WO 2006/135839 PCT/US2006/022719
PIPERAZINE-PIPERIDINE ANTAGONISTS AND AGONISTS OF THE
5-HT1A RECEPTOR
[0001] Throughout this application, various publications are referenced. The
disclosures of these publications in their entireties are hereby incorporated by
reference into this application in order to more fully describe the state of the art as
known to those skilled therein as of the date of the invention described and claimed
herein.
[0002] This patent disclosure contains material that is subject to copyright
protection. The copyright owner has no objection to the facsimile reproduction by
anyone of the patent document or the patent disclosure, as it appears in the U.S. Patent
and Trademark Office patent file or records, but otherwise reserves any and all
copyright rights whatsoever.
FIELD OF THE INVENTION
[0003] The present invention relates to novel piperazine-piperidine compounds.
The compounds are useful as 5-HT1A binding agents, particularly as 5-HT1A receptor
antagonists and agonists. These compounds are useful in treating central nervous
system disorders, such as cognition disorders, anxiety disorders, and depression.
BACKGROUND OF THE INVENTION
[0004] Certain N-aryl-piperazine derivatives possess pharmaceutical activity. In
particular, certain N-aryl piperazine derivatives act on the central nervous system
(CNS) by binding to 5-HT receptors. In pharmacological testing, it has been shown
that the certain N-aryl-piperazine derivatives bind to receptors of the 5-HT1A type.
Many of the N-aryl piperazine derivatives exhibit activity as 5-HT1A antagonists. See,
for example, W.C. Childers, et al., J. Med. Chem., 48: 3467-3470 (2005), U.S. Patent
Nos. 6,465,482, 6,127,357, 6,469,007, and 6,586,436, and PCT Publication No. WO
97/03982, the disclosures of which are incorporated herein by reference.
[0005] Pharmaceutical compounds that interact with the 5-HT1A receptor are
useful to treat a wide variety of central nervous system disorders, such as cognition
disorders, anxiety disorders, and depression. The present invention is directed to
novel 5-HT1A antagonists and agonists, which would be useful for these and other
uses.

WO 2006/135839 PCT/US2006/022719
SUMMARY OF THE INVENTION
[0006] In one aspect, the invention provides compounds of the Formula (I):

wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, and R16,
are each independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-aIkenyl, or (C2-
C6)-alkynyl, halogen, -CF3, -NO2, -CN, -OR25, -OSO2R25, -SR25, -SO2R25, -
SO2N(R25)2, -N(R25)2, C(O), -COR25, -CO2R25, -NR25CO2R25 -NR25COR25, -
NR25CON(R25)2, or -CONCR25)2;
Ra and Rb are each independently -H or -CH3; and
R25 is -H, linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl,
or (C2-C6)-alkynyl.
[0007] In another aspect, the invention provides compounds of the Formula (I'):

wherein R1, R2, R3, R4, R5, R6, R7, Rs, R9, R10, R11, R12, R13, R14, R15, and R16, are
each independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-
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WO 2006/135839 PCT/US2006/022719
alkynyl, halogen, -CF3, -NO2, -CN, -OR25, -OSO2R25, -SR25, -SO2R25, -SO2N(R25)2,
-N(R25)2) C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25, -NR25CON(R25)2, or
-CON(R25)2;
Ra and Rb are each independently -H or -CH3; and
R25 is -H, linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl,
or (C2-C6)-alkynyl; and
where n is an integer from 1 to 2.
[0008] In another aspect, the invention provides compounds of the Formula (I"):

wherein R1, R2, R3, R4, R5, R6, R7, R7, R8, R9, R10, R11, R12, R13, R14, R15, and
R16, are each independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or
(C2-C6)-alkynyl, halogen, -CF3, -NO2, -CN, -OR25, -OSO2R25, -SR25, -SO2R25, -
SO2N(R25)2, -N(R25)2, C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25, -
NR25CON(R25)2, or -CON(R25)2;
Ra and Rb are each independently -H or -CH3;
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-alkynyl and
where the piperidine group can be attached to the nonhetero atom containing
ring of the quinoline through positions R7, R7, R8, or R9.
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[0009] In another aspect, the invention provides compounds of the Formula (I"a):

wherein R1, R2, R3, R4, R5, R6, R7', R8, R9, R10, R11, R12, R13,
R14, R15, and R16, are each independently -H, (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen, -CF3,
-NO2) -CN, -OR25, -OSO2R25, -SR25, -SO2R25, -SO2N(R25)2, -N(R25)2, -
C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25, -NR25CON(R25)2,
or -CON(R25)2;
Ra and Rb are each independently -H or -CH3; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl.

WO 2006/135839 PCT/US2006/022719
[0010] In another aspect, the invention provides compounds of the Formula (II):

wherein R4, R5, R15, R16, R17, R18 and R19 are each independently -H, (C1-C6)-
alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen, -CF3, -NO2,
-CN, -OR25, -OSO2R25, -SR25, -SQ2R25, -SO2N(R25)2, -N(R25)2, C(O), -COR25,
-CO2R25, -NR25CO25, -NR25COR25, -NR25CON(R25)2, or -CON(R25)2;
Ra and Rb are each independently -H or -CH3;
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-alkynyl; and
R4 and R5 cannot both be hydrogen.
[0011] In a further aspect, the invention provides compounds of the Formula (III):

and pharmaceutically acceptable salts thereof,
wherein R99 is selected from:
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R7, Rs, R9, R10, R11, R12, R13, R14. R15, R16, R20, R21, R22, R23, R24. R26, R27,
R28, R29, and R30 are each independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-alkynyl, halogen, -CF3; -NO2, -CN, -OR25, -OSO2R25, -SR25, -
SO2R25, -SO2N(R25)2, -N(R25)2, C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25,
-NR25CON(R25)2, or -CON(R25)2;
Ra and Rb are each independently -H or -CH3;
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-alkynyl.
[0012] In yet another aspect, the invention provides compounds of the Formula
(IV):

wherein X is CR25, N, O or S; Y is CR25, NR25, O or S; with the proviso that
when X is CR25, Y is not N;
R13, R14, R15, R16, R31, R32, R33, R34, R35, R36, R37, R38 and R39 are each independently
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-H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen,
-CF3, -NO2, -CN, -OR25, -OSO2R25, -SR25, -SO2R25, -SO2N(R25)2, -N(R25)2, C(O), -
COR25, -CO2R25, -NR25CO2R25, -NR25COR25, -NR25CON(R25)2, or-CON(R25)2;
Ra and Rb are each independently -H or -CH3; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-alkynyl.
[0013] In another aspect, the compounds and pharmaceutically acceptable salts of
the compounds of Formulas (I), (I'), (I"), (I"a), (II), (III), and (IV) are also useful
when formulated as pharmaceutical compositions. These pharmaceutical
compositions comprise compounds and pharmaceutically acceptable salts of the
compounds of Formulas (I), (I'), (I"), (II), (III), or (IV) and a pharmaceutically
acceptable carrier.
[0014] In another aspect, the compounds and pharmaceutically acceptable salts of
the compounds of Formulas (I), (I'), (I"), (I"a), (II), (HI), and (TV) are useful as 5-
HT1A receptor agonists and antagonists.
[0015] In another aspect, the pharmaceutical compositions comprising one or
more compounds and pharmaceutically acceptable salts of the compounds of
Formulas (I), (I'), (I"), (I"a), (II), (III), or (IV) are useful as 5-HT1A receptor
agonists and antagonists.
[0016] In one aspect, the invention provides methods for treating a 5-HT1A-related
disorder, comprising administering to a patient in need thereof one or more of the
compounds or pharmaceutically acceptable salts of compounds of Formulas (I), (I'),
(I"), (I"a), (II), (III), and (IV) in a therapeutically effective amount to treat a 5-HT1A-
related disorder.
[0017] In one aspect, the invention provides methods for treating a 5-HT1A-related
disorder, comprising administering to a patient in need thereof a pharmaceutical
formulation comprising one or more of the compounds or pharmaceutically acceptable
salts of compounds of Formulas (I), (I'), (I"), (I"a), (II), (III), and (IV) in a
therapeutically effective amount to treat a 5-HT1A-related disorder.
[0018] In one aspect, the invention provides methods for treating a cognition-
related disorder, comprising administering to a patient in need thereof one or more of
the compounds or pharmaceutically acceptable salts of compounds of Formulas (I),
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(I'), (I"), (I"a), (II), (III), and (IV) in a therapeutically ettective amount to treat a
cognition-related disorder.
[0019] In one aspect, the invention provides methods for treating a cognition-
related disorder, comprising administering to a patient in need thereof a
pharmaceutical formulation comprising one or more of the compounds or
pharmaceutically acceptable salts of compounds of Formulas (I), (I'), (I"), (I"a), (II),
(III), and (IV) in an amount effective to treat a cognition-related disorder.
[0020] In another aspect, the invention provides methods for treating an anxiety-
related disorder, comprising administering to a patient in need thereof one or more of
the compounds or pharmaceutically acceptable salts of compound of Formulas (I),
(I'), (I"), (I"a), (II), (III), and (IV) in an amount effective to treat an anxiety-related
disorder.
[0021] In another aspect, the invention provides methods for treating an anxiety-
related disorder, comprising administering to a patient in need thereof a
pharmaceutical formulation comprising one or more of the compounds or
pharmaceutically acceptable salts of compound of Formulas (I), (I'), (I"), (I"a), (II),
(III), and (IV) in an amount effective to treat an anxiety-related disorder.
[0022] In one aspect, the invention provides methods for treating Alzheimer's
disease to a patient in need thereof. The method includes administering to the patient
an effective amount of a compound or a pharmaceutically acceptable salt of a
compound of Formula (I), Formula (I'), Formula (I"), Formula (I"a), Formula (II),
Formula (III), or Formula (IV). In one embodiment, the method includes
administering to the patient a pharmaceutical composition comprising one or more of
the compounds or pharmaceutically acceptable salts of compounds of Formulas (I),
(I'), (I"), (I"a), (II), (III), and (IV) in an amount effective to treat Alzheimer's
disease.
[0023] In one aspect, the invention provides methods for treating mild cognitive
impairment (MCI) to a patient in need thereof. The method includes administering to
the patient an effective amount of a compound or a pharmaceutically acceptable salt of
a compound of Formula (I), Formula (I'), Formula (I"), Formula (I"a), Formula (II),
Formula (III), or Formula (IV). In one embodiment, the method includes
administering to the patient a pharmaceutical composition comprising one or more of
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the compounds or pharmaceutically acceptable salts of compounds of Formulas (I),
(I'), (I"), (I"a), (II), (III), and (IV) in an amount effective to treat mild cognitive
impairment.
[0024] In one aspect, the invention provides methods for treating depression to a
patient in need thereof. The method includes administering to the patient an effective
amount of a compound or a pharmaceutically acceptable salt of a compound of
Formula (I), Formula (I'), Formula (I"), Formula (I"a), Formula (II), Formula (III),
or Formula (IV). In one embodiment, the method includes administering to the
patient a pharmaceutical composition comprising one or more of the compounds or
pharmaceutically acceptable salts of compounds of Formulas (I), (P), (I"), (I"a), (II),
(III), and (IV) in an amount effective to treat depression.
[0025] In one aspect, the treatment methods of the invention include administering
a second therapeutic agent.
[0026] In one aspect, the invention provides methods for treating sexual
dysfunction associated with drug treatment in a patient in need thereof. The method
includes administering to the patient an effective amount of a compound or a
pharmaceutically acceptable salt of a compound of Formula (I), Formula (I'), Formula
(I"), Formula (I"a), Formula (II), Formula (III), or Formula (IV). In one
embodiment, the method includes administering to the patient a pharmaceutical
composition comprising one or more of the compounds or pharmaceutically
acceptable salts of compounds of Formulas (I), (I'), (I"), (I"a), (II), (III), and (IV) in
an amount effective to treat sexual dysfunction.
[0027] In one aspect, the invention provides methods of improving sexual
function in a patient in need thereof, the method comprising administering to the
patient a pharmaceutically effective amount of a compound or a pharmaceutically
acceptable salt of a compound of Formula (I), Formula (I'), Formula (I"), Formula
(I"a), Formula (II), Formula (HI), or Formula (IV). In one embodiment, the method
includes administering to the patient a pharmaceutical composition comprising one or
more of the compounds or pharmaceutically acceptable salts of compounds of
Formulas (I), (I'), (I"), (Pa), (II), (III), and (IV) in an amount effective to improve
sexual function.
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[0028] la one aspect, the invention provides methods of synthesizing the
compounds and pharmaceutically acceptable salts of compounds of Formulas (I), (I'),
(I"),(I"a),(II),(III),and(IV).
[0029] In another aspect, the invention provides compounds and pharmaceutically
acceptable salts of compounds of Formulas (I), (I'), (I"), (I"a), (II), (III), and (IV)
made by particular processes.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0030] The term "(C1-C6)-alkyl" as used herein refers to a linear or branched,
saturated hydrocarbon having from 1 to 6 carbon atoms. Representative (C1-C6)-alkyl
groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-
butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, and neohexyl. In one
embodiment, the (C1-C6)-alkyl group is optionally substituted with one or more of the
following groups: halogen, -N3, -NO2, -CN, -OR', -SR', -SO2R', -SO2N(R')2, -N(R')2,
-COR', -CO2R', -NR'CO2R', -NR'COR', -NR'CONR', or -CON(R')2, wherein each
R' is independently hydrogen or unsubstituted (C1-C6)-alkyl.
[0031] The term "(C2-C6)-alkenyl" as used herein refers to a linear or branched
hydrocarbon having from 2 to 6 carbon atoms and having at least one carbon-carbon
double bond. In one embodiment, the (C2-C6)-alkenyl has one or two double bonds.
The (C2-C6)-alkenyl moiety may exist in the E or Z conformation and the compounds
of the present invention include both conformations. In one embodiment, the (C2-C6)-
alkenyl group is optionally substituted with one or more of the following groups:
halogen, -N3, -NO2, -CN, -OR', -SR', -SO2R', -SO2N(R')2, -N(R')2, -COR', -CO2R', -
NR'CO2R', -NR'COR', -NR'CONR', or -CON(R')2, wherein each R' is
independently hydrogen or unsubstituted (C1-C6)-alkyl.
[0032] The term "(C2-C6)-alkynyl" as used herein refers to a linear or branched
hydrocarbon having from 2 to 6 carbon atoms and having at least one carbon-carbon
triple bond. In one embodiment, the (C2-C6)-alkenyl group is optionally substituted
with one or more of the following groups: halogen, -N3, -NO2, -CN, -OR', -SR', -
SO2R', -SO2N(R')2, -N(R')2, -COR', -CO2R', -NR'CO2R', -NR'COR', -NR'CONR',
or -CON(R')2, wherein each R' is independently hydrogen or unsubstituted (C1-C6)-
alkyl.
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[0033] "(C1-C6)-haloalkyI" refers to a C1-C6 alkyl group, as defined above,
wherein one or more of the C1-C6 alkyl group's hydrogen atoms has been replaced
with -F, -Cl, -Br or -I. Representative examples of an alkylhalo group include, but are
not limited to, -CH2F, -CC13, -CF3, -CH2C1, -CH2CH2Br, -CH2CH2I, -CH2CH2CH2F,
-CH2CH2CH2C1, -CH2CH2CH2CH2Br, -CH2CH2CH2CH2I, -CH2CH2CH2CH2CH2Br,
-CH2CH2CH2CH2CH2I, -CH2CH(Br)CH3, -CH2CH(C1)CH2CH3, -CH(F)CH2CH3,
-C(CH3)2(CH2C1), -CH2CH2CH2CH2CH2CH2Br, and -CH2CH2CH2CH2CH2CH2I.
[0034] The term "administer", "administering", or "administration", as used
herein refers to either directly administering a compound or pharmaceutically
acceptable salt of the compound or a composition to an animal, or administering a
prodrug derivative or analog of the compound or pharmaceutically acceptable salt of
the compound or composition to the animal, which can form an equivalent amount of
active compound within the animal's body.
[0035] The term "animal" as used herein includes, without limitation, a human,
mouse, rat, guinea pig, dog, cat, horse, cow, pig, monkey, chimpanzee, baboon, or
rhesus. In one embodiment, the animal is a mammal. In another embodiment, the
animal is a human.
[0036] The term "aryl" as used herein refers to an aromatic species containing 1 to
3 aromatic rings, either fused or linked. In one embodiment, the aryl group is
optionally substituted with one or more of the following groups: -V-halogen, -V-N3, -
V-NO2, -V-CN, -V-OR', -V-SR', -V-SO2R', -V-SO2N(R')2, -V-N(R')2, -V-COR', -V-
CO2R', -V-NR'CO2R', -V-NR'COR', -V-NR'CONR', or -V-CON(R')2, wherein
each R' is independently hydrogen or unsubstituted (C1-C6)-alkyl; and wherein each V
is independently a bond or (C1-C6)-alkyl.
[0037] The term "conditions effective to" as used herein refers to synthetic
reaction conditions which will be apparent to those skilled in the art of synthetic
organic chemistry.
[0038] The term "cyclic group" as used herein includes a cycloalkyl group and a
heterocyclic group. Any suitable ring position of the cyclic group may be covalently
linked to the defined chemical structure. In one embodiment, the cyclic group is
optionally substituted with one or more of the following groups: -V-halogen, -V-N3, -
V-NO2, -V-CN, -V-OR', -V-SR', -V-SO2R', -V-SO2N(R')2, -V-N(R')2, -V-COR', -V-
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CO2R', -V-NR'CO2R', -V-NR'COR', -V-NR'CONR', or-V-CON(R')2, wherein
each R1 is independently hydrogen or unsubstituted (C1-C6)-alkyl; and wherein each V
is independently a bond or (C1-C6)-alkyl.
[0039] The term "cycloalkyl group" as used herein refers to a three- to seven-
membered saturated or partially unsaturated carbon ring. Any suitable ring position of
the cycloalkyl group may be covalently linked to the defined chemical structure.
Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and cycloheptyl. In one embodiment, the cycloalkyl group is optionally
substituted with one or more of the following groups: -V-halogen, -V-N3, -V-NO2, -V-
CN, -V-OR', -V-SR', -V-SO2R', -V-SO2N(R')2, -V-N(R')2, -V-COR', -V-CO2R', -V-
NR'CO2R', -V-NR'COR', -V-NR'CONR', or-V-CON(R')2, wherein each R' is
independently hydrogen or unsubstituted (C1-C6)-alkyl; and wherein each V is
independently a bond or (C1-C6)-alkyl.
[0040] The term "effective amount" as used herein refers to an amount of a
compound or pharmaceutically acceptable salt of a compound that, when administered
to an animal, is effective to prevent, to at least partially ameliorate, or to cure, a
condition from which the animal suffers or is suspected to suffer.
[0041] The term "halogen" as used herein refers to fluorine, chlorine, bromine,
and iodine.
[0042] The term "heterocyclic group" as used herein refers to a three- to
seven-membered saturated, partially saturated, or unsaturated cycloalkyl group in
which one to four of the ring carbon atoms have been independently replaced with a
N, O, or S atom. Any suitable ring position of the heterocyclic group may be
covalently linked to the defined chemical structure. Exemplary heterocyclic groups
include, but are not limited to, azepanyl, azetidinyl, aziridinyl, furanyl, furazanyl,
homopiperazinyl, irnidazolidinyl, imidazolinyl, isothiazolyl, isoxazolyl, morpholinyl,
oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl,
phenanthrolinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolidinyl,
pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl,
thiadiazinyl, thiadiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiomorpholinyl, thiophenyl, triazinyl, and triazolyl. In one embodiment, the
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heterocyclic group is optionally substituted with one or more of the following groups:
-V-halogen, -V-N3, -V-NO2, -V-CN, -V-OR', -V-SR', -V-SO2R', -V-SO2N(R')2, -V-
N(R')2, -V-COR', -V-CO2R', -V-NR'CO2R', -V-NR'COR', -V-NR'CONR', or -V-
CON(R')2, wherein each R' is independently hydrogen or unsubstituted (C1-G6)-alkyl;
and wherein each V is independently a bond or (C1-C6)-alkyl.
[0043] The term "isolated and purified" as used herein refers to separate from
other components of a reaction mixture or a natural source. In certain embodiments,
the isolate contains at least about 50%, at least about 55%, at least about 60%, at least
about 65%, at least about 70%, at least about 75%, at least about 80%, at least about
85%, at least about 90%, at least about 95%, or at least about 98% of the compound or
pharmaceutically acceptable salt of the compound by weight of the isolate.
[0044] The term "pharmaceutically acceptable salt", as used herein, refers to salts
derived from organic and inorganic acids of a compound of the present invention.
Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate,
chloride, hydrochloride, bromide, hydrobromide, iodide, nitrate, bisulfate, phosphate,
acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate,
pantothenate, bitartrate, ascoRbate, succinate, maleate, gentisinate, fumarate,
gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate,
ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate;
napthalenesulfonate, propionate, succinate, fumarate, maleate, malonate, mandelate,
malate, phthalate, and pamoate. The term "pharmaceutically acceptable salt" as used
herein also refers to a salt of a compound of the present invention having an acidic
functional group, such as a caRboxylic acid functional group, and a base. Exemplary
bases include, but are not limited to, hydroxide of alkali metals including sodium,
potassium, and lithium; hydroxides of alkaline earth metals such as calcium and
magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia,
organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-
alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine;
diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C1-C6)-alkylamine), such as
N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-
glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such
as arginine, lysine, and the like. The term "pharmaceutically acceptable salt" also
includes hydrates of a compound of the present invention.
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[0045] The term "phenyl" as used herein refers to a substituted or unsubstituted
phenyl group. In one embodiment, the phenyl group is optionally substituted with one
or more of the following groups: -V-halogen, -V-N3, -V-NO2, -V-CN, -V-OR', -V-
SR', -V-SO2R', -V-SO2N(R')2, -V-N(R')2, -V-COR', -V-CO2R', -V-NR'CO2R', -V-
NR'COR', -V-NR'CONR', or -V-CON(R')2, wherein each R' is independently
hydrogen or unsubstituted (C1-C6)-alkyl; and wherein each V is independently a bond
or (C1-C6)-alkyl.
[0046] The term "substantially free of its corresponding opposite enantiomer" as
used herein means that the compound contains no more than about 10% by weight of
its corresponding opposite enantiomer. In other embodiments, the compound that is
substantially free of its corresponding opposite enantiomer contains no more than
about 5%, no more than about 1%, no more than about 0.5%, or no more than about
0.1 % by weight of its corresponding opposite enantiomer. An enaotiomer that is
substantially free of its corresponding opposite enantiomer includes a compound that
has been isolated and purified or has been prepared substantially free of its
corresponding opposite enantiomer.
[0047] The term "5-HT1A-related disorder" as used herein refers to a condition
which is mediated through the 5-HT1A receptor. In some embodiments, a 5-HT1A-
related disorder is a condition for which it would be beneficial to prevent activation of
the 5-HT1A receptor. In other embodiments, a 5-HT1A-related disorder is a condition
for which it would be beneficial to activate the 5-HT1A receptor. In one embodiment,
a 5-HTlA-related disorder affects the central nervous system (i.e., a CNS-related
disorder). Exemplary 5-HT1A-related disorders include, without limitation,
depression, single episodic or recurrent major depressive disorders, dysthymic
disorders, depressive neurosis and neurotic depression, melancholic depression
including anorexia, weight loss, insomnia, early morning waking or psychomotor
retardation; atypical depression (or reactive depression) including increased appetite,
hypersomnia, psychomotor agitation or irritability, seasonal affective disorder,
pediatric depression, child abuse induced depression and postpartum depression;
bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II
disorder and cyclothymic disorder; conduct disorder; disruptive behavior disorder;
disorders of attention and learning such as attention deficit hyperactivity disorder
(ADHD) and dyslexia; behavioral disturbances associated with mental retardation,
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autistic disorder, pervasive development disorder and conduct disorder; anxiety
disorders such as panic disorder with or without agoraphobia, agoraphobia without
history of panic disorder, specific phobias, for example, specific animal phobias,
social anxiety, social phobia, obsessive-compulsive disorder, stress disorders
including post-traumatic stress disorder and acute stress disorder, and generalized
anxiety disorders; borderline personality disorder; schizophrenia and other psychotic
disorders, for example, scnizophreniform disorders, schizoaffective disorders,
delusional disorders, brief psychotic disorders, shared psychotic disorders, psychotic
disorders with delusions or hallucinations, psychotic episodes of anxiety, anxiety
associated with psychosis, psychotic mood disorders such as severe major depressive
disorder; mood disorders associated with psychotic disorders such as acute mania and
depression associated with bipolar disorder; mood disorders associated with
schizophrenia, substance-induced psychotic disorder, shared psychotic disorder, and
psychotic disorder due to a general medical condition; delirium, dementia, and
amnestic and other cognitive or neurodegenerative disorders, such as Parkinson's
disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia,
dementia of the Alzheimer's type, mild cognitive impairment (MCI), memory
disorders, loss of executive function, vascular dementia, and other dementias, for
example, due to HIV disease, head trauma, Parkinson's disease, Huntington's disease,
Pick's disease, Creutzfeldt-Jakob disease, or due to multiple etiologies; cognitive
deficits associated with neurological conditions including, for example, Parkinson's
disease (PD), Huntington's disease (HD), Alzheimer's disease; movement disorders
such as akinesias, dyskinesias, including familial paroxysmal dyskinesias, spasticities,
Tourette's syndrome, Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-
pyramidal movement disorders such as medication-induced movement disorders, for
example, neuroleptic-induced Parkinsonism, neuroleptic malignant syndrome,
neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-
induced tardive dyskinesia and medication-induced postural tremor; chemical
dependencies and addictions {e.g., dependencies on, or addictions to, alcohol, heroin,
cocaine, benzodiazepines, nicotine, or phenobaRbitol); behavioral addictions such as
an addiction to gambling; and ocular disorders such as glaucoma and ischemic
retinopathy; sexual dysfunction associated with drug treatment (e.g., sexual
dysfunction associated with SSRI's).
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WO 2006/135839 PCT/US2006/022719
[0048] One nonlimiting example of a 5-HT1A-related disorder is a cognition-
related disorder (e.g., cognitive dysfunction). Exemplary cognition-related disorders
include, without limitation, mild cognitive impairment (MCI), dementia, delirium,
amnestic disorder, Alzheimer's disease, Parkinson's disease, Huntington's disease,
memory disorders including memory deficits associated with depression, senile
dementia, dementia of Alzheimer's disease, cognitive deficits or cognitive dysfunction
associated with neurological conditions including, for example, Parkinson's disease
(PD), Huntington's disease (HD), Alzheimer's disease, depression and schizophrenia
(and other psychotic disorders such as paranoia and mano-depressive illness);
cognitive dysfunction in schizophrenia, disorders of attention and learning such as
attention deficit disorders (e.g., attention deficit hyperactivity disorder (ADHD)) and
dyslexia, cognitive dysfunction associated with developmental disorders such as
Down's syndrome and Fragile X syndrome, loss of executive function, loss of learned
information, vascular dementia, schizophrenia, cognitive decline, neurodegenerative
disorder, and other dementias, for example, due to HIV disease, head trauma,
Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease,
or due to multiple etiologies. Cognition-related disorders also include, without
limitation, cognitive dysfunction associated with MCI and dementias such as Lewy
Body, vascular, and post stroke dementias. Cognitive dysfunction associated with
surgical procedures, traumatic brain injury or stroke may also be treated in accordance
with the present invention. '
[0049] Another nonlimiting example of a 5-HT1A-related disorder is an anxiety-
related disorder. Exemplary anxiety-related disorders include, without limitation,
generalized anxiety disorder, attention deficit disorder, attention deficit hyperactivity
disorder, obsessive compulsive disorder, substance addiction, withdrawal from drug,
alcohol or nicotine addiction, panic disorder, panic attacks, post-traumatic stress
disorder, premenstrual dysphoric disorder, social anxiety disorder, eating disorders
such as anorexia nervosa and bulimia nervosa, vasomotor flushing, and phobias,
including social phobia, agoraphobia, and specific phobias. Substance addition
includes, without limitation, drug, alcohol or nicotine addiction.
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Compounds of the Invention
[0050] In one embodiment, the present invention is directed to compounds of the
Formula (I):

wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, and R16,
are each independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-
C6)-alkynyl, halogen, -CF3, -NO2, -CN, -OR25, -OSO2R25, -SR25, -SO2R25, -
SO2N(R25)2, -N(R25)2, -C(O), -COR25; -CO2R25, -NR25CO2R25, -NR25COR25, -
NR25CON(R25)2, or -CON(R25)2;
Ra and Rb are each independently -H or -CH3; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-alkynyl.
[0051] In one embodiment, R1 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3. In
another embodiment, R1 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R1
is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is -H, (C1-
C6)-alkyl, -OR25, or halogen, and R7, R8, R9, R10, R11, and R12 are each hydrogen. In
yet another embodiment, R1 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and R2, R3, R4, R5, R6, R7,
R8, R9, R10, Rn, and R12 are each hydrogen, hi one embodiment, R1 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3 and R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14,
R15, and R16 are each hydrogen.
[0052] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3. In
another embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13,
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WO 2006/135839 PCT/US2006/022719
R14, R15, and R25 is -H, (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R4
is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is -H, (C1-
C6)-alkyl, -OR25, or halogen, and R7, R8, R9, R10, R11, and R12 are each hydrogen. In
yet another embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and R1, R2, R3, R5, R5, R7,
R8, R9, R10, R11, and R12 are each hydrogen. In one embodiment, R4 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3 and R1, R2, R3, R5, R6, R7, Rs, R9, R10, R11, R12, R13, R-m,
R15, and R16 are each hydrogen.
[0053] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3. In
another embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13,
R14. R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R5
is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15. and R16 is -H, (C1-
C6)-alkyl, -OR25, or halogen, and R7, R8, R9, R10, Ru, and R12 are each hydrogen. In
yet another embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen; and R1, R2, R3, R4, R6, R7,
R8, R9, R10, Rn, and R12 are each hydrogen. In one embodiment, R5 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3 and R1; R2, R3, R4, Re, R7, R8, R9, R10, Ru, R12, R1s, Ru,
R15, and R16 are each hydrogen. In a further embodiment, one of R13, RH, R15, and
R16 is -H, (C1-C6)-alkyl, halogen, -CF3, or -OR25; R5 is -H, (C1-C6)-alkyl, -OR25,
halogen, or -CF3; and the remaining R groups are each hydrogen.
[0054] In one embodiment, R8 is -H, (C1-C6)-aIkyl, -OR25, halogen, -CF3, -NO2 or
-CN. In another embodiment, R8 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; Ra
and Rb are each independently -H or -CH3; and each remaining R group is hydrogen.
In a further embodiment, R8 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of
R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and each remaining R
group is hydrogen. In one embodiment, R8 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN and one of R4 or R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3, and
each remaining R group is hydrogen. In one embodiment R8 is -H, (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; and all other R groups are each hydrogen. In one
embodiment, R8 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R13,
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WO 2006/135839 PCT/US2006/022719
R14, R15, and R25 is -H, (C1-C6)-alkyl, -OR25, or halogen, and each remaining R group
is hydrogen.
[0055] In one embodiment, R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN. In another embodiment, R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
and Ra and Rb are each independently -H or -CH3; and each remaining R group is
hydrogen. In a further embodiment, R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; one of Rx, Rz, R3, R4, Rs and R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or
-CF3; one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and each
remaining R group is hydrogen. In one embodiment, R9 is -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN and one of R4 or R5 is -H, (C1-C6)-alkyl, -OR25, halogen,
or -CF3, and each remaining R group is hydrogen. In one embodiment R9 is -H,
(C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and all other R groups are each
hydrogen. In one embodiment, R9 is ~H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; one of R13, R14, R15, and R1e is -H, (C1-C6)-alkyl, -OR25, or halogen, and each
remaining R group is hydrogen.
[0056] In one embodiment, R7 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN. In one embodiment, R7 is -H, (C1-C6)-alkyl or halogen. In one embodiment, R7
is (C1-QO-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of Ku R2, R3, R4, R5 and Rg
is -H,-(C1-C6)-alkyl, -OR25, halogen, or -CF3; and Ra and Rb are each independently
-H or -CH3; and each remaining R group is hydrogen. In one embodiment, R7 is -H,
(C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is
-H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and each remaining R group is hydrogen.
[0057] In one embodiment, R10 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN. In one embodiment, R10 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3. In one
embodiment, R10 is -H, ~CH3, -OCH3, -F or -CF3. In one embodiment, R10 is -H, (C1-
C6)-alkyl, -OR25, halogen, -CF3, -NO2 or-CN; one of Rx, R2, R3, R4, R5 and R6 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; and Ra and Rb are each independently ~H or
-CH3; and each remaining R group is hydrogen. In one embodiment, R10 is -H, (Q-
C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; and each remaining R group is hydrogen.
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WO 2006/135839 PCT/US2006/022719
[0058] In one embodiment, R11 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN. In one embodiment, R11 is -H, (C1-C6)-alkyl, halogen, or -CF3. In one
embodiment, R11 is -CH3, -F or -CF3. In one embodiment, R11 is -H, (C1-C6)-alkyl,
-OR25, halogen, ~CF3, or -NO2. In one embodiment, R11 is -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or-CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3; and Ra and Rb are each independently -H or -CH3; and each
remaining R group is hydrogta. In one embodiment, R11 is -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; one of R:, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3; and each remaining R group is hydrogen.
[0059] In one embodiment, R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN. In one embodiment, R12 is -H, (C1-C6)-alkyl, halogen, or -CF3. In one
embodiment, R12 is -CH3, -F or -CF3. In one embodiment, R12 is -H, (C1-C6)-alkyl,
-OR25, halogen, -CF3, or -NO2. In one embodiment, R12 is -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3; and Ra and Rb are each independently -H or -CH3; and each
remaining R group is hydrogen. In one embodiment, R12 is -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3; and each remaining R group is hydrogen.
[0060] In one embodiment, R5 is ~H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
one of R7, R8, R9, R10, R11 and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN. In another embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
one of R7, R8, R9, R10, R11, R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; and each remaining R group is hydrogen. In some embodiments, R5 is -H, (C1-
C6)-alkyl, -OR25, halogen, or -CF3 and R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; and each remaining R group is hydrogen. In one embodiment, R5 is
-OR25 and one of R7, R8, R9, R10, R11 and R12 is ~H, (C1-C6)-aIkyl, -OR25, halogen,
-CF3, -NO2 or -CN. In one embodiment, R5 is -OR25 and R9 is halogen. In one
embodiment, R5 is -OR25 and R9 is halogen and each remaining R group is hydrogen.
[0061] In a further embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
one of R7, Rg, R9, R10, Rn, and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN; one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and each
remaining R group is hydrogen.
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WO 2006/135839 PCT/US2006/022719
[0062] In a further embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
two of R7, R8, R9, R10, R11 and R12 are each independently -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25,
or halogen, and each remaining R group is hydrogen.
[0063] In a further embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
three of R7, R8, R9, R10, R11, and R12 are each independently -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyI, -OR25,
or halogen, and each remaining R group is hydrogen.
[0064] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is
-H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and two of R10, R11 and R12 are
each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN. In another
embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is -H, (C1-C6)-
allcyl, -OR25, halogen, -CF3i -NO2 or -CN; two of R10, R11, R12 are each independently
-H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and each remaining R group is
hydrogen. In some embodiments, R5 is -OR25; R9 is halogen; two of R10, Rn, R12 are
each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and each
remaining R group is hydrogen. In some embodiments, R5 is -OCH3; R9 is halogen;
two of R10, R11, R12 are each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; and each remaining R group is hydrogen.
[0065] In some embodiments, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9
is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; R10 and R12 are each
independently-H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and each
remaining R group is hydrogen. In some embodiments, R5 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3; R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
R10 and R11 are each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; and each remaining R group is hydrogen. In some embodiments, R5 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; R11 and R12 are each Independently -H, (Ci~C6)-alkyl, -OR25, halogen,
-CF3, -NO2 or -CN; and each remaining R group is hydrogen.
[0066] In some embodiments, R5 is -H or -OR25, R9 is -H or halogen, R10 and R12
are each independently, -H, halogen, or -CF3; and each remaining R group is
hydrogen.
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[0067] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
one of R7, R8, R9, R10, R11 and R12 is -H, (C1-C6)-aIkyl, -OR25, halogen, -CF3, -NO2 or
-CN. In another embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of
R7, R8, R9, R10, R11, and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
and each remaining R group is hydrogen. In a further embodiment, R4 is -H, (C1-C6)-
alkyl, -OR25, halogen, or -CF3; one of R7, Rg, R9, R10, R11; R12 is -H, (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl,
-OR25, or halogen, and each remaining R group is hydrogen.
[0068] In one embodiment, one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl,
halogen, -CF3, or -OR25.
[0069] In one embodiment, R1, R2, R3, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15,
and R16 are each hydrogen.
[0070] In one embodiment, R1, R2, R3, R4, R7, R9, R10, R11, and R12 are each
hydrogen.
[0071] In one embodiment, R1, R2, R3, R4, R7, Rg, R10, R11, and R12 are each
hydrogen.
[0072] In one embodiment, R1, R2, R3, R4, R7, R8, R9, R11, and R12 are each
hydrogen.
[0073] In one embodiment, R1, R2, R3, R4, R7, R8, R9, R10, and R12 are each
hydrogen.
[0074] In one embodiment, R1,R2,R3, R4,R7,R8,R9, R10, and R11 are each
hydrogen.
[0075] In one embodiment, R1, R2, R3, R4, R7, Rg, and R11 are each hydrogen.
[0076] In one embodiment, R1, R2, R3, R4, R7, R8, R9 and R11 are each hydrogen.
[0077] In one embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R12 are each
hydrogen.
[0078] In another embodiment, R13, R11, R15, and R16 are each hydrogen.
[0079] In one embodiment, R3, R6, R7, R8, R9, R12, R13, R11, R15, and R25 are each
hydrogen.
[0080] In one embodiment, R1, R2, R3, R4, R6, R7, R8, and R11 are each hydrogen.
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[0081] In one embodiment, R1, R2, R3, R4, R6, R7, R8, R11, R13, R11, R15, and R16
are each hydrogen.
[0082] In one embodiment, R11 R2, R3, R4, R6, R7, R8, R10, R11, R12, R13, R11, R15.
and R16 are each hydrogen.
[0083] In one embodiment, R1, R2, R3, R4, R6, R7, R8, R8, R10, R11 and R11 are
each hydrogen.
[0084] In one embodiment, R11 R2, R3, R4, R6, R7, R8, R9, R10, R11, R12 R13, R14,
R15, and R16 are each hydrogen.
[0085] In one embodiment, R1 is -H, -CF3 or (C1-C6)-alkyl; R4 and R5 are each -
H, halogen, -OR25, or -CF3; R7, R8, R9, R10, R11, and R12 are each -H, halogen, -alkyl,
-OR25, -CF3, or -NO2; and R16 is -H or -CH3.
[0086] In one embodiment, any one of R1, R2, R3, R4, R5, and R6 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3; and any one of R7, R8, R9, R10, R11, and R12 is -H, (C1-
C6)-alkyl, -OR25, halogen, or -CF3, -NO2, or -CN.
[0087] In one embodiment, any one of R1, R2, R3, R4, R5, and R6 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2, or -CN; and any two of R7, R8, R9, R10, R11, and
R12 are each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3.
[0088] In one embodiment, any one of R1, R2, R3, R4, R5, and R6 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2, or -CN; and any three of R7, R8, R9, R10, R11, and
R12 are each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3.
[0089] In one embodiment, any one of R1, R2, R3, R4, R5, and R6 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3; and any one of R13, R14, R15, and R16 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3.
[0090] In one embodiment, any one of R7, R8, R9, R10, R11, and R12 is -H, C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2, or -CN; and any one of R11, R14, R15, and R16 is -H,
(C1-C6)-alkyl, -OR25, halogen, -CF3.
[0091] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
any one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and any
one of R7, R8, R9, R10, R11, and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3,
-NO2, or -CN.
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WO 2006/135839 PCT/US2006/022719
[0092] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
any one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and any
two of R7, R8, R9, R10, R11, and R12 are each independently -H, (C1-C6)-alkyl, -OR25,
halogen, or -CF3, -NO2, or -CN; wherein the any two of R7, R8, R9, R10, R11, and R12
can be either on the same ring of the quinoline or on different rings.
[0093] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
any one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and any
one of R7, R8, R9, R10, R11, and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3,
-NO2, or -CN. In one embodiment, R5 is -OR25; any one of R13, R14, R15, and R16 is -
H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and any one of R7, R8, R9, R10, R11, and R11
is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3, -NO2, or -CN.
[0094] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
any one of R13, R11, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and any
two of R7, R8, R9, R10, R11, and R12 are each independently -H, (C1-C6)-alkyl, -OR25,
halogen, or -CF3, -NO2, or -CN; wherein the any two of R7, R8, R9, R10, R11, and R12
can be either on the same ring of the quinoline or on different rings.
[0095] In one embodiment, R5 is -OR25; R9 is halogen; any one of R13, R14, R15,
and R16 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and any two of R7, R8, R10, R11,
and R12 are each independently -OR25, halogen, or -CF3; wherein the any two of R7,
R8, R9, R10, R11, and R12 can be either on the same ring of the quinoline or on different
rings.
[0096] In one embodiment, R1 is -H or (C1-C6)-alkyl; R2, R8, and R9 are each -H
or halogen; R4 is -H, halogen, -OR25, or -CF3; R5 is -H, halogen, or -OR25; and R3, R6,
R7, R12, R13, R14, R15, R16, Ra and Rb are each hydrogen.
[0097] In one embodiment, R1 is -H or -CH3; R2, R8, and R9 are each -H or F; R4
is -H, F, -OCH3, or -CF3; R5 is -H, F, or -OCH3; and R3, R6, R7, R10, R11, R12, R13, R14,
R15, R16, Ra and Rb are each hydrogen.
[0098] In one embodiment, R25 is (C1-C6)-haloalkyl.
[0099] In another embodiment, R25 is (C1-C6)-fluoroalkyl.
[0100] In one embodiment, R25 is (C1-C6)-alkyl. In one embodiment, R25 is -CH3.
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WO 2006/135839 PCT/US2006/022719
[0101] In one embodiment, the compounds of Formula (I) are antagonists of the 5-
HT1A receptor. In another embodiment, the compounds of Formula (I) are agonists of
the 5-HT1A receptor.
[0102] In another aspect, the invention provides compounds of the Formula (I'):

