalkyl-, (C1-C6)alkoxy-(C1- C6)alkyl-, phenyKCrCeJalkyl-, naphthyl(C.|-C6)alkyl-, and -SOt(CrC6)alkyl;
R8 is hydrogen or optionally one to four substituents independently selected from chloro, fluoro, bromo, iodo, cyano, hydroxy, nitro, amino, -CHO, -CONR6R7, -(C1- C6)alkylCO2Rn, -(C3-C8)cycloalkyiC02Rii, (CrCeJalkylCONRn-,
Figure imgf000086_0001
(C1- C6)alkyl, (CrCeOperfluoroalkyl, trifluoromethoxy, (CrC6)hydroxyalkyl-, (C4- C8)hydroxycycloalkyl-, (CrC6)alkoxy, (C3-C8)cycloalkyloxy-, (C1-C6)alkoxy-(C1-C6)alkyl-, (C3- C8)cycloalkyloxy-(CrC6)alkyl-, (CrC6)alkoxycycloaIkyl-, R9, R10, and a 5 to 7 membered non- aromatic heterocyclic ring having in addition to carbon atoms 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur atoms or any combination thereof with the proviso that said non-aromatic heterocyclic ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, wherein any of said non-aromatic heterocyclic rings can be the same or different and wherein each said non-aromatic heterocyclic ring may be optionally substituted with one to three substituents, as valency allows, independently selected from chloro, fluoro, bromo, iodo, (CrC6)alkyl, (CrC6)perfluoroalkyl, (CrC6)hydroxyalkyl-, (C1- C6)alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl-, or R12(CrC6)alkyl-; or R8 is -CH=CH-CH=CH- wherein said -CH=CH-CH=CH- is linked to 2 adjacent carbon atoms to form a fused 6 membered aromatic ring;
R9 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, -CONR6R7, -(d-CeJalkylCO∑R^, -(C3-C8)CyClOaIk^CO2R11, (C1- C^alkylCONRn-, -SOt(CrC6)alkyl, (d-C^alkyl, (CrC6)perfluoroalkyl, trifluoromethoxy, (C1- C6)hydroxyalkyl-, (C4-C8)hydroxycycloalkyl-, (CrC6)alkoxy, (C3-C8)cycloalkyloxy-, (C1- C6)alkoxy-(CrC6)alky!-, (C3-C8)cycloalkyloxy-(CrC6)alkyl-, (CrC6)alkoxy(C3-C8)cycloalkyl-, Ri2, Ri3> Ri2(C1-C6)BlRyI-, R12(C3-C8)cycloalkyl-, R12(C1-C6)BIkOXy-, R12(C4-C8)cycloalkyloxy-, R13(CrC6)alkyl-, R13(C3-C8)cycloalkyl-, R13(CrC6)alkoxy-, or R13(C3-C8)cycloalkyloxy-;
R10 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, -CONR6R7, -(C1-
C6JaIkYlCO2R1 ^ -(QrQOcycloalkylCOaRn, (CrC^alkylCONRn-, -SOt(C.rC6)alkyl, (CrC6)alkyl,
(C1-C6)perfluoroalkyl, trifluoromethoxy, (CrC^hydroxyalkyl-, (C4-C8)hydroxycycloalkyl-, (C1-
C6)alkoxy, (C3-C8)cycloalkyloxy-, (C1-C6)alkoxy-(C1-C6)alkyl-, (C3-C8)cycloalkyloxy-(C1-
C6)alkyl-, (C1-C6)alkoxy(C3-C8)cycloalkyl-, R12, R13, R12(C1-C6)BIkYl-, R12(C3-C8)cycloalkyI-, R12(C1-C6)BIkOXy-, R12(C4-C8)cycloalkyloxy-, R13(CrC6)alkyl-, R13(C3-C8)cycloalkyl-, R13(C1-
C6)alkoxy-, or R13(C3-C8)cycloalkyloxy-;
R11 is hydrogen or (C1-C6JaIkYl;
R12 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, (Ci-CeJalkyl, (C1-C6)perfluoroalkyl, trifluoromethoxy, (C1-
C6)hydroxyalkyl-, (C4-C8)hydroxycycloalkyl-, (CrC6)alkoxy, (C3-C8)cycloalkyloxy-, (C1-
C6)alkoxy-(CrC6)alkyl-, (C3-C8)cycloalkyloxy-(CrC6)alkyl-, or (C1-C6)alkoxy(C3-C8)cycloalkyl-;
R13 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; and wherein any ring of R13 may optionally be substituted as valency allows, with one to three substituents independently selected from chloro, fluoro, bromo, iodo, nitro, amino, oxo, (CrC6)aIkyl, (CrCeJperfluoroalkyl, trifluoromethoxy, (CrC6)hydroxyalkyl-, (C4-
C8)hydroxycycloalkyl-, (CrC6)alkoxy, (C3-C8)cycloalkyloxy-, (C1-C6)alkoxy-(C1-C6)alkyl-, (C3-
C8)cycloalkyloxy-(C1-C6)alkyl-, Or (C1-C6)BIkOXy(C3-C8)CyClOaIkYl-; R14 is 1-8 substituents independently selected from hydrogen, (C^C^alkyl, (C1- C6)alkyl-phenyl, (CrC^alkyl-naphthyl, wherein phenyl or naphthyl, may optionally be substituted with one or more substituents independently selected from (C1 -C6)alkyl, (C1 - C6)alkoxy, trifluoromethyl, chloro, fluoro, bromo, iodo, cyano and -SOt(C1 -C6)alkyl; or, R14 is a (CrC4)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 R3, when R3 has a ring structure having an available bonding site;
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 R1 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 R1 bonds directly to -CH2- and R2 is not present; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein R1 is G1, G2, or G3; X, Y and Z are independently CH or N; and
R4 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, (Ci-Cβ)alkyl, (C1- C6)perfluoroalkyl, trifluoromethoxy, (CrC6)hydroxyalkyl-, (C4-C8)hydroxycycloalkyl-, (C1- C6)alkoxy, (C3-C8)cycloalkyloxy-, (C1-Cβ)alkoxy-(C1-Cβ)alkyl-, (C3-C8)cycloalkyloxy-(C1- C6)a!kyh (C1-C6)alkoxy-(C3-C8)cycloalkyl-! R12, R13, R12(C1-C6JaIk^-, R12(C3-C8)cycloalkyl-, Ri2(CrC6)alkoxy-, R12(C4-C8)cycloalkyloxy-, R13(C1-C6)alkyl-, R13(C3-C8)cycloalkyl-, Ri3(C1- C6)alkoxy-, and R13(C3-C8)cycloalkyloxy-, wherein Ri2 is phenyl or naphthyl and Ri3 is selected from pyridyl, pyrrolyl, pyrimidyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, tetrahydropyranyl, dioxanyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, and oxetanyl, wherein said R12 or R13 may be optionally substituted as valency allows, with one to three substituents independently selected from chloro, fluoro, bromo, iodo, nitro, amino, oxo, (CrC6)alkyl, (CrC6)perfluoroalkyl, trifluoromethoxy, (CrC6)hydroxyalkyl-, (C4-C8)hydroxyl(C3-C8)cycloalkyl-, (C1-C6)BIkOXy and (C1-C6)alkoxy-(C1-C6)alkyl-.
3. The compound of claim 1 wherein R1 is G4, G5, G6, G7, G8, or G9; X and Y are independently CH or N; and R8 is hydrogen or optionally one to four substituents independently selected from chloro, fluoro, bromo, iodo, cyano, hydroxy, nitro, amino, and CHO.