wherein R1, R2, R3, R4, R5, R8, R7, R8, R9, R10, R11, R12, R13, R14, R15, and R16,
are each independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-
C6)-alkynyl, halogen, -CF3, -NO2, -CN, -OR25, -OSO2R25, -SR25, -SO^, -
SO2N(R25)2, -N(R25)2, -C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25, -
NR25CON(R25)2, or -CON(R25)2;
Ra and Rb are each independently -H or -CH3;
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-alkynyl; and n is 0,1, or 2.
[0103] In one embodiment, R1 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3. In
another embodiment, R1 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13,
R14, R15, and R1g is -H, (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R1
is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of RJ3, R14, R15, and R16 is -H, (Cr
C6)-alkyl, -OR25, or halogen, and R7, R8, R9, R10. R11, and R12 are each hydrogen. In
yet another embodiment, R1 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and R2, R3, R4, R5, R6, R7, R8,
R9, R10, R11, and R12 are each hydrogen. In one embodiment, R1 is -H, (C1-C6)-alkyl,
-OR25, halogen or -CF3 and R2, R3, R4,R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15,
and R16 are each hydrogen.
[0104] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3. In
another embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13,
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WO 2006/135839 PCT/US2006/022719
R11, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R4
is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is -H, (C1-
C6)-alkyl, -OR25, or halogen, and R7, R8, R9, R10, R11, and R12 are each hydrogen. In
yet another embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and R1 R2, R3, R5, R6, R7,
R8, R9, R10, R11, and R12 are each hydrogen. In one embodiment, R4 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3 and R1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14,
R15, and R16 are each hydrogen.
[0105] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3. In
another embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13,
R11, R15, and R16 is -H, (C1-C6)-alkyl, ~OR25, or halogen. In a further embodiment, R5
is -H, (C1-C6)-alkyl, -OR25, or halogen, one of R13, R14, R15, and R16 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3, and R7, R8, R9, R10, R11, and R12 are each hydrogen. In
yet another embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen; and R1, R2, R3, R4, R8, R7,
R8, R9, R10, R11, and R12 are each hydrogen. In one embodiment, R5 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3 and R1, R2, R3, R4, R6, R7, R8, R9, R10, R11, R12, R13, R14,
R15, and R16 are each hydrogen. In a further embodiment, one of R13, R11, R15, and
R16 is -H, (C1-C6)-alkyl, halogen, -CF3, or -OR25; R5 is -H, (C1-C6)-alkyl, -OR25,
halogen, or -CF3; and each remaining R group is hydrogen.
[0106] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; R1,
R2, R3, R4, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, and R16 are each hydrogen; and
n is 1. In one embodiment, R5 is -H or -OR25; R1, R2, R3, R4, R6, R7, R8, R9, R10, R11.
R12, R13, R14, R15, and R16 are each hydrogen; and n is 1. In one embodiment, R5 is
-H, (C1-C6)-alkyl, -OR25, halogen or -CF3; R11 R2, R3, R4, R6, R7, R8, R9, R10, R11, R12,
R13, R14, R15, and R16 are each hydrogen; and n is 2. In one embodiment, R5 is -H or
-OR25; R1, R2, R3, R4, R5, R7, R8, R9, R10, R11, R12, R13, R14, R15, and R16 are each
hydrogen; and n is 2.
[0107] In one embodiment, R8 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN. In another embodiment, R8 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; Ra
and Rb are each independently -H or -CH3; and each remaining R group is hydrogen.
In a further embodiment, R8 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
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WO 2006/135839 PCT/US2006/022719
one of R1, R2, R3, R25 R5 and R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of
R13, R14, R153 and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and each remaining R
group is hydrogen. In one embodiment, Rs is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN and one of R4 or R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3, and
each remaining R group is hydrogen. In one embodiment Rg is -H, (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; and all other R groups are each hydrogen. In one
embodiment, R8 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R13,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and each remaining R group
is hydrogen.
[0108] In one embodiment, R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN. In another embodiment, R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; one of R11 R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
and Ra and Rb are each independently -H or -CH3; and each remaining R group is
hydrogen. In a further embodiment, R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; one of R1, R2, R3, R25, R5 and R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or
-CF3; one of R11, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and each
remaining R group is hydrogen. In one embodiment, R9 is -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN and one of R4 or R5 is -H, (C1-C6)-alkyl, -OR25, halogen,
or -CF3, and each remaining R group is hydrogen. In one embodiment R9 is -H,
(C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and all other R groups are each
hydrogen. In one embodiment, R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and each
remaining R group is hydrogen.
[0109] In one embodiment, R7 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN, In one embodiment, R7 is -H, (C1-C6)-alkyl or halogen. In one embodiment, R7
is -H, (C1-C6)-ahcyl, -OR25, halogen, -CF3, -NO2 or-CN; one of R1, R2, R3, R4, R5 and
R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and Ra and Rb are each independently
-H or -CH3; and each remaining R group is hydrogen. In one embodiment, R7 is -H,
(C1-C6)-alkyl, -OR2S, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is
-H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and each remaining R group is hydrogen.
[0110] In one embodiment, R10 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN. In one embodiment, R10 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3. In one
embodiment, R10 is -H, -CH3, -OCH3, -F or -CF3. In one embodiment, R10 is -H, (C1-
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WO 2006/135839 PCT/US2006/022719
C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; Ra and Rb are each independently -H or -CH3;
and each remaining R group is hydrogen. In one embodiment, R10 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R25 is -H,
(C1-C6)-aIkyl, -OR25, halogen, or -CF3; and each remaining R group is hydrogen.
[0111] In one embodiment, R11 is -H, (C1-C6)-alkyI, -OR25, halogen, -CF3, -NO2
or-CN. In one embodiment, R11 is -H, (C1-C6)alkyl, halogen, or -CF3. In one
embodiment, R11 is -H, -CH3, -F or -CF3. In one embodiment, R11 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; Ra and Rb are each independently -H or -CH3;
and each remaining R group is hydrogen. In one embodiment, R11 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, Rs and R6 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; and each remaining R group is hydrogen.
[0112] In one embodiment, R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN. In one embodiment, R12 is -H, (C1-C6)-alkyl, halogen, or -CF3. In one
embodiment, R12 is -H, -CH3, -F or -CF3. In one embodiment, R12 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; and Ra and Rb are each independently -H or
-CH3; and each remaining R group is hydrogen. In one embodiment, R11 is -H, (C1-
C6)-aIkyl, -OR25, halogen, -CF3, -NO2 or-CN; one of R11 R2, R3, R4, R5 and R6 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; and each remaining R group is hydrogen.
[0113] In one embodiment, R5 is -H, (C1-C6)alkyl, -OR25, halogen, or -CF3 and
one of R7, R8, R9, R10, R11 and R12 is -H, (C1-C6)-alkyI, -OR25, halogen, -CF3, -NO2 or
-CN. In another embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
one of R7, Ra, R9, R10, R11, R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; and each remaining R group is hydrogen. In some embodiments, R5 is -H, (Q-
C6)-alkyl, -OR25, halogen, or -CF3 and R9 is (C1-C6)-allcyl, -OR25, halogen, -CF3, -NO2
or -CN; and each remaining R group is hydrogen.
[0114] In a further embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
one of R7, R8, R9, R10, R11, and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and each
remaining R group is hydrogen.
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[0115] In a further embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
two of R7, R8, R9, R10, R11, and R12 are each independently -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and Rl6 is -H, (C1-C6)-alkyl, -OR25,
or halogen, and each remaining R group is hydrogen.
[0116] In a further embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
three of R7, R8, R9, R10, R11, and R25 are each independently -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is -H, (C1-C6)-aikyl, -OR25,
or halogen, and each remaining R group is hydrogen.
[0117] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is
-H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and two of R10, R11 and R12 are
each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN. In another
embodiment, R5 is -H, (C1-C6)-alkyl, -OR2S, halogen, or -CF3; R9 is -H, (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; two of R10, R11, R12 are each independently -H,
(C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and each remaining R group is
hydrogen. In some embodiments, R5 is -H or -OR25; R9 is ~H or halogen; two of R10,
R11, R12 are each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
and each remaining R group is hydrogen. In some embodiments, R5 is -H, or -OCH3;
R9 is -H or halogen; two of R10, R11, R12 are each independently -H, (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; and each remaining R group is hydrogen. In
some embodiments, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is -H, (C1-
C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; R10 and R12 are each independently -H,
(C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and each remaining R group is
hydrogen. In some embodiments, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9
is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; R10 and R11 are each
independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and each
remaining R group is hydrogen. In some embodiments, R5 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3; R9 is -H, (C1-C6)~alkyL -OR25, halogen, -CF3, -NO2 or -CN;
R11 and R12 are each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; and each remaining R group is hydrogen.
[0118] In some embodiments, R5 is -H or -OR25; R9 is -H or halogen; and each
remaining R group is hydrogen. In some embodiments, R5 is -H or -OR25, R9 is -H or
halogen; R10 and R12 are each independently -H, halogen, or -CF3; and each
remaining R group is hydrogen.
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WO 2006/135839 PCT/US2006/022719
[0119] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
one of R7, R8, R9, R10, R11 and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN. In another embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of
R7, R8, R9, R10, R11, and R12 is -H, (C1-C6)-allcyl, -OR25, halogen, -CF3, -NO2 or -CN;
and each remaining R group is hydrogen. In a further embodiment, R4 is -H, (C1-C6)-
alkyl, -OR25, halogen, or -CF3; one of R7, R8, R9, R10, R11; R12 is -H, (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl,
-OR25, or halogen, and each remaining R group is hydrogen.
[0120] In one embodiment, one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl,
halogen, -CF3, or -OR25.
[0121] In one embodiment, R1, R2, R3, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15,
and R16 are each hydrogen.
[0122] In one embodiment, R1, R2, R3, R4, R7, R9, R10, R11, and R12 are each
hydrogen.
[0123] In one embodiment, R1, R2, R3, R4, R7, R8, R10, R11, and R12 are each
hydrogen.
[0124] In one embodiment, R1, R2, R3, R4, R7, R8, R9, R11, and R12 are each
hydrogen.
[0125] In one embodiment, R1, R2, R3, R4, R7, R8, R9, R10, and R12 are each
hydrogen.
[0126] In one embodiment, R1, R2, R3, R4, R7, R8, R9, R10, and R11 are each
hydrogen.
[0127] In one embodiment, R1, R2, R3, R4, R7, R8, and R11 are each hydrogen.
[0128] In one embodiment, R1, R2, R3, R4, R7, R8, R9 and R11 are each hydrogen.
[0129] In one embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R12 are each
hydrogen.
[0130] In another embodiment, R13, R14, R15, and R16 are each hydrogen.
[0131] In one embodiment, R3, R6, R7, R8, R9, R12, R13, R14, R15, and R16 are each
hydrogen.
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WO 2006/135839 PCT/US2006/022719
[0132] In one embodiment, R1, R2, R3, R4, R6, R7, R8, R9, R11, R13, R14, R15, and
R16 are each hydrogen.
[0133] In one embodiment, R1, R2, R3, R4, R6. R7, R8, R9, R10, R11, R12, R13, R14,
R15, and R16 are each hydrogen.
[0134] In one embodiment, R1, R2, R3, R4, R6, R7. R8, R10, R11, R12, R13, R14, R15,
and R16 are each hydrogen.
[0135] In one embodiment, any one of R1, R2, R3, R4, R5, and R25 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3; and any one of R7, R8, R9, R10, R11, and R12 is -H, (C1-
C6)-alkyl, -OR25, halogen, or -CF3, -NO2, or -CN.
[0136] In one embodiment, any one of R1, R2, R3, R4, R5, and R6 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2, or -CN; and any two of R7, R8, R8, R10, R11, and
R12 are each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3.
[0137] In one embodiment, any one of R1, R2, R3, R4, R5, and R6 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2, or -CN; and any three of R7, R8, R9, R10, R11, and
R12 axe each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3.
[0138] In one embodiment, any one of R1, R2, R3, R4, R5, and R6 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3; and any one of R13, R14, R15, and R16 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3.
[0139] In one embodiment, any one of R7, R8, R9, R10, R11, and R12 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2, or -CN; and any one of R13, R14, R15, and R16, is -H,
(C1-C6)-alkyl, -OR25, halogen, -CF3.
[014O] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
any one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and any
one of R7, R8, R9, R10, R11, and R11 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3,
-NO2, or -CN.
[0141] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
any one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and any
two of R7, R8, R9, R10, R11, and R12 are each independently -H, (C1-C6)-alkyl, -OR25,
halogen, or -CF3, -NO2, or -CN; wherein the any two of R7, R8, R9, R10, R11, and R12
can be either on the same ring of the quinoline or on different rings.
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WO 2006/135839 PCT/US2006/022719
[0142] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
any one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and any
one of R7, R8, R9, R10, R11, and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3,
-NO2,or-CN.
[0143] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
any one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and any
two of R7, R8, R9, R10, R11, and R12 are each independently -H, (C1-C6)-alkyl, -OR25,
halogen, or -CF3, -NO2, or -CN; wherein the any two of R7, R8, R9, R10, R11, and R12
can be either on the same ring of the quinoline or on different rings.
[0144] In one embodiment, R1 is -H or (C1-C6)-alkyl; R2, R8, and R9 are each -H
or halogen; R4 is -H, halogen, -OR25, or -CF3; R5 is -H, halogen, or -OR25; and R3, R6,
R7, R12, R13, R14, R15, R16, Ra and Rb are each hydrogen.
[0145] In one embodiment, R1 is -H or -CH3; R2, R8, and R9 are each -H or F; R4
is -H, F, -OCH3, or -CF3; R5 is -H, F, -OCH3; and R3, R6, R7, R10, R11, R12, R13, R11,
R15, R16, Ra and Rb are each hydrogen.
[0146] In one embodiment, R1 is -H, -CF3 or (C1-C6)-alkyl; R4 and R5 are each -
H, halogen, -OR25, or -CF3; R7, R8, R9, R10, R11, and R12 are each -H, halogen, -alkyl,
-OR25, -CF3, or -NO2; R16 is -H or -CH3.
[0147] In one embodiment, R25 is (C1-C6)-haloalkyl.
[0148] In another embodiment, R25 is (C1-C6)-fluoroalkyl.
[0149] In one embodiment, R25 is (C1-C6)-alkyl. In one embodiment, R25 is -CH3.
[0150] In one embodiment, the compounds of Formula (I) are antagonists of the 5-
HTIA receptor. In another embodiment, the compounds of Formula (I) are agonists of
the 5-HT1A receptor.
[0151] In another aspect, the invention provides compounds of the Formula (P):
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WO 2006/135839 PCT/US2006/022719