4. The compound of claim 1 wherein R1 is G4, G5, G6, G7, G8, or G9; X and Y are independently CH or N; and R8 is one to four substituents independently selected from -CONR6Rr wherein R6 and
R7 together with the nitrogen to which they are attached, form a heteroalkyl saturated or 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, (C1-C6JaIRyI, (C1- C6)perfluoroalkyl, (CrC6)hydroxyalkyl-, (CrC6)alkoxy, (CrCeOalkoxy-^CrC^alkyl-, phenyl(Cr C6)alkyl-, and naphthyl(CrC6)alkyk
5. The compound of claim 1 wherein R1 is G4, G5, G6, G7, G8, or G9, X and Y are independently CH or N and R8 is one to four 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, (C^C^alkyl, (CrC^perfluoroalkyl, (CrC^hydroxyalkyl-, (CrC6)alkoxy, (CrC^alkoxy-CCrC^alkyl-, and R12(CrC6)alkyl.
6. The compound of claim 1 wherein R1 is G4, G5, G6, G7, G8, or G9; X and Y are independently CH or N; and R8 is one to four 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, oxo, (^-C^alky!, (Ci-C6)perfluoroalkyl, trifluoromethoxy, (CrC6)hydroxyalkyl-, (C4-C8)hydroxycycloalkyl-, (CrC6)alkoxy, (C3- C8)cycloalkyloxy-, (C1-C6)alkoxy-(C1-C6)alkyl-, (C3-C8)cycloalkyloxy-(C1-C6)alkyi-, (C1- C6)alkoxy-(C3-C8)cycloalkyl-, R12, R13, R12(C1 -C6)alkyl-, R12(C3-C8)cycloalkyl-, R12(Cr C6)a!koxy-, R12(C4-C8)cycloalkyloxy-, R13(CrC6)alkyl-, R13(C3-C8)cycloalkyl-, R13(CrC6)alkoxy- or R13(C3-C8)cycloalkyloxy-, and wherein R12 is phenyl or napthyl and R13 is selected from pyridyl, pyrrolyl, pyrimidyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, tetrahydropyranyl, dioxanyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, and oxetanyl, wherein said R12 and R13 may be optionally substituted as valency allows, with one to three substituents independently selected from chloro, fluoro, bromo, iodo, nitro, amino, oxo, (C1-C6)SlRyJ, (CrC6)perfluoroaIkyl, trifluoromethoxy, (CrC^hydroxyalkyl-, (C4-C8)hydroxycycloalkyl-, (CrC6)alkoxy, and (C1- C6)alkoxy-(CrC6)alkyk
7. The compound of claim 1 wherein R1 is G4, G5, G6, G7, G8 or G9, X and Y are independently CH or N and R8 is -CH=CH-CH=CH- wherein said -CH=CH-CH=CH- is linked to two adjacent carbon atoms to form a fused 6 membered aromatic ring.
8. The compound of any of claims 1-7 wherein R2 is hydrogen, methyl or benzyl.
9. The compound of any of claims 1-7 wherein R3 is H, methyl or benzyl.
10. The compound of claim 1 wherein R1 is G1 or G4, and R5 is H, methyl or benzyl.
11. The compound of claim 1 wherein R1 is G1, G2, G3, G4, G5, G6, G7, G8 or G9;
X, Y and Z are independently CH or N; n is zero, m is zero.
12. The compound of claim 1 wherein R1 is G1, G2, G3, G4, G5, G6, G7, G8 or G9; X, Y and Z are independently CH or N; n is one, m is zero.
13. The compound of claim 1 wherein R1 is G1, G2, G3, G4, G5, G6, G7, G8 or G9; X, Y and Z are independently CH or N; n is one and m is one.