wherein R1, R2, R3, R4, R5, R6, R7, Rr, R8, R9, R10, R11, R12, R13, R11, R15, and
R16, are each independently -H, (C1-C6)-alkyl, (C1-C6)-haloaIkyl, (C2-C6)-alkenyl, or
(C2-C6)-alkynyl, halogen, -CF3, -NO2, -CN, -OR25, -OSO2R25, SR25, -SO2R25, -
SO2N(R25)2, -N(R25)2, -C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25, -
NR25CON(R25)2, or -CON(R25)2 except for the R groups through which the piperidine
is connected;
Ra and Rb are each independently -H or -CH3; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-alkynyl; and
where the piperidine group can be attached to the non-hetero atom containing
ring of the quinoline through positions R7, R7, R8, or R9.
[0152] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3. In
another embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13,
R14, R15, and R25 is -H, (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R4
is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is -H, (C1-
C6)-alkyl, -OR25, or halogen or -CF3; the piperidine is connected through one of R7,
R7, R8, or R9; and the remainder of the R groups of the quinoline attached to the
piperidine are each hydrogen. In yet another embodiment, R4 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3; one of R13, R14, R15, and R1e is -H, (C1-C6)-aIkyl, -OR25, or
halogen; the piperidine is connected through R7'; and each remaining R group is
hydrogen. In yet another embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or
-CF3; one of R13, R14, R15, and R16 is -H, (C1-C6)alkyl, -OR25, or halogen; the
piperidine is connected through R7; and each remaining R group is hydrogen. In yet
another embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14,
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WO 2006/135839 PCT/US2006/022719
R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen; the piperidine is connected
through R8; and each remaining R group is hydrogen. In yet another embodiment, R4
is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is -H, (C1-
C6)-alkyl, -OR25, or halogen; the piperidine is connected through R9; and each
remaining R group is hydrogen. In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25,
halogen or -CF3, the piperidine is connected through R7', and each remaining R group
is hydrogen. In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3, thr
piperidine is connected through R7, and each remaining R group is hydrogen. In one
embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3, the piperidine is
connected through R8, and each remaining R group is hydrogen. In one embodiment,
R4 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3, the piperidine is connected through
R9, and each remaining R group is hydrogen.
[0153] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3. In
another embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R5
is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is -H, (C1-
C6)-alkyl, -OR25, or halogen; the piperidine is connected through one of R7, R7', R8, or
R9; and the remainder of the R groups of the quinoline attached to the piperidine are
each hydrogen. In yet another embodiment, R5 is -H, (C1-C<5)-alkyl, -OR25, halogen,
or -CF3; one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen; the
piperidine is connected through R7'; and each remaining R group is hydrogen. In yet
another embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14,
R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen; the piperidine is connected
through R7; and each remaining R group is hydrogen. In yet another embodiment, R5
is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is -H, (C1-
C6)-alkyl, -OR25, or halogen; the piperidine is connected through R8; and each
remaining R group is hydrogen. In yet another embodiment, R5 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or
halogen; the piperidine is connected through R9; and each remaining R group is
hydrogen. In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3i the
piperidine is connected through R7', and each remaining R group is hydrogen. In one
embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3, the piperidine is
connected through R7, and each remaining R group is hydrogen. In one embodiment,
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WO 2006/135839 PCT/US2006/022719
R5 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3, the piperidine is connected through
R8, and each remaining R group is hydrogen. In one embodiment, R5 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3, the piperidine is connected through R9, and each
remaining R group is hydrogen. In a further embodiment, one of R13, R14, R15, and
R1e is -H, (C1-C6)-alkyl, halogen, -CF3, or -OR25; R5 is -H, (C1-C6)-alkyl, -OR25,
halogen, or -CF3; and each remaining R group is hydrogen.
[0154] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
one of R7, R7', R8, R9, R10, R11 and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN except for the R group through which the piperidine is connected. In
another embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R7,
R7., R8, R9, R10, R11, or R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN
except for the R group through which the piperidine is connected; and each remaining
R group is hydrogen except for the R group through which the piperidine is
connected. In some embodiments, R5 is -H or -OR25 and R9 is -H, (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; and each remaining R group is hydrogen except
for the R group through which the piperidine is connected. In some embodiments, R5
is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3, R9 is -H or halogen and each remaining
R group is -H or hydrogen except for the R group through which the piperidine is
connected.
■ [0155] m a further embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
one of R7, Rr, R8, R9, R10, R11; R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN except for the R group through which the piperidine is connected; one of R13,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and each remaining R group
is hydrogen except for the R group through which the piperidine is connected.
[0156] In a further embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
and R7' is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN, and each remaining
R group is hydrogen except for the R group through which the piperidine is
connected. In one embodiment, the piperidine is connected through R7; R5 is -H, (C1-
C6)-alkyl, -OR25, halogen, or -CF3; and R7' is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN. In one embodiment, the piperidine is connected through R7; R5 is -H or
-OR25; and R7- is -H or halogen.
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WO 2006/135839 PCT/US2006/022719
[0157] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; two
of R7, R7., R8, R9) R10, R11; R12 are each independently -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN except for the R group through which the piperidine is
connected; and each remaining R group is hydrogen except for the R group through
which the piperidine is connected.
[0158] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; two
of R7, R7., R6, R9, R10, R11; R12 are each independently -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN except for the R group through which the piperidine is
connected; one of R13, R14, R15, and R1g is -H, (C1-C6)-alkyl, -OR25, or halogen, and
each remaining R group is hydrogen except for the R group through which the
piperidine is connected.
[0159] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; three
of R7, R7S R8, R9, R10, R11; R12 are each independently -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN except for the R group through which the piperidine is
connected; one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and
each remaining R group is hydrogen except for the R group through which the
piperidine is connected.
[0160] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is
-H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and two of R10, R11 and R12 are
each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN. In another
embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is -H, (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; two of R10, R11, R12 are each independently -H,
(C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and each remaining R group is
hydrogen except for the R group through which the piperidine is connected. In some
embodiments, R5 is -H or -OR25; R9 is -H or halogen; two of R25, R11, R12 are each
independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and each
remaining R group is hydrogen except for the R group through which the piperidine is
connected. In some embodiments, R5 is -H or -OCH3; R9 is -H or halogen; two of
R10. R11, R12 are each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; and each remaining R group is hydrogen except for the R group through which
the piperidine is connected.
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WO 2006/135839 PCT/US2006/022719
[0161] In some embodiments, R8 is -H, -(C1-C6)-alkyl, -OR25, halogen, or -CF3;
R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; Rr, R10 and R12 are each
independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and each
remaining R group is hydrogen except for the R group through which the piperidine is
connected. In some embodiments, R5 is -H, -(C1-C6)-alkyl, -OR25, halogen, or -CF3;
R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; R10 and R11 are each
independently -H, (C1-C6)-alkyl, OR25, halogen, -CF3, -NO2 or -CN; and each
remaining R group is hydrogen except for the R group through which the piperidine is
connected. In some embodiments, In some embodiments, R5 is -H, -(C1-C6)-alkyl,
-OR25, halogen, or -CF3; R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
R11 and R12 are each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; and each remaining R group is hydrogen except for the R group through which
the piperidine is connected.
[0162] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
one of Rr, R7, R8, R9, R10, R11 and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN. In another embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or
-CF3; one of Rr, R7, R8, R9, R10, R11, and R12 is -H, (C1-C6)-alkyl, -OR25, halogen,
-CF3, -NO2 or -CN; and each remaining R group is hydrogen except for the R group
through which the piperidine is connected. In a further embodiment, R4 is -H, (C1-
C6)-alkyl, -OR25, halogen, or -CF3; one of Rr, R7, R8, R9, R10, R11, R12 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is -H, (C1-C6)-
alkyl, -OR25, or halogen, and each remaining R group is hydrogen except for the R
group through which the piperidine is connected.
[0163] In one embodiment, one of R13, R14, R25, and R16 is -H, (C1-C6)-alkyl,
halogen, -CF3, or -OR25.
[0164] In one embodiment, R8 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN. In another embodiment, R8 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; one of R11 R2, R3, R4, and R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; Ra
and Rb are each independently -H or -CH3; and each remaining R group is hydrogen
except for the R group through which the piperidine is connected. In a further
embodiment, R8 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1,
R2, R3, R4, R5, and R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14,
R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, Ra and Rb are each independently
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WO 2006/135839 PCT/US2006/022719
-H or -CH3; and each remaining R group is hydrogen except for the R group through
which the piperidine is connected. In one embodiment, R8 is -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN and one of R4 or R5 is -H, (C1-C6)-alkyl, -OR25, halogen,
or -CF3 and each remaining R group is hydrogen except for the R group through
which the piperidine is connected. In one embodiment Rs is -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; and all other R groups are each hydrogen except for the
R group through which the piperidine is connected. In one e;:iDodiment, Rs is -H, (C1-
C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is -H, (C1-
C6)-alkyl, -OR25, or halogen, Ra and Rb are each independently -H or -CH3; and each
remaining R group is hydrogen except for the R group through which the piperidine is
connected.
[0165] In one embodiment, R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN. In another embodiment, R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -
-CN; one of R1, R2, R3, R4, R5 and R6, is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
Ra and Rb are each independently -H or -CH3; and each remaining R group is
hydrogen except for the R group through which the piperidine is connected. In a
further embodiment, R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one
of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen; Ra and Rb are each
independently -H or -CH3; and each remaining R group is hydrogen except for the R
group through which the piperidine is connected. In one embodiment, R9 is -H, (C1-
C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN and one of R4 or R5 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3. In one embodiment R9 is -H, (C1-C6)-alkyl, -OR25, halogen,
-CF3, -NO2 or -CN; and all other R groups are each hydrogen except for the R group
through which the piperidine is connected. In one embodiment, R9 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is -H, (C1-C6)-
alkyl, -OR25, or halogen, and each remaining R group is hydrogen except for the R
group through which the piperidine is connected.
[0166] In one embodiment, R7 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN. In one embodiment, R7 is -H, (C1-C6)-alkyl or halogen. In one embodiment, R7
is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and
R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and Ra and Rb are each independently
-H or -CH3; and each remaining R group is hydrogen, except for the R group through
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WO 2006/135839 PCT/US2006/022719
which the piperidine is connected. In one embodiment, R7 is -H, (C1-C6)-alkyl, -OR25,
halogen, -CP3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3; and each remaining R group is hydrogen, except for the R
group through which the piperidine is connected.
[0167] In one embodiment, R10 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN. In one embodiment, R10 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3. In one
embodiment, R25 is -H, CH3, -OCH3, -F or -CF3. In one embodiment, R10 is -H, (C1-
C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of Rh R2, R3, R4, R5 and R6 is -H,
(C1-C6)-aIkyl, -OR25, halogen, or -CF3; and Ra and Rb are each independently -H or
-CH3; and each remaining R group is hydrogen, except for the R group through which
the piperidine is connected. In one embodiment, R10 is -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3; and each remaining R group is hydrogen, except for the R
group through which the piperidine is connected.
[0168] In one embodiment, R11 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN. In one embodiment, R11 is -H, (C1-C6)-alkyl, halogen, or -CF3. In one
embodiment, R11 is -H, -CH3, -F or -CF3. In one embodiment, R11 is -H,(C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; and Ra and Rb are each independently -H or
-CH3; and each remaining R group is hydrogen, except for the R group through which
the piperidine is connected. In one embodiment, R11 is -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or-CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3; and each remaining R group is hydrogen, except for the R
group through which the piperidine is connected.
[0169] In one embodiment, R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN. In one embodiment, R12 is -H, (C1-C6)-alkyl, halogen, or -CF3. In one
embodiment, R12 is -H, -CH3, -F or -CF3. In one embodiment, R12 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and Ra is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; and Ra and Rb are each independently -H or
-CH3; and each remaining R group is hydrogen, except for the R group through which
the piperidine is connected. In one embodiment, R12 is -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl,
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WO 2006/135839 PCT/US2006/022719
-OR25, halogen, or -CF3; and each remaining R group is hydrogen, except for the R
group through which the piperidine is connected.
[0170] In one embodiment, R1, R2, R3, R4, R7, R7', R9, R10, R11, and R12, are each
hydrogen except for the R group through which the piperidine is connected.
[0171] In one embodiment, R1, R2, R3, R4, R7, R7', R8, R10, R11, and R12, are each
hydrogen except for the R group through which the piperidine is connected.
[0172] In one embodiment, Rt, R2, R3, R4, R7, R7', R8, R9, R11, and R12, are each
hydrogen except for the R group through which the piperidine is connected.
[0173] In one embodiment, R1, R2, R3, R4, R7, Rr, R8, R9, R10, and R11, are each
hydrogen except for the R group through which the piperidine is connected.
[0174] In one embodiment, R1, R2, R3, R4, R7, R7', R8, and R11, are each hydrogen
except for the R group through which the piperidine is connected.
[0175] In one embodiment, R1, R2, R3, R4, R7, R?-, R& R9, and R11, are each
hydrogen except for the R group through which the piperidine is connected.
[0176] In one embodiment, R1, R2, R3, R4, R7, R7', R8, R9, R10, R11, and R12, are
each hydrogen except for the R group through which the piperidine is connected.
[0177] In one embodiment, R1, R2, R3, R6, Rr, R7, R8, R9, R10, R11, R12, R13, R14,
R15, and R25 are each hydrogen except for the R group through which the piperidine is
connected.
[0178] In one embodiment, R11 R2, R3, R6, R7', R7, R8, R9, R10, R11, and R12 are
each hydrogen except for the R group through which the piperidine is connected.
[0179] In one embodiment, R1, R2, R3, R4, R5, R6, R7', R7, R10, R11, R12, R13, R14,
R15, and R16 are each hydrogen except for the R group through which the piperidine is
connected.
[0180] In one embodiment, R1, R2, R3, R4, R5, R8, R7', R7, R10, R11, and R12 are
each hydrogen.
[0181] In another embodiment, R13, R14, R15, and R16 are each hydrogen.
[0182] In one embodiment, R3, R6, R7', R7, R10, R11, R12, R13, R14, R15, and R16 are
each hydrogen except for the R group through which the piperidine is connected.
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WO 2006/135839 PCT/US2006/022719
[0183] In one embodiment, R25 R2, R3, R4, R6, R7, R8, R10, R11, R12, R13, R14, R15,
and R16 are each hydrogen except for the R group through which the piperidine is
connected.
[0184] in one embodiment, R11 R2, R3, R4, R6, R7, R8, R9, R10, R11, R12, R13, R14,
R15, and R16 are each hydrogen except for the R group through which the piperidine is
connected.
[0185] In one embodiment, R1 is -H or (C1-C6)~alkyl; R4 and R5 are each
independently -H, halogen, -OR25, or -CF3; R7, R7',R8, R9, R10, R11, and R12 are each
independently ~H, halogen, (C1-C6)-alkyI, -OR25, ~CF3,NO2 or CN except for the R
group through which the piperidine is connected.
[0186] In one embodiment, R5 is -H, halogen, or -OR25; and R3, R6, R7', R7, R8,
R9, R12, R13, R14, R15, and R16 are each hydrogen except for the R group through
which the piperidine is connected.
[0187] In one embodiment, R1 is -H or (C1-C6)-alkyl; R2, R8, and R9 are each -H
or halogen; R4 is -H, halogen, -OR25, or -CF3; R5 is -H, halogen, or -OR25; and R3, R8,
R7', R7, R8, R9, R12, R13, R14, R15, and R16 are each hydrogen except for the R group
through which the piperidine is connected. In one embodiment, R1 is -H or (C1-C6)-
alkyl; R2, R8, and R9 are each -H or F; R4 is H, F, -OR25, or -CF3; R5 is -H, F, or
-OR25; and R3, R6, R7, R7', R8, R9, R12, R13, R14, R15, and R16 are each hydrogen except
for the R group through which the piperidine is connected.
[0188] In one embodiment, any one of R1, R2, R3, R4, R5, and R5 is -H, (C1-C6)-
alkyl, -OR25, halogen; and any one of R7', R7, R8, R9, R10, R11, and R12 is -H, (C1-C6)-
alkyl, -OR25, halogen, or -CF3, -NO2, or -CN except for the R group through which the
piperidine is connected.
[0189] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and
any one of R7, R7', R8, R9, R10, R11, and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, or
-CF3, -NO2, or -CN, except for the R group through which the piperidine is
connected.
[0190] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and
any two of R7, R7', R8, R9, R10, R11, and R12 are each independently -H, (C1-C6)-alkyl,
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WO 2006/135839 PCT/US2006/022719
-OR25, halogen, or -CF3, -NO2, or -CN, except for the R group through which the
piperidine is connected.
[0191] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and
any three of R?, R7', R%, R9, R10, R11, and R12 are each independently -H, (C1-C6)-
alkyl, -OR25, halogen, or -CF3, -NO2, or -CN, except for the R group through which
the piperidine is connected.
[0192] In one embodiment, any one of R1, R2, R3, R4, R5, and Rs is -H, (C1-C6)-
alkyl, -OR25, halogen; and any one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl,
-OR25, or halogen.
[0193] In one embodiment, any one of R7', R7, R8, R9, R10, R11, and R12 is -H, (C1-
C6)-alkyl, -OR25, halogen, or -CF3, -NO2, or -CN except for the R group through
which the piperidine is connected; and any one of R13, R14, R15, and R16 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3.
[0194] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
any one of R13, R14, R15, and R]6 is -H, (C1-C6)-alkyl, -OR25, or halogen; and any one
of R7', R7, R8, R9, R10, R11, and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3,
-NO2, or -CN except for the R group through which the piperidine is connected
[0195] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
any one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen; and any two
of R7', R7, R8, R9, R10, R11, and R12 are each independently -H, (C1-C6)-alkyl, -OR25,
halogen, or -CF3, -NO2, or -CN except for the R group through which the piperidine is
connected; wherein the any two of R7', R7, R8, R9, R10, R11, and R12 can be either on
the same ring of the quinoline or on different rings.
[0196] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
any one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen; and any one
of R7', R7, R8, R8, R10, R11, and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3,
-NO2, or -CN except for the R group through which the piperidine is connected
[0197] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
any one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen; and any two
of R7', R7, R8, R9, R10, R11, and R12 are each independently -H, (C1-C6)-alkyl, -OR25,
halogen, or -CF3, -NO2, or -CN except for the R group through which the piperidine is
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WO 2006/135839 PCT/US2006/022719
connected; wherein the any two of R7', R7, R8, R9, R10, R11, and R12 can be either on
the same ring of the quinoline or on different rings.
[0198] In one embodiment, the piperidine N is connected through the R7 of the
quinoline. In another embodiment, the piperidine N is connected through the R7' of the
quinoline. In yet another embodiment, the piperidine N is connected through the R8 of
the quinoline. In still another embodiment, the piperidine N is connected through the
R9 of the quinoline.
[0199] In one embodiment, R25 is (C1-C6)-haloalkyl.
[0200] In another embodiment, R25 is (C1-C6)-fluoroalkyl.
[0201] In one embodiment, R25 is (C1-C6)-alkyl. In one embodiment, R25 is -CH3.
[0202] In one embodiment, the compounds of Formula (I") are antagonists of the
5-HT1A receptor. In another embodiment, the compounds of Formula (I") are agonists
of the 5-HT1A receptor.
[0203] In another embodiment, the compounds of Formula (F) have the Formula
(I"a):

wherein Ra, Rb, R1, R2, R3, R4, R5, R6, R7', R8, R9, R10, R11, R12, R13, R14, R16,
R16, and R25 are defined as above for Formula (I")
[0204] In one embodiment, R1, is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3. In
another embodiment, R1 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R1
is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is -H, (C1-
43

WO 2006/135839 PCT/US2006/022719
C6)-alkyl, -OR25, or halogen, and R7', R8, R9, R10, R11, and R12 are each hydrogen. In
yet another embodiment, R1 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13,
R11, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and R2, R3, R4 R5, R6, R7',
R8, R9, R10, R11, and R12 are each hydrogen. In one embodiment, R1 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3 and R2, R3, R4, R5, R6, R7', R8, R9, R10, R11, R12, R13,
R14, R15, and R16 are each hydrogen.
[0205] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3. In
another embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R4
is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R11, R15, and R16 is -H, (Cr
C6)-alkyl, -OR25, or halogen, and R7', R8, R9, R10, R11, and R12 are each hydrogen. In
yet another embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and R1, R2, R3, R5, R6, R7',
R8, R9, R10, R11, and R12 are each hydrogen. In one embodiment, R4 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3 and R1, R2, R3, R5, R6, R7', R8, R9, R10, R11, R12, R13,
R14, R15, and R25 are each hydrogen.
[0206] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3. In
another embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of RJ3,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R5
is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is -H, (C1-
C6)-alkyl, -OR25, or halogen, and R7', R8, R9, R10, R11, and R12 are each hydrogen. In
yet another embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen; and R1; R2, R3, R4, R6, R7',
R8, R9, R10, R11, and R11 are each hydrogen. In one embodiment, R5 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3 and R1, R2, R3, R4, R6, R7', R8, R9, R10, R11, R12, R13,
R14, R15, and R16 are each hydrogen. In a further embodiment, one of R13, R14, R15,
and R16 is -H, (C1-C6)-alkyl, halogen, -CF3, or -OR25; R5 is -H, (C1-C6)-alkyl, -OR25,
halogen, or -CF3; and each remaining R group is hydrogen.
[0207] In one embodiment, R7- is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN. In one embodiment, R7' is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -
CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
and Ra and Rb are each independently -H or -CH3; and each remaining R group is
hydrogen. In one embodiment, R7' is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
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WO 2006/135839 PCT/US2006/022719
-CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
and each remaining R group is hydrogen. In one embodiment, R7' is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and each remaining R group is hydrogen.
[0208] In one embodiment, R8 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN. In another embodiment, R8 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; one of R1, R2, R3, R4, R5 and R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; Ra
and Rb are each independently -H or -CH3; and each remaining R group is hydrogen.
In a further embodiment, R8 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of
R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, Ra and Rb are each
independently -H or -CH3, and each remaining R group is hydrogen. In one
embodiment, Rb is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R4
or R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3, Ra and Rb are each independently
-H or -CH3, and each remaining R group is hydrogen. In one embodiment R8 is -H,
(C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and all other R groups are each
hydrogen. In one embodiment, Rs is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; one of R13, R1,, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, Ra and Rb
are each independently -H or -CH3, and each remaining R group is hydrogen.
[0209] In one embodiment, R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN. In another embodiment, R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; one of R11 R2, R3, R4, R5 and R8 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; Ra
and Rb are each independently -H or -CH3; and each remaining R group is hydrogen.
In a further embodiment, R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
one of R1, R2, R3, R4, R5 and Rs is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of
R13, R1,, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and each remaining R
group is hydrogen. In one embodiment, R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; one of R4 or R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3, and each
remaining R group is hydrogen. In one embodiment R9 is -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; and all other R groups are each hydrogen. In one
embodiment, R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R13,
R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen; and each remaining R group
is hydrogen.
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WO 2006/135839 PCT/US2006/022719
[0210] In one embodiment, R10 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN. In one embodiment, R10 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3. In one
embodiment, R10 is -H, -CH3, -OCH3, -F or -CF3. In one embodiment, R10 is -H, (C1-
C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; Ra and Rb are each independently -H or -CH3;
and each remaining R group is hydrogen. In one embodiment, R10 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R11 R2, R3, R1,, R5 and R6 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; and each remaining R group is hydrogen.
[0211] In one embodiment, R1, is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN. In one embodiment, R11 is -H, (C1-C6)-alkyl, halogen, or -CF3. In one
embodiment, R11 is -H, -CH3, -F or -CF3. In one embodiment, R11 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, or -NO2. In one embodiment, R11 is -H, (C1-C6)-alkyl,
-OR25, halogen, -CF3 -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)- ,
alkyl, -OR25, halogen, or -CF3; and Ra and Rb are each independently -H or -CH3; and
each remaining R group is hydrogen. In one embodiment, R11 is -H, (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-
alkyl, -OR25, halogen, or -CF3; and each remaining R group is hydrogen.
[0212] In one embodiment, R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN. In one embodiment, R12 is -H, (C1-C6)-alkyl, halogen, or -CF3. In one
embodiment, R12 is -H, -CH3, -F or -CF3. In one embodiment, R12 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, or -NO2. In one embodiment, R12 is -H, (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-
alkyl, -OR25, halogen, or -CF3; Ra and Rb are each independently -H or -CH3; and each
remaining R group is hydrogen. In one embodiment, R12 is -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3; and each remaining R group is hydrogen.
[0213] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
one of R7', R8, R9, R10, R11 and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN. In another embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
one of R7', R8, R9, R10, R11, R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; and each remaining R group is hydrogen. In some embodiments, R5 is -H, (C1-
C6)-alkyl, -OR25, halogen, or -CF3 and R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; and each remaining R group is hydrogen. In some embodiments, R5 is -
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WO 2006/135839 PCT/US2006/022719
H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and R7- is -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; and each remaining R group is hydrogen. In some
embodiments, R5 is -H or -OR25 and R7- is -H or halogen; and each remaining R
group is hydrogen.
[0214] In a further embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
one of R7', R8, R9, R10, R11, and R]2 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN; one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen, and each
remaining R group is hydrogen.
[0215] In a further embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
two of R7', R8, R9, R10, R11, and R12 are each independently -H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; one of R13, R14,, R15, and R16 is -H, (C1-C6)-alkyl, -OR25,
or halogen, and each remaining R group is hydrogen.
[0216] In a further embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
three ofR7', R8, R9, R10, R11, and R12 are each independently-H, (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25,
or halogen, and each remaining R group is hydrogen.
[0217] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is
-H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and two of R10, R11 and R12 are
each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN. In another
embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; two of R10, R11, R12 are each independently
-H, (C1-C6)-alkyi, -OR25, halogen, -CF3, -NO2 or -CN; and each remaining R group is
hydrogen. In some embodiments, R5 is -H or -OR25; R9 is -H or halogen; two of R10,
R11, R12 are each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; and each remaining R group is hydrogen. In some embodiments, R5 is -H or
-OCH3; R9 is -H or halogen; two of R10, R11, R12 are each independently -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and each remaining R group is hydrogen.
In some embodiments, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is -H, (C1-
C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; R10 and R12 are each independently -H,
(C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and each remaining R group is
hydrogen. In some embodiments, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9
is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; R10 and R11 are each
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WO 2006/135839 PCT/US2006/022719
independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and each
remaining R group is hydrogen. In some embodiments, R5 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3; R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
R11 and R12 are each independently -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; and each remaining R group is hydrogen.
[0218] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
one of R7', R8, R9, R10, R11 and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN. In another embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one
of R7., R8, R9, R10, R11, and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; and each remaining R group is hydrogen. In a further embodiment, R4 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R7', R8, R9, R10, R11; R12 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R13, R14,, R15, and R]6 is -H, (C1-C6)-
alkyl, -OR25, or halogen, and each remaining R group is hydrogen.
[0219] In one embodiment, one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl,
halogen, -CF3, or -OR25.
[0220] In one embodiment, R1, R2, R3, R6, R7', R8, R9, R10, R11, R12, R13, R14,, R15,
and R16 are each hydrogen.
[0221] In one embodiment, R1, R2, R3, R4, R7', R8, R10, R11, and R12 are each
hydrogen.
[0222] In one embodiment, R11 R2, R3, R4, R7', R8, R10, R11, and R12 are each
hydrogen.
[0223] In one embodiment, R1, R2, R3, R4, R7', R8, R9, R11, and R12 are each
hydrogen.
[0224] In one embodiment, R1, R2, R3, R4, R7', R8, R9, R10, and R12 are each
hydrogen.
[0225] In one embodiment, R1, R2, R3, R4, R7', R8, R9, R10, and R11 are each
hydrogen.
[0226] In one embodiment, R1, R2, R3, R4, Rv, R8, and R11 are each hydrogen.
[0227] In one embodiment, R1, R2, R3, R4, R7', R8, R9 and R11 are each hydrogen.
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WO 2006/135839 PCT/US2006/022719
[0228] In one embodiment, R1, R2, R3, R4. R5, R6, R7', R8, R9, and R12 are each
hydrogen.
[0229] In another embodiment, R13, R14, R15, and R25 are each hydrogen.
[0230] In one embodiment, R3, R6, R7', R8, R9, R12, R13, R14, R15, and R1,6 are each
hydrogen.
[0231] In one embodiment, R1, R2, R3, R4. R5, R8, R9, R10, R11, R12, R13, R14, R15,
and R16 are each hydrogen.
[0232] In one embodiment, R1, R2, R3, R4, R6, R8, R10, R11, R12, R13, R14, R15, and
R16 are each hydrogen.
[0233] In one embodiment, any one of R7', R8, R9, R10, R11, and R12 is -H, (C1-
C6)-alkyl, -OR25, halogen, -CF3, -NO2, or -CN; and any one of R13, R14, R15, and R16 is
-H, (C1-C6)-alkyl, -OR25, halogen, -CF3.
[0234] In one embodiment, any one of R1, R2, R3, R4, R5, and R6 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3; and any one of R7', R8, R9, R10, R11, and R12 is -H, (C1-
C6)-alkyl, -OR25, halogen, or -CF3, -NO2, or -CN.
[0235] In one embodiment, any one of R1, R2, R3, R4, R5, and R6 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3; and any one of R13, R14, R15, and R16 is -H, (C1-C6)-
alkyl, -OR25, halogen or -CF3.
[0236] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
any one of R13, R1,, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and any
one of R7', R8, R9, R10, R11, and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3,
-NO2, or -CN.
[0237] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
any one of R13, R14, R15, and R25 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and any
two of R7, R8, R9, R10, R11, and R12 are each independently -H, (C1-C6)-alkyl, -OR25,
halogen, or -CF3, -NO2, or -CN; wherein the any two of R7', R8, R9, R10, R11, and R12
can be either on the same ring of the quinoline or on different rings.
[0238] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
any one of R13, R14, R15, and R16 is -H, (C1-C6)alkyl, -OR25, halogen or -CF3; and any
one of R7', R8, R9, R10, R11, and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3,
-NO2, or -CN.
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WO 2006/135839 PCT/US2006/022719
[0239] In one embodiment, R5 is -H, (C1-C6)-aIkyl, -OR25, halogen, or -CF3 and
any one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and any
two of R7', R8, R9, R10, R11, and R12 are each independently -H, (C1-C,5)-alkyl, -OR25,
halogen, or -CF3, -NO2, or -CN; wherein the any two of R7', R8, R9, R10, R11, and R12
can be either on the same ring of the quinoline or on different rings.
[0240] In one embodiment, R1 is -H or (C1-C6)-alkyl; R2, R8, and R9 are each
independently -H or halogen; R4 is -H, halogen, -OR25, or -CF3; R5 is -H, halogen, or
-OR25; and R3, R6, R7', R12, R13, R14, R15, R16, Ra and Rb are each hydrogen.
[0241] In one embodiment, R1 is -H or -CH3; R2, R8, and R9 are each
independently -H or F; R4 is -H, F, -OCH3, or -CF3; R5 is -H, F, -OCH3; and R3, R6,
R7', R10, R11, R12, R13, R14, R15, R16, Ra and Rb are each hydrogen.
[0242] In one embodiment, R1 is -H, -CF3 or (C1-C6)-alkyl; R4 and R5 are each
independently -H, halogen, -OR25, or -CF3; R7', R8, R9, R10, R11, andR11 are each
independently-H, halogen, (C1-C6)-alkyl, -OR25, -CF3, or -NO2; R16 is -H or -CH3.
[0243] In one embodiment, R25 is (C1-C6)-haloalkyl.
[0244] In another embodiment, R25 is (C1-C6)-fluoroalkyl.
[0245] In one embodiment, R25 is (C1-C6)-alkyl. In one embodiment, R25 is -CH3.
[0246] In another aspect, the invention provides compounds of the Formula (II):