14. The compound of claim 1 selected from the group consisting of:
1 -{2-[2-(4-Methyl-piperazin-1 ~yl)-phenyl]-ethyl}-3-(4-trifluoromethyl-phenyl)-1 ,3- dihydro-imidazol-2-one;
1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]- ethyl}-1 ,3-dihydro-imidazol-2-one;
1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]-ethyl}- 1 ,3-dihydro-imidazol-2-one;
1 -[6-(1 -Hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]- ethyl}-1 ,3-dihydro-imidazol-2-one; 1-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-3-pyridin-2-yl-1 ,3-dihydro-imidazol-2- one;
1 -(4-tert-Butyl-phenyl)-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]-ethyl}-1 ,3-dihydro- imidazol-2-one;
1 -{2-[2-(4-Methyl-piperazin-1 -yl)-phenyl]-ethyl}-3-(4-oxazol-2-yl-phenyl)-1 ,3-dihydro- imidazol-2-one;
1 -{2-[2-(4-Methyl-piperazin-1 -yl)-phenyl]-ethyl}-3-(4-oxazol-5-yl-phenyl)-1 ,3-dihydro- imidazol-2-one;
1-[4-(2-Methyl-oxazol-4-yl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}- 1 ,3-dihydro-imidazol-2-one; 1 -{2-[2-(4-Methyl-piperazin-1 -yl)-phenyl]-ethyl}-3-(4-oxazol-4-yl-phenyl)-1 ,3-dihydro- imidazol-2-one; 1-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-3-[4-(tetrahydro-pyran-4-yl)-phenyl]- 1 ,3-dihydro-imidazol-2-one;
1-(4-lsopropoxy-phenyl)-3-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}-1 ,3-dihydro- imidazol-2-one; 1-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-3-(3-oxo-1 ,3-dihydro-isobenzofuran-5- yl)-1 ,3-dihydro-imidazol-2-one;
1 -[4-(5-MethyI-[1 ,3,4]oxadiazol-2-yl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]- ethyl}-1 ,3-dihydro-imidazol-2-one;
1 -(6-Methoxy-pyridin-3-yl)-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]-ethyl}-1 ,3-dihydro- imidazoI-2-one;
1 -(2-Methyl-benzothiazol-5-y!)-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]-ethyl}-1 ,3- dihydro-imidazol-2-one;
1-[4-(2-lsopropyl-oxazol-4-yl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}- 1 ,3-dihydro-imidazol-2-one; 1 -[4-(2-Hydroxy-2-methyl-propyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]- ethyl}-1 ,3-dihydro-imidazoi-2-one;
1-[4-(1-Methoxy-cyclobutyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}- 1 ,3-dihydro-imidazoI-2-one;
1 -[4-(1 -Hydroxy-cyclopentyI)-phenyl]-3-{1 -methyl-2-[2-(4-methyl-piperazin-1 -yl)- phenyl]-ethyl}-1 ,3-dihydro-imidazol-2-one;
1 -[6-(1 -Hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-3-{1 -methyl-2-[2-(4-methyl-piperazin-1 - yl)-phenyl]-ethyl}-1 ,3-dihydro-imidazol-2-one;
3-[4-(1 -Hydroxy-cyclobutyl)-phenyl]-4-methyl-1 -{2-[2-(4-methyl-piperazin-1 -yl)- phenyl]-ethyl}-1 ,3-dihydro-imidazol-2-one; 3-[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-4-methyl-1 -{2-[2-(4-methyl-piperazin-1 -yl)- phenyl]-ethyl}-1 ,3-dihydro-imidazol-2-one;
3-[4-(1 -Hydroxy-cyclopentyl)-phenyl]-4-methyl-1 -{2-[2-(4-methyl-piperazin-1 -yl)- phenyl]-ethyl}-1,3-dihydro-imidazol-2-one;
3-[4-(1 -Methoxy-cyclobutyO-phenyO^-methyl-i -{2-[2-(4-methyl-piperazin-1 -yl)- phenyl]-ethyl}-1 ,3-dihydro-imidazol-2-one;
3-[6-(1 -Hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-4-methyl-1 -{2-[2-(4-methyl-piperazin-1 - yl)-phenyI]-ethyI}-1 ,3-dihydro-imidazol-2-one;