wherein Ra, Rb, R4, R5, R15, R16, and R25 are defined as above for Formula (I);
R11, R19, and R19 are each independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen, -CF3, -NO2, -CN, -OR25, -OSO2R25, -
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WO 2006/135839 PCT/US2006/022719
SR25, -SO2R25, -SO2N(R25)2, -N(R25)2, -C(O), -COR25, -CO2R25, -NR25CO2R25,
-NR25COR25, -NR25CON(R25)2, or -CON(R25)2; and
R4 and R5 cannot both be hydrogen.
[0247] In one embodiment, R4 and R5 are each independently -H, -OR25, halogen,
or (C1-C6)-alkyl; R15 and R16 are each independently -H or -CH3; and R17, R1s, and
R19 are each independently -H, -OR25, halogen, (C1-C6)-alkyl, -CF3, -NO2, -CN. In
one embodiment, R4 and R5 are each independently -H, -OCH3, F, or -CH3; R15 and
R16 are each independently -H or -CH3; and R17, R18, and R19 are each independently -
H, -OCH3, -F, -CH3, -CF3, -NO2, -CN, or -Br.
[0248] In one embodiment, R4 and R5 are each independently -H, or -OR25; R15
and R16 are each independently -H or -CH3; and R11, R18, and R19 are each
independently -H, -OR25, halogen, (C1-C6)-alkyl, or -CF3. In one embodiment, R4 and
R5 are each independently -H, or -OR25; Ra, Rb, R15 and R16 are hydrogen; and R17,
R1s, and R19 are each independently -H, -OR25, halogen, (C1-C6)-alkyl, or -CF3.
[0249] In another embodiment, R19 is in the para position relative to the nitrogen
of the piperidine.
[0250] In one embodiment, R17 and R18 are located at positions 2 and 4 of the
quinoline ring (i.e., at the ortho and para positions relative to the nitrogen of the
quinoline ring).
[0251] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3.
[0252] In another embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3
and one of R15 and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen.
[0253] In yet another embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or
-CF3; R15 is -H, (C1-C6)-alkyl, -OR25, or halogen, and R4 and R16 are each hydrogen.
[0254] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; R16
is -H, (C1-C6)-alkyl, -OR25, or halogen, and R4 and R15 are each hydrogen.
[0255] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3 and
R4, R15, R16, R11, R18 and R19 are each hydrogen.
[0256] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
one of R11, R18 and R19 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3. In another
embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R11, R18 and R19
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WO 2006/135839 PCT/US2006/022719
is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and each remaining R group is
hydrogen.
[0257] In one embodiment, R8, R17, R18, and R19 are each independently -H, (C1-
C6)-alkyl, -OR25, halogen or -CF3 and R4, R25, and R16 are each hydrogen. In one
embodiment, R5 is -H, -OR25 or halogen; R11 and R18 are each independently -H, (C1-
C6)-alkyl, -OR25, halogen or -CF3; R19 is -H or halogen; and Ra, Rb, R4, R15, and R16
are each hydrogen.
[0258] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3.
[0259] In another embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3
and one of R15, and R25 is -H, (C1-C6)-alkyl, -OR25, or halogen.
[0260] In a further embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
one of R15 and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen; and R17, R18 and R19 are
each hydrogen.
[0261] In yet another embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or
-CF3; R15 is -H, (C1-C6)-alkyl, -OR25, or halogen, and R5 and R16 are each hydrogen.
[0262] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; R16
is -H, (C1-C6)-alkyl, -OR25, or halogen, and R5 and R15 are each hydrogen.
[0263] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3 and
R5, R15, R16, R17, R18 and R19 are each hydrogen.
[0264] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
one of R11, R18 and R19 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3.
[0265] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
two of R11, R1s and R19 are each independently -H, (C1-C6)-alkyl, -OR25, halogen, or
-CF3.
[0266] In one embodiment, R5> R17> R18 and R19 are each independently -H, (Cr
C6)-alkyl, -OR25, halogen, or -CF3.
[0267] In another embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3
and one of R1,7, R18 and R19 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and each
remaining R group is hydrogen.
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WO 2006/135839 PCT/US2006/022719
[0268] In another embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3
and two of R11, R18 and R19 are each independently -H, (C1-C6)-alkyl, -OR25, halogen,
or -CF3; and each remaining R group is hydrogen.
[0269] In one embodiment, R5, R17, R11 and R19 are each independently -H, (C1-
C6)-alkyl, -OR25, halogen, or -CF3 and each remaining R group is hydrogen.
[0270] In a further embodiment, R5 is -H, (C1-C6)-alkyl, -OR?.s. halogen, or -CF3;
one of R11, R18 and R19 is -H, (C1-C6)-allcyl, -OR25, halogen, or -CF3; one of R15 and
R16 is -H, (C1-C6)-alkyl, -OR25, or halogen; and each remaining R group is hydrogen.
[0271] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and
any two of R17, R1s and R19 are each independently -H, (C1-C6)-alkyl, -OR25, halogen,
or -CF3; and one of R15, and R16 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3.
[0272] In one embodiment, R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; RJ7,
R1s and R19 are each independently -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and
one of R15, andR16 is -H, (C1-C6)alkyl, -OR25, halogen, or -CF3.
[0273] In one embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and
one of R11, R18 and R19 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3.
[0274] In another embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3
and one of R17, R18 and R19 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and each
remaining R group is hydrogen.
[0275] In a further embodiment, R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
one of R17, R1s and R19 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R15 and
R16 is -H, (C1-C6)-alkyl, -OR25, or halogen; and each remaining R group is hydrogen.
[0276] In a further embodiment, R4 is -H, (C1-C6)-alkyl, 'OR25, halogen, or -CF3;
and any two of R11, R18 and R19 are each independently -H, (C1-C6)-alkyl, -OR25,
halogen, or -CF3, In one embodiment, R4, R11, R1s and R19 are each independently -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3 and each remaining R group is hydrogen.
[0277] In one embodiment, one of R15 and R16 is -H, (C1-C6)-alkyl, halogen, -CF3,
or -OR25. In a further embodiment, one of R15 and R16 is -H, (C1-C6)-alkyl, halogen,
-CF3, or -OR25; R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and each remaining
R group is hydrogen.
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WO 2006/135839 PCT/US2006/022719
[0278] In a further embodiment, one of R15 and R25 is -H, (C1-C6)-alkyl, halogen,
-CF3, or -OR25; R4 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and each remaining
R group is hydrogen.
[0279] In one embodiment, R4, R15, R16, R11, R1s and R19 are each hydrogen.
[0280] In one embodiment, R4, R15, R16, R17, and R1s are each hydrogen.
[0281] In one embodiment, R4, R15, and R16 are each hydrogen.
[0282] In one embodiment, R5, R15, R16, R11, R18 and R19 are each hydrogen.
[0283] In one embodiment, R5, R15, R16, R11, and R18 are each hydrogen.
[0284] In one embodiment, R4, R15, R16, and R19 are each hydrogen.
[0285] In one embodiment, R5, R15, and R16 are each hydrogen.
[0286] In one embodiment, R5 is -H, -OR25 or halogen; R4, R15, R16, R11, and R18
are each hydrogen; and R19 is -H or halogen.
[0287] In one embodiment, R5 is -H, -OCH3 or F; R4, R15, R16, R11, and R18 are
each hydrogen; and R19 is -H or F.
[0288] In one embodiment, R5 is -H, -OCH3 or F; R4, R15, and R16 are each
hydrogen; and one of R1S or R19 is -H or F. In one embodiment, R5 is -H, -OCH3 or
F; R4, R15, R16 and R11 are each hydrogen; and R1s and R19 are each independently -H,
-CH3 or halogen.
[0289] In one embodiment, R4 is hydrogen, R5 is -H, -OR25; and R11, R18, and RJ9
are each independently -H, -OR25, halogen, (C1-C6)-alkyl, or -CF3. In one
embodiment, R4 is hydrogen, R5 is -OR25; R11, and R18 are each independently -H, -
OR25, halogen, (C1-C6)-alkyl, or -CF3; and R19 is -H or halogen.
[0290] In one embodiment, R5 is -H, -OR25 or halogen; R11 and R1S are each
independently -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; R19 is H or halogen; and Ra,
Rb, R4, R15, and R1,g are each hydrogen.
[0291] In one embodiment, R5 is -H, -OCH3 or F; R11 is -H, -OCH3; R18 is -H, -
CF3; R19 is -H, F; and Ra, Rb, R4, R15, and R16 are each hydrogen.
[0292] In one embodiment, R4 is -H, -OR25 or halogen; R5, R15, R16, R11 and R18
are each hydrogen; and R19 is -H or halogen. In one embodiment, R5 is -H, -OCH3 or
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WO 2006/135839 PCT/US2006/022719
F; R4, R15, R16 and R19 are each hydrogen; and R17 and R18 are each -H, -CH3 or
halogen.
[0293] In one embodiment, R4 is ~H, -OCH3 or F; R5, R15, R16, R1,7 and R18 are
each hydrogen; and R19 is -H or F.
[0294] In one embodiment, R4 is -H, -OCH3 or F; R5, R15, and R18 are each
hydrogen; and one of R18 or R19 is -H or F. In one embodiment. R4 is -H, -OCH3 or F;
R5, R15, R16 and R11 are each hydrogen; and R1s and R19 are each -H, -CH3 or
halogen. In one embodiment, R4 is -H, -OCH3 or F; R4, R15, R16 and R19 are each
hydrogen; and R11 and R18 are each -H, -CH3 or halogen.
[0295] In one embodiment, the compounds of Formula (ID are antagonists of the
5-HT1A receptor.
[02.96] In another embodiment, the compounds of Formula (H) are agonists of the
5-HT1A receptor.
[0297] Illustrative examples of compounds of Formula (I), Formula (I), Formula
(I"), or Formula (l"a) and Formula (D) are set forth below and include, without
limitation:
6-methoxy-8-[4-(l-quinolin-8-yI-piperidin-4-yl)-piperazin-l-yl]-quinoline;
6-fluoro-8-[4-(l -quinoIin-8-yl-piperidin-4-yl)-piperazin-1 -yl]-quinoline;
5-fluoro-8-[4-(l-quinohin-8-yl-piperidin-4-yl)-piperazin-l-yl]-quinoline;
7-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1 -yl)piperidin~l -
yl)quinoline;
6-fluoro-8-{4-[l-(8-fluoroquinolin-7-yl)piperidin-4-yl]piperazin-l-
yl}quinoline;
3-trifluoromethyl-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-l-
yl)quinoline;
6-methoxy-8-(4-(l-(quinolin-8-ylmethyl)piperidin-4-yI)piperazin-l--
yl)quinoline;
5-fluoro-4-methoxy-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-
1 -yl)-2-(trifluoromethyl)quinoline;
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WO 2006/135839 PCT/US2006/022719
5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-l-
yl)quinoline;
8-[4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-quinoline;
6-chloro-8- [4-(4-(6-chloro)-quinolin-8-yl-piperidin-1 -yl)-piperazin-1 -yl] -
quinoline;
6-fluoro-8- [4-(4-(6-chloro)-quinolin-8-yl-piperidin-1 -yl)-piperazin-1 -yl] -
quinoline;
5-chloro-8-[4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-quinoline;
2-methyl-8-[4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-quinoline;
6-chloro-8-[4-( 1 -quinolin-8-yl-piperidin-4-yl)-piperazin-1 -yl] -quinoline;
8-[4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-5-trifluoromethyl-
quinoline;
5-methoxy-8-[4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-quinoline;
5-fluoro-8-[4-(4-quinolin-8-yl-piperazin-l-yl)-piperidin-l-yl]-quinoline;
6-methoxy-8-[4-(2-methylquinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-
quinoline;
6-fluoro-8-(4-( 1 -(2-methylquinolin-8-yl)piperidin-4-yl)piperazin-1 -
yl)quinoline;
6-methoxy-8-[4-(3-methylquinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-
quinoline;
6-methoxy-8-(4-(l-(4-methylquinolin-8-yl)piperidin-4-yl)piperazin-l-
yl)quinoline;
6-methoxy-8-(4-( 1 -(2,4-dimethylquinolin-8-yl)piperidin-4-yl)piperazin-1 -
yl)quinoline;
6-methoxy-8-(4-(l-(2,4-dimethyl-5-fluoroquinolin-8-yl)piperidin-4-
yl)piperazin4-yl)quinoline;
6-methoxy-8-(4-(l-(2-(trifluoromethyl)quinolin-8-yl)piperidin-4-yl)piperazin-
l-yl)quinoline;
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6-fluoro-8-(4-(l-(5-fluoroquinolin-8-yl)piperidin-4-yl)piperazin-
l-yl)quinoline;
6-methoxy-8-(4-(l-(6-bromoquinolin-8-yl)piperidin-4-yl)piperazin-
l-yl)quinoline;
6-methoxy-8-(4-(l-(6-fluoroquinolin-8-yl)piperidin-4-yl)piperazin-
l-yl)quinoline;
6-fluoro-8-(4-(l-(7-fluoroquinolin-8-yl)piperidin-4-yl)piperazin-
l-yl)quinoline;
6-methoxy-8- {4- [ 1 -(8-fluoroquinolin-7-yl)piperidin-4-yl]piperazin-1 -
yl}quinoline;
6-methoxy-8-{4-[l-(2-trifluoromethyl-4-methoxyquinolin-7-yl)piperidin-4-
yl]piperazin-1 -yl} quinoline;
6-methoxy-8-(4-(l-(2-trifluoromethyl-4-methoxyquinolin-8-yl)piperidin-4-
yl)piperazin-1 -yl)quinoline;
5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-l-yl)-
2-trifluoromethylquinoline;
5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-l-yl)-
3-trifluoromethylquinoline;
5-fluoro-8~(4-(4-(6-methoxyquinolin-8-yl)piperazin-1 -yl)piperidin-1 -yl)-
4-trifluoromethylquinoline;
2,5-difluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-
l-yl)quinoline;
3,5-difluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-
l-yl)quinoline;
4,5-difluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-
l-yl)quinoline;
and pharmaceutically acceptable salts thereof.
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[0298] In a further aspect, the invention provides compounds of the Formula (HI):