3-[6-(1-Methoxy-1-methyl-ethyl)-pyridin-3-yl]-4-methyl-1-{2-[2-(4-methyl-piperazin-1- yl)-phenyl]-ethyl}-1 ,3-dihydro-imidazol-2-one; 3-[6-(1 -Methoxy-cyclopentyO-pyridin-S-yll^-methyl-i -{2-[2-(4-methyl-piperazin-1 -yl)- phenyl]-ethyl}-1 ,3-dihydro-imidazol-2-one; 3-[4-(1 -Methoxy-1 -methyl-ethyl)-phenyl]-4-methyl-1 -{2-[2-(4-methyl-piperazin-1 -yl)- phenyl]-ethyl}-1 ,3-dihydro-imidazol-2-one;
1 -(4-lsopropoxy-phenyl)-3-{2-[2-(4-methyl-piperazin-1 -yl)-pyridin-3-yl]-ethyl}-1 ,3- dihydro-imidazoI-2-one; 1-{2-[2-(4-Methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-3-(4-oxazol-2-yl-phenyl)-1 ,3- dihydro-imidazol-2-one;
1 -(6-Methoxy-pyridin-3-yl)-3-{2-[2-(4-methyl-piperazin-1 -yl)-pyridin-3-yl]-ethyl}-1 ,3- dihydro-imidazol-2-one;
1-(2-Methyl-benzothiazol-5-yl)-3-{2-[2-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}- 1 ,3-dihydro-imidazol-2-one;
1-[4-(1-Methoxy-cyclobutyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1-yl)-pyridin-3-yl]- ethyl}-1 ,3-dihydro-imidazoI-2-one;
1-{2-[2-(4-Methyl-piperazin-1-yI)-pyridin-3-yl]-ethyl}-3-(4-oxazol-5-yl-phenyl)-1 ,3- dihydro-imidazol-2-one; 1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-pyridin-3-yl]- ethyl}-1 ,3-dihydro-imidazol-2-one;
1-{2-[2-(4-Methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-3-[4-(tetrahydro-pyran-4-yl)- phenyl]-1 ,3-dihydro-imidazol-2-one;
1 -[6-(1 -Hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-pyridin- 3-yl]-ethyl}-1 ,3-dihydro-imidazol-2-one;
1-[4-(2-Hydroxy-2-methyl-propyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1-yl)-pyridin-3- yl]-ethyl}-1 ,3-dihydro-imidazol-2-one;
1-[4-(2-Methoxy-2-methyi-propyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1-yl)-pyridin-3- yl]-ethyl}-1 ,3-dihydro-imidazol-2-one; 1-{2-[2-(4-Methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-3-(1 -oxo-1 ,3-dihydro- isobenzofuran-5-yl)-1 ,3-dihydro-imidazol-2-one;
1 -lsochroman-6-yl-3-{2-[2-(4-methyl-piperazin-1 -yl)-pyridin-3-yl]-ethyl}-1 ,3-dihydro- imidazol-2-one;
1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-pyridin-3-yl]- ethyl}-1 ,3-dihydro-imidazoI-2-one;
1 -[4-(5-Methyl-[1 ,3,4]oxadiazol-2-yl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-pyridin- 3-yl]-ethyl}-1 ,3-dihydro-imidazol-2-one;
1 -[4-(1 -Methoxy-1 -methyl-ethyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-pyridin-3-yl]- ethyl}-1 ,3-dihydro-imidazol-2-one; 1-[6-(1 -Methoxy-1 -methyl-ethyl)-pyridin-3-yl]-3-{2-[2-(4-methyl-piperazin-1-yl)-pyridin-
3-yl]-ethyl}-1 ,3-dihydro-imidazol-2-one; 1-[4-(3-Methyl-[1 ,2,4]oxadiazol-5-yl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1-yI)-pyridin- 3-yl]-ethyl}-1 ,3-dihydro-imidazol-2-one;
1-[6-(1-Methoxy-cyclopentyl)-pyridin-3-yl]-3-{2-[2-(4-methyl-piperazin-1-yl)-pyridin-3- yl]-ethyl}-1 ,3-dihydro-imidazol-2-one; 1-[4-(1-Hydroxy-cyclopentyl)-phenyl]-3-{2-[3-(4-methyl-piperazin-1-yl)-pyridin-2-yl]- ethyl}-1 ,3-dihydro-imidazol-2-one;
1-[4-(1-Hydroxy-1-methyl-ethyI)-phenyl]-3-{2-[3-(4-methyl-piperazin-1-yl)-pyridin-2-yl]- ethyl}-1 ,3-dihydro-imidazol-2-one;
1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-{2-[3-(4-methyl-piperazin-1 -yl)-pyridin-2-yl]- ethyl}-1 ,3-dihydro-imidazol-2-one;
1-[4-(1-Methoxy-cyclobutyl)-phenyl]-3-{2-[3-(4-methyl-piperazin-1-yl)-pyridin-2-yl]- ethyl}-1 ,3-dihydro-imidazol-2-one;
1 -[4-(1 -Methoxy-1 -methyl-ethyl)-phenyl]-3-{2-[3-(4-methyl-piperazin-1 -yl)-pyridin-2-yl]- ethyl}-1 ,3-dihydro-imidazol-2-one; 1-[6-(1 -Methoxy-1 -methyl-ethyl)-pyridin-3-yl]-3-{2-[3-(4-methyl-piperazin-1-yl)-pyridin-
2-yl]-ethyl}-1 ,3-dihydro-imidazol-2-one;
1-[4-(1-Hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl-3,4,5,6-tetrahydro-2H- [1 ,2']bipyrazinyl-3'-yl)-ethyl]-1 ,3-dihydro-imidazol-2-one;
1-[4-(1-Methoxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-3,4,5,6-tetrahydro-2H- [1 ,2']bipyrazinyl-3'-yl)-ethyl]-1 ,3-dihydro-imidazol-2-one;
1 -[4-(1 -Methoxy-1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-3,4,5,6-tetrahydro-2H- [1 ,2']bipyrazinyl-3'-yl)-ethyl]-1 ,3-dihydro-imidazoI-2-one;
1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[2-(4-methyI-piperazin-1 -yl)-benzyl]- imidazolidin-2-one; 1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]- ethyl}-imidazolidin-2-one;
1-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-3-(4-trifluoromethyl-phenyl)- imidazolidin-2-one;
1-[4-(1-Hydroxy-cyclopentyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}- imidazolidin-2-one;
1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-pyridin-3-yl]- imidazolidin-2-one;
1-[4-(1-Hydroxy-cyclobutyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}- tetrahydro-pyrimidin-2-one; 1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]- ethyl}-1 ,3-dihydro-benzoimidazol-2-one; 1-[4-(1-Hydroxy-cyclopentyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}- 1 ,3-dihydro-benzoimidazol-2-one;
1-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-3-(4-oxazol-4-yl-phenyl)-1 ,3-dihydro- benzoimidazol-2-one; 1 -{2-[2-(4-Methyl-piperazin-1 -yl)-phenyl]-ethyl}-3-(4-oxazol-2-yl-phenyl)-1 ,3-dihydro- benzoimidazol-2-one;
1 -{2-[2-(4-Methyl-piperazin-1 -yl)-phenyl]-ethyl}-3-(3-oxo-1 ,3-dihydro-isobenzofuran-5- yl)-1 ,3-dihydro-benzoimidazol-2-one;
1 -(6-Methoxy-pyridin-3-yl)-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]-ethyl}-1 ,3-dihydro- benzoimidazol-2-one;
1-[4-(2-Methyl-oxazol-4-yl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}- 1 ,3-dihydro-benzoimidazol-2-one;
1-[4-(1-Methoxy-cyclobutyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}- 1 ,3-dihydro-benzoimidazol-2-one; 1 -[4-(2-Methoxy-2-methyl-propyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]- ethyl}-1 ,3-dihydro-benzoimidazol-2-one;
1-[4-(1-Hydroxy-cyclopentyl)-phenyl]-3-{2-t2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}- 1 ,3-dihydro-imidazo[4,5-b]pyridin-2-one;
1-[4-(1-Hydroxy-cyclopentyl)-phenyl]-3-{2-t3-(4-methyl-piperazin-1-yl)-pyridin-2-yl]- ethyl}-1 ,3-dihydro-imidazo[4,5-b]pyridin-2-one;
1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-{2-[3-(4-methyl-piperazin-1 -yl)-pyridin-2-yl]- ethyl}-1 ,3-dihydro-imidazo[4,5-b]pyridin-2-one;
1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]- ethyl}-1 ,3-dihydro-imidazo[4,5-b]pyridin-2-one; 1 -[6-(1 -Hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]- ethyl}-1 ,3-dihydro-imidazo[4,5-b]pyridin-2-one;
1 -[6-(1-Methoxy-1 -methyl-ethyl)-pyridin-3-yl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]- ethyl}-1 ,3-dihydro-imidazo[4,5-b]pyridin-2-one;
1 -[4-(1 -Methoxy-1 -methyl-ethyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]- ethyl}-1 ,3-dihydro-imidazo[4,5-b]pyridin-2-one;
3-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-1-[4-(tetrahydro-pyran-4-yl)-phenyl]- 1 ,3-dihydro-imidazo[4,5-b]pyridin-2-one;