and R7, R8, R8, R10, R11, R12, R13, R14, R15, R16, R20, R21, R22, R23, R24, R26, R27,
R28, R29 and R30 are each independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C1-C6)-
alkenyl, or (C2-C6)-alkynyl, halogen, -CF3, -NO2, -CN, -OR25, -OSO2R25, -SR25, -
SO2R25, -SO2N(R25)2, -N(R25)2, -C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25,
-NR25CON(R25)2, or -CON(R25)2;
Ra and Rb are each independently -H or -CH3; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-alkynyl.
[0299] In one embodiment, any of R7, R8, R9, R10, R11, and R12 are each
independently -H, (C1-C6)-alkyl, halogen, -CF3l -OR25, -NO2 or -CN; and the
remaining R7-R12 are each hydrogen. In one embodiment, any of R7, R8, R9, R10, R11,
and R12 are each independently -H, (C1-C6)~alkyl, halogen, -CF3, -OR25, -NO2 or -CN;
and the remaining R7-R16 are each hydrogen.
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[0300] In one embodiment, any of R7, R8, R9, R10. R1b and R12 are each
independently -H, halogen, or -CF3; and the remaining R7-R12 are each hydrogen. In
one embodiment, any of R7, R8, R9, R10, R11. and R12 are each independently -H,
halogen, or -CF3; and the remaining R7-R16 are each hydrogen.
[0301] In one embodiment, any two of R7, R8, R9, R10, R11, and R12 are each
independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR2S, -NO2 or -CN; and the
remaining R7-R12 are each hydrogen. In one embodiment, any two of R7, R8, R9, R10,
R11, and R12 are each independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -
CN; and the remaining R7-R16 are each hydrogen.
[0302] In one embodiment, any three of R7, R8, R9, R10, R11, and R12 are each
independently -H, halogen, or -CF3 and the remaining R7-R12 are each hydrogen. In
one embodiment, any three of R7, R8, R9, R10, R11, and R12 are each independently -H,
halogen, or -CF3 and the remaining R7-R16 are each hydrogen.
[0303] In one embodiment, R7 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN. In one embodiment, R7 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -
CN; one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
and Ra and Rb are each independently -H or -CH3; and each remaining R group is
hydrogen. In one embodiment, R7 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; one of R1, R2, R3, R4, R5 and Rg is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
and each remaining R group is hydrogen.
[0304] In one embodiment, R10 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN. In one embodiment, R10 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CFj. In one
embodiment, R10 is -H, -CH3, -OCH3, -F or -CF3. In one embodiment, R10 is -H, (C1-
C6)-alkyl, -OR25, halogen, -CF3, -NO2 or-CN; one of R1, R2, R3, R4, R5 and Rg is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; and Ra and Rb are each independently -H or
-CH3; and each remaining R group is hydrogen. In one embodiment, R10 is -H, (C1-
C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of Rlf R2, R3, R4, R5 and R6 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; and each remaining R group is hydrogen.
[0305] In one embodiment, R11 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or-CN. In one embodiment, R11 is-H, (C1-C6)-alkyl, halogen, or-CF3. In one
embodiment, R11 is -H, -CH3, -F or -CF3. In one embodiment, R11 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H,
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(C1-C6)-alkyl, -OR25, halogen, or -CF3; Ra and Rb are each independently -H or -CH3;
and each remaining R group is hydrogen. In one embodiment, R11 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; and each remaining R group is hydrogen.
[0306] In one embodiment, R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or -CN. In one embodiment, R12 is -H, (C1-C6)-alkyl, halogen, or -CF3. In one
embodiment, R12 is -H, -CH3, -F or -CF3. In one embodiment, R12 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; Ra and Rb are each independently -H or -CH3;
and each remaining R group is hydrogen. In one embodiment, R12 is -H, (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, R5 and R6 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; and each remaining R group is hydrogen.
[0307] In one embodiment, R7 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or
-CN and R8, R9, R10, R11 and R12 are each hydrogen. In one embodiment, R7 is -H,
(C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; Ra and Rb are each independently
-H or -CH3; and each remaining R group is hydrogen.
[0308] In one embodiment, R8 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or
-CN and R7, R9, R10, R11 and R12 are each hydrogen. In one embodiment, R8 is -H,
(C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; Ra and Rb are each independently
-H or -CH3; and each remaining R group is hydrogen.
[0309] In one embodiment, R9 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or
-CN and R7, R8, R10, R11 and R12 are each hydrogen. In one embodiment, R9 is -H,
(C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; Ra and Rb are each independently
-H or -CH3; and each remaining R group is hydrogen.
[0310] In one embodiment, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R20, R21,
R22, R23, R24, R26, R27, R28, R29 and R30 are each hydrogen.
[0311] In one embodiment, R25 is (C1-C6)-alkyl.
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[0312] In one embodiment, R99 is
and R20, R21, R22. and R23 are each independently -H, -OR25, -CH3, halogen,
-CF3,-NO2 or-CN.
[0313] In one embodiment, R99 is the benzofuran above and R20, R21, R22, and R23
are each -H.
[0314] In one embodiment, R99 is the benzofuran above; R7, R8, R9, R10, R11, R12,
R20, R21, R22 andR23 are each independently-H, (C1-C6)-alkyl, halogen, -CF3, -OR25,
-NO2 or -CN.
[0315] In one embodiment, R99 is the benzofuran above; R7, R8, R9, R10, R11, and
R12, are each independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN;
and R13, R14, R15, and R15 are each hydrogen.
[0316] In one embodiment, R99 is the benzofuran above; R8 is -H, (C1-C6)-alkyl,
halogen, -CF3, -OR25, -NO2 or -CN; and R7, R9, R10, R11, and R12 are each
independently -H, (C1-C6)-alkyl, halogen, -CF3, or -OCH3.
[0317] In one embodiment, R99 is the benzofuran above; R8 is -H, (C1-C6)-alkyl,
halogen, -CF3, -OR25, -NO2 or -CN; R15 and R16 are each independently -H, (C1-C6)-
alkyl, halogen, -CF3, or -OR25; and R7, R9, R10, R11, R12, R13 and R14 are each
hydrogen.
[0318] In one embodiment, R99 is the benzofuran above; R8 is -H, (C1-C6)-alkyl,
halogen, -CF3, -OR25, -NO2 or -CN; and R7, R9, R10, R11, R12, R13, R14, R15, and R16
are each hydrogen.
[0319] In one embodiment, R99 is the benzofuran above; R8 is -H, (C1-C6)-alkyl,
halogen, -CF3, -OR25, -NO2 or -CN; and R7, R9, R10, R11, R12, R20, R21, R22 and R23 are
each hydrogen.
[0320] In one embodiment, R99 is the benzofuran above; R8 is -H or halogen and
R7, R9, R10, R11, R12, R20, R21, R22 and R23 are each hydrogen. In one embodiment, R99
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WO 2006/135839 PCT/US2006/022719
is the benzofuran above; Rg is -H or halogen and R7, R9, R10, R11, R12, R13, R14, R15,
R16, R20, R21, R22 and R23 are each hydrogen.
[0321] In one embodiment, R99 is the benzofuran above; and R8 and R22 are each —
H or halogen. In one embodiment, R99 is the benzofuran above; Rg and R22 are each —
H or halogen; and each remaining R group is hydrogen.
[0322] In one embodiment, R99 is the benzofuran above; and R8 and R22 are each
independently -H, -Cl or -F.
[0323] In one embodiment, R99 is the benzofuran above; Rg and R22 are each
independently -H, -Cl or -F; and R7, R9, R10, R11, R12, R20, R21, and R23 are each
hydrogen.
[0324] In one embodiment, R99 is the benzofuran above; R8 and R22 are each
independently -H, -Cl or -F; and R7, R9, R10, R11, R12, R13, R14,, R15, R16, R20, R21, and
R23 are each hydrogen.
[0325] In one embodiment, R99 is the benzofuran above; R9 is -H, (C1-C6)-alkyl,
halogen, -CF3, -OR25, -NO2 or -CN; R7, R8, R10, and R12 are each independently -H,
(C1-C6)-alkyl, halogen, -CF3, or -OCH3; and R13, R14, R15, and R16 are each hydrogen.
[0326] In one embodiment, R99 is the benzofuran above; R9 is -H, (C1-C6)-alkyl,
halogen, -CF3, -OR25, -NO2 or -CN; R15 and R16 are each independently -H, (C1-C6)-
alkyl, halogen, -CF3, or -OR25; and R7, R8, R10, R11, R12, R13 and R14 are each
hydrogen.
[0327] In one embodiment, R99 is the benzofuran above; R9 is -H, (C1-C6)-alkyl,
halogen, -CF3, -OR25, -NO2 or -CN; and R7, R8, R10, R11, R12, R13, R11, R15, and R!6
are each hydrogen.
[0328] In one embodiment, R99 is the benzofuran above; R9 is -H, (C1-C6)-alkyl,
halogen, -CF3, -OR25, -NO2 or -CN; and R7, R8, R10, R11, R12, R20, R21, R22 and R23 are
each hydrogen.
[0329] In one embodiment, R99 is the benzofuran above; one of R7, R8, R9, R10,
R11, and R11 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and each
remaining R group is H.
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[0330] In one embodiment, R99 is the benzofuran above; one of R20, R21, R22, and
R23 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and each remaining R
group is H.
[0331] In one embodiment, R99 is the benzofuran above; one of R7, R8, R9, R10,
R11, and R12 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; one of R13, R14,
R15, and R16 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and each
remaining R group is H.
[0332] In one embodiment, R99 is the benzofuran above; one of R7, R8, R9, R10,
R11 and R12 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and one of R20,
R21, R22, and R23 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN.
[0333] In one embodiment, R99 is the benzofuran above; one of R7, R8, R9, R10,
R11 and R12 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; one of R20, R21,
R22, and R25 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and the
remaining R groups are hydrogen.
[0334] In one embodiment, R99 is the benzofuran above; two of R7, R8, R9, R10,
R11, and R12 are each independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or
-CN; and each remaining R group is hydrogen.
[0335] In one embodiment, R99 is the benzofuran above; two of R7, R8, R9, R10,
R11, and R]2 are each independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or
-CN; one of R20, R21, R22, and R23 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or
-CN; and each remaining R group is hydrogen.
[0336] In one embodiment, R99 is the benzofuran above; two of R7, R8, R9, R10,
R11, and R12 are each independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or
-CN; one of R20, R2i, R22, and R23 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or
-CN; one of R13, R11, R15, and R16 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or
-CN; and each remaining R group is hydrogen.
[0337] In one embodiment, R99 is the benzofuran above; R9 and R22 are each
independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and each
remaining R group is hydrogen. In one embodiment, R99 is the benzofuran above; R9
and R22 are each independently -H or halogen; and each remaining R group is
hydrogen.
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[0338] In another embodiment, R99 is
and R24, R26, and R27 are each independently, -H, (C1-C6)-alkyl, halogen, -CF3,
-OR25, -NO2 or -CN. In one embodiment, R99 is the benzo[l,4]dioxane above and R24,
R26, and R27 are each hydrogen.
[0339] In one embodiment, R99 is the benzo[l,4]dioxane above and R7, R8, R9, R10, R11, R12, R13, R14, R15, and R16 are each independently -H, (C1-C6)-alkyl, halogen,
-CF3, -OR25, -NO2 or -CN.
[0340] In one embodiment, R99 is the benzo[l,4]dioxane above; R7, R8, R9, R10,
R11, and R12 are each independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or
-CN; and R13, R25, R15, and R15 are each hydrogen.
[0341] In one embodiment, R99 is the benzo[l,4]dioxane above and R7, R6, R9, R10, R11, R12, R13, R14, R15, R16, R24, R26, and R27 are each hydrogen. In one
embodiment, R99 is the benzo[l,4]dioxane above and R7, R8, R9, R10, R11, R12, R13,
R14, R15, R16, R24, R26, R27, Ra and Rb are each hydrogen.
[0342] In one embodiment, R99 is the benzo[l,4]dioxane above and R9 is -H, (C1-
C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN.
[0343] In one embodiment, R99 is the benzo[l,4]dioxane above; R9 is —H, (C1-C6)-
alkyl, halogen, -CF3, -OR25, -NO2 or -CN; R15 and R16 are each independently -H, (C1-
C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and R7, R8, R10, R11, and R!2 are each
hydrogen.
[0344] In one embodiment, R99 is the benzo[l,4]dioxane above; R9 is -H, (C1-C6)-
alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and R7, R8, R10, R11, R12, R13, R14. R15, and
R16 are each hydrogen.
[0345] In one embodiment, R99 is the benzo[l,4]dioxane above; R8 is -H, (C1-C6)-
alkyl, halogen, -CF3, -OR25, -NO2 or -CN.
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[0346] In one embodiment, R99 is the benzo[l,4]dioxane above; R8 is -H, (C1-C6)-
alkyl, halogen, -CF3, -OR25, -NO2 or -CN; R15 and R16 are each independently -H, (C1-
C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and R7, R9, R10, R11, and R12 are each
hydrogen.
[0347] In one embodiment, R99 is the benzo[l,4]dioxane above; R8 is -H, (C1-C6)-
alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and R7, R9, R10, Rn, R12, R13, R14, R15, and
R16 are each hydrogen.
[0348] In one embodiment, R99 is the benzo[l,4]dioxane above; one of R7, R8, R9,
R10, Rn, and R12 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and each
remaining R group is hydrogen.
[0349] In one embodiment, R99 is the benzo[l,4]dioxane above; one of R7, R8, R9,
R10, Rn, and R12 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; one of R24,
R26, and R27 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and each
remaining R group is hydrogen.
[0350] In one embodiment, R99 is the benzo[l,4]dioxane above; one of R7, R8, R9,
R10, Rn, and R12 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; one of R24,
R26, and R27 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; one of R13, R14,
R15, and R16 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and each
remaining R group is hydrogen.
[0351] In one embodiment, R99 is the benzo[l,4]dioxane above; two of R7, R8, R9,
R10, Rn, and R12 are each independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25,
-NO2 or -CN; and each remaining R group is hydrogen.
[0352] In one embodiment, R99 is the benzo[l,4]dioxane above; two of R7, R8, R9,
R10, Rn, and R12 are each independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25,
-NO2 or -CN; one of R24, R26, and R27 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25,
-NO2 or -CN; and each remaining R group is hydrogen.
[0353] In one embodiment, R99 is the benzo[l,4]dioxane above; two of R7, R8, R9,
Rio, Rn, and R12 are each independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25,
-NO2 or -CN; one of R24, R26, R27 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or
-CN; one of R13, R14, R,5, and R16 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or
-CN; and each remaining R group is hydrogen.
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WO 2006/135839 PCT/US2006/022719
[0354] In a further embodiment, R99 is
and R28, R29 and R30 are each independently -H, (C1-C6)-alkyl, halogen, -CF3,
-OR25,-NO2or-CN.
[0355] In one embodiment, R99 is the indole above and R28, R29, and R30 are each
hydrogen.
[0356] In one embodiment, R99 is the indole above and R7, R8, R9, R10, R11, R12.
R13, R14, R15, and R16 are each independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25,
-NO2 or -CN.
[0357] In one embodiment, R99 is the indole above; R7, R8, R9, R10, R11, and R12
are each independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and
R13, R14, R15, and R16 are each hydrogen.
[0358] In one embodiment, R99 is the indole above; R8 is -H, (C1-C6)-alkyl,
halogen, -CF3, -OR25, -NO2 or -CN.
[0359] In one embodiment, R99 is the indole above; Rg is -H, (C1-C6)-alkyl,
halogen, -CF3, -OR25, -NO2 or -CN; and R7, R9, R10, R11, R12, R28, R29, and R30 are
each hydrogen. In one embodiment, R99 is the indole above; R8 is -H or halogen and
R7, R9, R10, R11, R12, R28, R29, and R30 are each hydrogen. In one embodiment, R99 is
the indole above; Rg is -H or halogen and R7, R9, R10, R11. R12, R13, R14, R15, R16, R28,
R29, and R30 are each hydrogen. In one embodiment, R99 is the indole above; R8 is —H
or halogen and R7, R9, R10, R11, R12, R13, R11, R15, R16, R28, R29, R30, Ra and Rb are
each hydrogen.
[0360] In one embodiment, R99 is the indole above; R8 is -H, (C1-C6)-alkyl,
halogen, -CF3, -OR25, -NO2 or -CN; and R7, R9, R10, R11, R12, R13, R14, R15, and R16
are each hydrogen.
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WO 2006/135839 PCT/US2006/022719
[0361] In one embodiment, R99 is the indole above; R8 is -H, (C1-C6)-alkyl,
halogen, -CF3, -OR25, -NO2 or -CN; R15 and R16 are each -H, (C1-C6)-alkyl, halogen,
-CF3, -OR25, -NO2 or -CN; and R7, R9, R10, R11, and R12 are each hydrogen.
[0362] In one embodiment, R99 is the indole above; R9 is -H, (C1-C6)-alkyl,
halogen, -CF3, -OR25, -NO2 or -CN.
[0363] In one embodiment, R99 is the indole above; R9 is -H, (C1-C6)-alkyl,
halogen, -CF3, -OR25, -NO2 or -CN; and R7) R8, R10, R11, R12, R28, R29, and R30 are
each hydrogen.
[0364] In one embodiment, R99 is the indole above; R9 is -H, (C1-C6)-alkyl,
halogen, -CF3, -OR25, -NO2 or -CN; and R7, R8, R10, R11, R12, R13, R11, R15, and R16
are each hydrogen.
[0365] In one embodiment, R99 is the indole above; R9 is -H, (C1-C6)-alkyl,
halogen, -CF3, -OR25, -NO2 or -CN; R15 and R16 are each -H, (C1-C6)-alkyl, halogen,
-CF3, -OR25, -NO2 or -CN; and R7, R8, R10, R11, and R12 are each hydrogen.
[0366] In one embodiment, R99 is the indole above; one of R7, R8, R9, R10, R11,
and R12 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and each remaining
R group is H. In one embodiment, R99 is the indole above; one of R7, R8, R9, R10,R11,
and R12 is -H or halogen and each remaining R group is H.
[0367] In one embodiment, R99 is the indole above; one of R7, R8, R9, R10, R11,
and R12 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; one of R28, R29, and
R30 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and each remaining R
group is H.
[0368] In one embodiment, R99 is the indole above; one of R7, R8, R9, R10, R11,
and R12 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; one of R28, R29, and
R30 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; one of R13, R14, R15, and
R16 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and each remaining R
group is hydrogen.
[0369] In one embodiment, R99 is the indole above; two of R7, R8, R9, R10, R11,
and R12 are each independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN;
and each remaining R group is hydrogen.
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WO 2006/135839 PCT/US2006/022719
[0370] In one embodiment, R99 is the indole above; two of R7, R8, R9, R10, R11,
and R12 are each independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN;
one of R28, R29, and R30 is -H, -OR25, -CH3, halogen, -CF3, -NO2 or —CN; and each
remaining R group is hydrogen.
[0371] In one embodiment, R99 is the indole above; two of R7, R8, R9, R10, R11,
and R12 are each independently -H, (C1-C6)alkyl, halogen, -CF3, -OR25, -NO2 or -CN;
one of R28, R29, and R30 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; one
of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and
each remaining R group is hydrogen.
[0372] In yet another aspect, the invention provides compounds of the Formula
(IV):

wherein X is CR25, N, O or S; Y is CR25, NR25, O or S; with the proviso that
when X is CR25, Y is not NR25; R13, R14,, R15, R16, R31, R32, R33, R34, R35, R36, R37, R38
and R39 are each independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl,
or (C2-C6)-alkynyl, halogen, -CF3, -NO2, -CN, -OR25, -OSO2R25, -SR25, -SO2R25, -
SO2N(R25)2, -N(R2S)2, -C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25, -
NR25CON(R25)2, or -CON(R25)2; Ra and Rb are each independently -H or -CH3; R25 is
-H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6-
alkynyl).
[0373] In one embodiment, X is CR25 or N; Y is O or S; one of R31, R32, R33, R34
and R35 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and each remaining R group is
hydrogen.
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WO 2006/135839 PCT/US2006/022719
[0374] In one embodiment, X is CR25 or N; Y is O or S; one of R31, R32, R33, R34
and R35 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R36, R37, R38 and R39 is -
H, (C1-C6)-alkyl, -OR25, -CH3, halogen, or-CF3; and each remaining R group is
hydrogen.
[0375] In one embodiment, X is CR25 or N; Y is O or S; one of R31, R32, R33, R34
and R35 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is
-H, (C1-C6)-alkyl, -OR25, -CH3, halogen, or -CF3; and each remaining R group is
hydrogen.
[0376] In one embodiment, X is CR25 or N; Y is O or S; one of R31, R32, R33, R34
and R35 is -H, (C1-C6)-alkyl, -OR25, halogen, or-CF3; one of R13, R14, R15, and R16 is
-H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R36, R37, R38 and R39 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3; and each remaining R group is hydrogen.
[0377] In one embodiment, X is CR25 or N; Y is O or S; R13, R14, R15, R16, R31,
R32, R33, R34, R35, R36, R37, R38, and R39 are each independently -H, (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2, or -CN.
[0378] In one embodiment, X is CR25 or N; Y is O or S; R13, R14, R15, and R15 are
each independently -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and R31, R32, R33; R34,
R35, R36. R37. R38 and R39 are each hydrogen.
[0379] In one embodiment, X is CR25 or N; Y is O or S; R31, R32, R33, R34, R35,
R36, R37, R38 and R39 are each independently -H, (C1-C6)-alkyl, -OR25, halogen, or -
CF3; and R13, R14, R15, and R15 are each hydrogen.
[0380] In one embodiment, X is CR25 or N; Y is O or S; R31 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3. In one embodiment, X is CR25 or N; Y is O or S; R31 is -H
or -OR25.
[0381] In one embodiment, X is CR25 or N; Y is O or S; R31 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3 and each remaining R group is hydrogen. In one
embodiment, X is CR25 or N; Y is O or S; R31 is -H or -OR25 and each remaining R
group is hydrogen.
[0382] In one embodiment, X is CR25 or N; Y is O or S; R3i is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3; and R13, R14,, R15, R16, R32, R33, R34, R35, R36, R37, R38, and
R39 are each hydrogen.
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WO 2006/135839 PCT/US2006/022719
[0383] In one embodiment, X is CR25 or N; Y is O or S; R31 is -H, (C1-C6)-alkyl,
-OR25, -CH3, halogen, or -CF3; R16 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and
R13, R14, R15, R32, R33, R34, R35, R36, R37, R38, and R39 are each hydrogen.
[0384] In one embodiment, X is CR25 or N; Y is 0 or S; R31 is -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3; R15 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and R13,
R14, R16, R32, R33, R34, R35, R36, R37, R38, and R39 are each hydrogen.
[0385] In one embodiment, R31 is -H, (C1-C6)-alkyl, halogen, -CF3, or -OR25; R32,
R33, R34, R35, R36, R37, R38 and R39 are each independently -H, -CH3, halogen, -CF3, or
-OR25; and R13, R14, R15, and R16 are each hydrogen.
[0386] In one embodiment, R31 is -H, (C1-C6)-alkyl, halogen, -CF3, or -OR25; R1s
and R14, are each independently -H, -CH3, halogen, -CF3, or -OR25; and R32, R33, R34,
R35, R36, R37, R38 and R39 are each hydrogen.
[0387] Illustrative examples of compounds of Formula (III) and Formula (IV) are
set forth below and include, without limitation:
6-chloro-8-{4-[4-(lH-indole-4-yl)-piperazin-l-yl]-piperidin-l-yl}-quinoline;
8- {4-[4-(lH-indole-4-yl)-piperazin- l-yl]-piperidin- 1-yl} -quinoline;
8-{4-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-piperidin-l-
yl}-quinoline;
8-[4-(4-benzofuran-3yl-piperazin-l-yl)-piperidin-l-yl]-6-chloro-quinoline;
5-fluoro-8-{4-[4-(5-fluoro-benzofuran-3-yl)-piperazin-l-yl]-piperidin-l-yl}-
quinoline;
l-(l-benzo[6]thiophen-3-yl-piperidin-4-yl)-4-(2-methoxy-phenyl)-piperazine;
or
3- {4- [4-(2-methoxyphenyl)-piperazin-1 -yl]-1 -piperidinyl} -1,2-benzisoxazole;
and pharmaceutically acceptable salts thereof.
[0388] The compounds and pharmaceutically acceptable salts of compounds of the
present invention can contain an asymmetric carbon atom and some of the compounds
or pharmaceutically acceptable salts of compounds of the invention can contain one or
more asymmetric centers, and can thus give rise to optical isomers and diastereomers.
While depicted without respect to stereochemistry in the compounds and
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pharmaceutically acceptable salts of compounds of the present invention, the present
invention includes such optical isomers and diastereomers, as well as racemic and
resolved, enantiomerically pure R and S stereoisomers, and also other mixtures of the
R and S stereoisomers and pharmaceutically acceptable salts thereof. Where a
stereoisomer is preferred, it can in some embodiments be provided substantially free
of its corresponding opposite enantiomer.
[0389] In addition, the compounds and pharmaceutically acceptable salts of
compounds of the present invention can exist as polymorphs. Such polymorphs can
be transient or isolatable as a stable product.
[0390] Prodrugs of the compounds or pharmaceutically acceptable salts of
compounds are also within the scope of the present invention.
Methods for Making the Compounds of the Invention
[0391] The compounds and pharmaceutically acceptable salts of compounds of the
present invention can be prepared using a variety of methods starting from
commercially available compounds, known compounds, or compounds prepared by
known methods. General synthetic routes to many of the compounds of the invention
are included in the following schemes. The methods for making some intermediates
of the invention are described in WO2004/024731 and U.S. Patent No. 4,465,482,
both of which are hereby incorporated by reference. It is understood by those skilled
in the art that protection and deprotection steps not shown in the Schemes may be
required for these syntheses, and that the order of steps may be changed to
accommodate functionality in the target molecule.
[0392] Scheme 1 illustrates the coupling of piperazine-piperidine compounds of
Formulas (I), (IT), (IE), and (IV) through reductive amination, wherein Ra, Rb, R7, R8,
R9, R10, R11, R12, R13, R14, R15, R16, and R99 are as defined above, and R99 can also be a
substituted or unsubstituted quinoline. A compound of Formula (X) is reacted with a
compound of Formula (XIV) under conditions effective to bring about reductive
amination at the piperidine carbonyl, thereby providing the piperazine-piperidine
compound of Formulas (I), (II), (III), and (IV). R6agents that can effect this coupling
include, but are not limited to, sodium cyanoborohydride and sodium
triacetoxyborohydride. Suitable solvents for performing the reaction include, but are
not limited to, dichloroethane and methanol and acids such as acetic acid and
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WO 2006/135839 PCT/US2006/022719
hydrochloride may optionally be added to the reaction. R6action temperatures can
vary, depend on the nature of the reactants, but usually span the range from 0°C to the
boiling point of the solvent.
Scheme 1