3-{2-[2-(4-Methy!-piperazin-1 -yl)-phenyl]-ethyl}-1 -(3-oxo-1 ,3-dihydro-isobenzofuran-5- yl)-1 ,3-dihydro-imidazo[4,5-b]pyridin-2-one; 1 -(4-tert-Butyl-phenyl)-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]-ethyl}-1 ,3-dihydro- imidazo[4,5-b]pyridin-2-one;
3-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-6-phenyl-1 H-quinazoline-2,4-dione; 3-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-7-phenyl-1 H-quinazoline-2,4-dione;
1 -Methyl-3-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]-ethyl}-7-phenyl-1 H-quinazoline-2,4- dione;
1-Methyl-3-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}-7-(4-trifluoromethyl-phenyl)- 1 H-quinazoline-2,4-dione;
7-[4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-1-methyl-3-{2-[2-(4-methyl-piperazin-1-yl)- phenyl]-ethyl}-1 H-quinazoline-2,4-dione;
3-{2-[2-(4-Methyl-piperazin-1-yl)-phenyI]-ethyl}-6-(morpholine-4-carbonyl)-1 H- quinazoline-2,4-dione; 5-tert-Butyl-2-{2-[2-(4-methyl-piperazin-1 ~yl)-phenyl]-ethyl}-isoindole-1 ,3-dione;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-benzo[f]isoindole-1 ,3-dione;
5-Methyl-2-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}-isoindole-1 ,3-dione;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-5-nitro-isoindoIe-1 ,3-dione;
5-Fluoro-2-{2-[2-(4-methyl-piperazin-1-yi)-phenyl]-ethyl}-isoindole-1 ,3-dione; 5-Chloro-2-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]-ethyl}-isoindole-1 ,3-dione;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-isoindole-1 ,3-dione;
5-Methoxy-2-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}-isoindole-1 ,3-dione;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-5-phenyl-isoindole-1 ,3-dione;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-5-morpholin-4-yl-isoindole-1 ,3-dione; 5-[4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-2-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]- ethyl}-isoindole-1 ,3-dione;
5-[4-(1-Hydroxy-cyclopentyl)-phenyl]-2-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}- isoindole-1 ,3-dione;
5-[6-(1 -Hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-2-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]- ethyl}-isoindole-1 ,3-dione;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-5-(4-trifluoromethyl-phenyl)-isoindole- 1 ,3-dione;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-5-pyridin-2-yl-isoindole-1 ,3-dione;
2-{2-[2-(4-Methyl-piperazin-1-y!)-phenyl]-ethyl}-5-pyridin-3-yl-isoindole-1 ,3-dione; 5-(4-tert-Butyl-phenyl)-2-{2-[2-(4-methyl-piperazin-1 -yl)-phenyl]-ethyl}-isoindole-1 ,3- dione;
5-Amino-2-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}-isoindole-1 ,3-dione;
2-[2-(4-Methyl-piperazin-1-yl)-benzyl]-7-phenyl-3,4-dihydro-2H-isoquinolin-1-one;
2-[2-(4-Methyl-piperazin-1-yl)-benzyl]-7-morpholin-4-yl-3,4-dihydro-2H-isoquinoIin-1- one;
2-[2-(4-Methyl-piperazin-1-yI)-benzyl]-7-morpholin-4-y]-1 ,2,3,4-tetrahydro- isoquinoline; 2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-7-morpholin-4-yl-1 ,2,3,4-tetrahydro- isoquinoline;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-5-phenyl-2,3-dihydro-isoindol-1-one;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-5-(morpholine-4-carbonyl)-2,3- dihydro-isoindol-1-one;
6-Bromo-2-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}-3,4-dihydro-2H-isoquinolin-1- one;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-6-phenyl-3,4-dihydro-2H-isoquinolin-1- one; 2-{2-[2-(4-Methyl-piperazin-1 -yl)-phenyl]-ethyI}-6-pyridin-4-yl-3,4-dihydro-2H- isoquinolin-1-one;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-6-pyridin-3-yl-3,4-dihydro-2H- isoquinolin-1-one;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-6-morpholin-4-yl-3,4-dihydro-2H- isoquinolin-1-one;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-6-(morpholine-4-carbonyl)-3,4- dihydro-2H-isoquinolin-1-one;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-6-phenyl-1 ,2,3,4-tetrahydro- isoquinoline; 2-{2-[2-(4-Methyl-piperazin-1 -yl)-phenyl]-ethyl}-5-phenyl-2,3-dihydro-1 H-isoindole;
2-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-2,3-dihydro-1 H-isoindol-5-ylamine;
1-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-1 ,3-dihydro-imidazol-2-one;
1-{2-[2-(4-Methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-1 ,3-dihydro-imidazol-2-one;
1-{1-Methyl-2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}-1 ,3-dihydro-imidazol-2-one; 4-Methyl-1-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}-1 ,3-dihydro-imidazol-2-one;
1-{2-[3-(4-Methyl-piperazin-1-yl)-pyridin-2-yl]-ethyl}-1 ,3-dihydro-imidazol-2-one;
1 -[2-(4-Methyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-3'-yl)-ethyl]-1 ,3-dihydro- imidazol-2-one;
1-[2-(4-Methyl-piperazin-1-yl)-pyridin-3-yl]-imidazolidin-2-one; 1-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-imidazolidin-2-one;
1-[2-(4-Methyl-piperazin-1-yl)-benzyl]-imidazolidin-2-one;
1-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-tetrahydro-pyrimidin-2-one;
1 -{2-[2-(4-Methyl-piperazin-1 -yl)-phenyl]-ethyl}-1 ,3-dihydro-benzoimidazol-2-one;
3-{2-[2-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-1 ,3-dihydro-imidazo[4,5-b]pyridin-2- one;
3-{2-[3-(4-Methyl-piperazin-1-yl)-pyridin-2-yl]-ethyl}-1 ,3-dihydro-imidazo[4,5-b]pyridin- 2-one; 6-Bromo-3-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}-1 H-quinazoline-2,4-dione;
7-Bromo-3-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}-1 H-quinazoline-2,4-dione;
7-Bromo-1-methyl-3-{2-[2-(4-methyl-piperazin-1-yI)-phenyl]-ethyl}-1 H-quinazoline-2,4- dione; 5-Bromo-2-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyI}-isoindole-1 ,3-dione;
5-Bromo-2-{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}-2,3-dihydro-isoindol-1 -one; and, pharmaceutically acceptable salts thereof.
15. 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, dependencies on, or addictions to nicotine or tobacco products, alcohol, benzodiazepines, barbiturates, opioids or cocaine, headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome, comprising an amount of a compound of any one of claims 1 to 14 that is effective in treating such disorder or condition and a pharmaceutically acceptable carrier.
16. 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, dependencies on, or addictions to nicotine or tobacco products, alcohol, benzodiazepines, barbiturates, opioids or cocaine, headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome, comprising administering to a mammal in need of such treatment an amount of a compound of any one of claims 1 to 14 that is effective in treating such disorder or condition.
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