[0393] Scheme la illustrates the coupling of piperazine-piperidine compounds of
Formula (F), through reductive amination, wherein Ra, Rb, R7, R8, R9, R10, R11, R12,
R13, R14, R15, R16, and R99 are as defined above, and R99 can also be a substituted or
unsubstituted quinoline. A compound of Formula (X) is reacted with a compound of
Formula (XIVb) under conditions effective to bring about reductive amination at the
piperidine carbonyl, such as those described in Scheme 1, thereby providing the
piperazine-piperidine compound of Formulas (I').
Scheme la

[0394] Scheme la' illustrates another method for making compounds of Formula
(I'), wherein Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R11, R15, and
R16 are as defined above, and R99 is an optionally substituted quinoline (n is also as
defined above). A compound of Formula (Xa) is reacted under conditions effective to
provide the compound of Formula (XXXI). The compound of Formula (XXXI) is
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reacted under conditions effective to provide the removal of the phenyl-methyl group,
thereby providing the compound of Formula (XXXII). The compound of Formula
(XXXII) is reacted with an alkyl-substituted quinoline of Formula (XXXIII) having a
good leaving group (W) under conditions effective to produce a compound of Formula
(F). Suitable leaving groups are known to those of skill in the art and include, without
limitation, halogen, -OTs, -OMs or-OTr.
Scheme la'

[0395] Scheme lb illustrates the coupling of piperazine-piperidine compounds of
Formula (I"), through reductive amination, wherein Ra, Rb, R7, R7', R8, R9, R10, R11,
R12, R13, R14, R15, R16, R99 are as defined above except for the R group through which
the piperidine is connected; and n is as defined above; and R99 can also be a
substituted or unsubstituted quinoline. A compound of Formula (X) is reacted with a
compound of Formula (XIVc) under conditions effective to bring about reductive
amination at the piperidine carbonyl, such as those described in Scheme 1, thereby
providing the piperazine-piperidine compound of Formula (I").
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Scheme 1b

[0396] Scheme 2 illustrates the production of compounds of Formula (I). As
shown in Scheme 2, a compound of Formula (Xa) and a compound of Formula (XIV)
can be reacted under conditions effective to produce the di-quinoline substituted
piperazine-piperidine compound of Formula (I), such as those described in Scheme 1.
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[0397] Scheme 3 illustrates the production of compounds of Formula (Xb) and
Formula (XV) in which R1, R2, R3, R10, R11, R12, R13» R14. R15, and R16 are each
hydrogen and Ra, Rb, R4, R5, R6, R7, Rs and R9 are as defined above. An optionally
substituted aniline compound of Formula (VII) is reacted with an appropriate reagent
under conditions effective to produce the quinoline compound of Formula (VTH).
Numerous reagents and conditions affect this transformation. Many of these can be
xound in a review by G. Jones (Synthesis of the Quinoline R1ng System, in
Heterocyclic Compounds: Volume 32 (Quinolines), Interscience, New York, New
York, 1977, pp. 93-318). One such reagent is glycerol, as originally described by
Skraup (Monatsh. (1880), 1, 316). R1, R2, R3, R4, R5 and R6 of (VII) and (VIII) are as
above for (I) and W is a good leaving group, for example halogen, p-toluenesulfonyl
(-OTs), methanesulfonyl (-OMs) or trifluoromethanesulfonyl (-OTr). The compound
of Formula (VIII) is then reacted with a protected piperazine derivative under
conditions effective to provide a protected piperazino-quinoline of Formula (IX),
where X1 is a protecting group. Protecting groups are well known to those of skill in
the art and include, without limitation, tert-butoxycarbonyl. Conditions that can effect
this reaction include, but are not limited to, reacting the two components in the
presence of a palladium complex such as those described by Buchwald et al., J. Am.
Chem. Soc. 118:7215 (1996) and Hartwig et al, J. Am. Chem. Soc. 118:7217 (1996).
The protected piperazino-quinoline of Formula (IX) is then reacted under conditions
to promote the removal of the protecting group (e.g., aqueous acid or mixtures of a
water miscible organic solvent and aqueous acid), providing the substituted
piperazino-quinoline compound of Formula (Xb). Separately, compounds of Formula
(XIV) are produced by beginning with an optionally substituted aniline compound of
Formula (XI) and reacting it as described above with an appropriate reagent under
conditions effective to produce the quinoline compound of Formula (XII). R7, R8, R9,
R10, R11, and R12 of (XI) and (XII) are as above for Formula (I) and W is a suitable
leaving group such as halogen, -OTs, -OMs or -OTr. The quinoline compound of
Formula (XIII) is then reacted with a piperidin-4-one derivative under conditions
effective to provide the compound of Formula (XIII) (e.g., a palladium-catalyzed
coupling such as that described above). The carbonyl group of the piperidin-4-one
derivative is protected with a protecting group (X2). Suitable protecting groups are
well known to those of skill in the art and include, without limitation, 1,4-dioxolane.
The compound of Formula (XIII) is then reacted under conditions to promote the
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removal of the protecting group (e.g., aqueous acid or a mixture of a water miscible
organic solvent and aqueous acid), providing the piperidin-4-one compound of
Formula (XIVa). The piperidin-4-one compound of Formula (XIVa) is then reacted
with the piperazino-quinoline compound of Formula (Xb) as described above in
Schemes 1 and 2 to produce the di-quinoline piperazine-piperidine compound of
Formula (XV).
Scheme 3

[0398] Alternative syntheses for the quinoline compounds of Formulae (VIII) and
(XII) are provided in Scheme 3a. The aniline compounds of Formulae (VII) and (XI)
are reacted with an appropriate reagent under conditions effective to product the
quinoline compounds of Formulae (XXXIV) and (XXXV) where W is a leaving
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group. R6agents and conditions suitable for affecting this transformation are known to
those of skill in the art and include, for example, methods described in G. Jones,
supra. One exemplary reagent is glycerol, as described above. The compounds of
Formulae (XXXIV) and (XXXV) are then reacted with appropriate reagents to yield
the desired intermediate compounds of Formulae (VIII) and (XI).
[0399] In some embodiments, compounds of Formula (I) and Formula (XV) are
further reacted to form a salt of the compounds of Formula (I) and Formula (XV)
through an acid addition process. In one nonlimiting example, one or more
equivalents of an acid {e.g., hydrochloride, succinic, or adipic acids) are reacted with
the free base of a compound of Formula (I) and Formula (XV) to form an acid
addition salt. Exemplary salts include, without limitation, mono-, di-, tri- and tetra-
acid salts.
[0400] In some embodiments, the acid addition step is modified to allow for
isolation of the salts of the compounds of Formula (I) and Formula (XV) without the
use of potentially environmentally hazardous materials. In one embodiment,
compounds of Formula (I) and Formula (XV) are reacted in the presence of non-
chlorinated solvents. In one embodiment, the non-chlorinated solvent is toluene.
[0401] In some embodiments, the acid addition reaction is performed under
conditions that result in relatively low amounts of residual solvent found in the final
product. In some embodiments, the amount of each individual residual solvent is
present in an amount that is less than about 0.25 w% of the resulting salt form of the
compound of Formula (I) or Formula (XV). In one embodiment, the amount of each
residual solvent is less than about 0.2 w% of the resulting salt form of the compound
of Formula (I) or the compound of Formula (XV). In still other embodiments, the
amount of each solvent is less than about 0.15 w% of the resulting salt form of the
compound of Formula (I) or the compound of ormula (XV). In further embodiments,
the amount of each solvent is less than about 0.1 w% of the resulting salt form of the
compound of Formula (I) or the compound of Formula (XV). In yet more
embodiments, the amount of each solvent is less than about 0.05 w% of the resulting
salt form of the compound of Formula (I) or the compound of Formula (XV). In still
more embodiments, the amount of each solvent is less than about 0.025 w% of the
resulting salt form of the compound of Formula (I) or the compound of Formula (XV).
In additional embodiments, the amount of each solvent is less than about 0.02 w% of
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the resulting salt form of the compound of Formula (I) or the compound of Formula
(XV). In another embodiment, the amount of each solvent is less than about 0.01 w%
of the resulting salt form of the compound of Formula (I) or the compound of Formula
(XV). In one embodiment, the presence of chlorinated solvents is decreased
significantly from the final isolated salt form of the compound of Formula (I) or the
compound of Formula (XV). In one embodiment, there are no detectable chlorinated
solvents is the find isolated salt form of the compound of Formula (I) or the
compound of Formula (XV). In one embodiment, the amount of chlorinated solvent
present in the final isolated salt form of the compound of Formula (I) or the compound
of Formula (XV) is less than about 0.1%. In one embodiment, the amount of
chlorinated solvent present in the final isolated salt form of the compound of Formula
(I) and the compound of Formula (XV) is less than about 0.05%. In one embodiment,
the amount of chlorinated solvent present in the final isolated salt form of the
compound of Formula (I) and the compound of Formula (XV) is less than about
0.01%. In one embodiment, the amount of chlorinated solvent present in the final
isolated salt form of the compound of Formula (I) and the compound of Formula (XV)
is less than about 0.001%.
[0402] In some embodiments, the acid addition reaction occurs in the presence of
organic solvents including, but not limited to, tetrahydrofuran (THF), acetone,
dichloromethane, and dichloroethane. In one embodiment, the organic solvents are
THF and acetone. In one embodiment, a compound of Formula (I) or a compound of
Formula (XV) is mixed with a first organic solvent and then added to a solution that
includes a second organic solvent and an acid. In one embodiment, the first organic
solvent is THF or acetone. In one embodiment, the second organic solvent is THF or
acetone. In one embodiment, the first organic solvent is THF and the second organic
solvent is acetone. In one embodiment, a compound of Formula (I) or a compound of
Formula (XV) is mixed with THF prior to addition to a solution of acetone and an
acid. In one embodiment, the acid is an organic acid. In one embodiment, the acid is
a dicaRboxylic acid. In one embodiment, the organic acid is succinic acid.
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Scheme 3a

[0403] Scheme 4 illustrates the production of a compound of Formula (HI) in
which R99 is an indole compound and R7, R8, R9, R10, R11, R12, R28, R29 and R30 are
defined as above for Formula (HI). A piperidin-4-one compound of Formula (XIVa)
is produced as described above in Scheme 3. A dinitro-toluene compound of Formula
(XVI) is reacted with N,N-dimemylformamide dimethyl acetal and pyrrolidine under
conditions effective to bring about cyclization, thereby providing an indol-4-ylamine
compound of Formula (XVII). The compound of Formula (XVII) is then reacted with
a bis(2-chloroethyl)-benzylamine under conditions effective to produce the compound
of Formula (XVIII). The compound of Formula (XVIII) is then reacted under
conditions effective to remove the benzyl protecting group to produce a 4-piperazin-l-
yl-indole of Formula (XIX). The piperazin-1-yl-indole compound of Formula (XIX)
is then reacted with the piperidin-4-one compound of Formula (XIVa) as described
above in Scheme 1 to produce the piperazine-piperidine compound of Formula (XX),
which is a compound of Formula (IE).
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Scheme 4

[0404] Scheme 5 illustrates the production of compounds of Formula (HI) in
which R99 is a benzo[l,4]dioxane compound and Ra, Rb, R7, R8, R9, R10, R11, R12, R24,
R26 and R27 are defined as above for Formula (HI). A piperidin-4-one compound of
Formula (XIVa) is produced as described above in Scheme 3. A benzo[l,4]dioxane- .
piperazine compound having the Formula (XXIII) is produced by reacting a piperidine
with a benzo[l,4]dioxane substituted with a good leaving group, for example a
halogen -OTs, -OMs or -OTr, under conditions effective to produce a compound of
Formula (XXIII). The compound of Formula (XXIII) is reacted with the piperidin-4-
one compound of Formula (XIVa) as described above in Scheme 1 to produce the
benzo[l,4]dioxane piperazine-piperidine quinoline compound of Formula (XXIV).
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Scheme 5

[0405] Scheme 5a illustrates an alternative production of a benzo[l,4]dioxane-
piperazine compound having the Formula (XXIII) in which Ra, Rb, R24, R26, and R27
are defined as above for Formula (III). A nitro-benzodioxane of Formula (XXI) is
reacted under conditions effective to produce a compound of Formula (XXII). The
compound of Formula (XXII) is reacted with a bis(2-chloroethyl)amine under
conditions effective to produce a compound of Formula (XXIII).
Scheme 5a

[0406] Scheme 6 illustrates the production of a compound or pharmaceutically
acceptable salt of a compound of Formula (III) in which R99 is a benzofuran
compound and Ra, Rb, R7, R8, R9, R10, R11, R12, R20, R21, R22 and R23 are defined as
above for Formula (III). A piperidin-4-one compound of Formula (XIVa) is produced
as described above in Scheme 3. The benzofuranone of Formula (XXXI) is reacted
with a protected piperazine under conditions effective to produce benzofuran-N-
protected piperazine compound of Formula (XXXII). Suitable protecting groups (X1
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are well known to those of skill in the art and include, without limitation,
ethoxycarbonyl. Deprotection of the N-protecting group (such as by hydrolysis) of the
compound of Formula (XXXII) gives a compound of formula (V). The benzofuran-
piperazine of Formula (V) is then reacted with the piperidin-4-one compound of
Formula (XIV) as described above in Scheme 1 to produce the piperazine-piperidine
compound of Formula (XXV).
Scheme 6

[0407] Scheme 7 illustrates the production of a compound or pharmaceutically
acceptable salt of a compound of Formula (IV) in which Ra, Rb, R13, R14,, R15, R16, R31
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R32, R33, R34, R35. R36, R37, R38 and R39 are defined as above for Formula (IV). As
shown in Scheme 7, an optionally substituted phenyl-piperazine compound of
Formula (XXVI) is reacted with an optionally substituted protected-piperazine under
conditions effective to provide the compound of Formula (XXVII), wherein X1 is a
protecting group. Suitable protecting groups are well known to those of skill in the art
and include, without limitation, tert-butoxycarbonyl. The compound of Formula
(XXVII) is reacted under conditions effective to remove the protecting group,
providing a phenyl-piperazine-piperidine compound of Formula (XXVIII). The
phenyl-piperazine-piperidine compound of Formula (XXVIII) is reacted with a
bicyclic aryl compound of Formula (XXIX) possessing a suitable leaving group (W)
under conditions effective to provide the compound of Formula (IV).
Scheme 7

[0408] Schemes 1-7 illustrate the synthetic methodology used to prepare particular
compounds of the present invention.
[0409] One of skill in the art will recognize that Schemes 1-7 can be adapted to
produce the other compounds according to the present invention and that other
methods may be used to produce the compounds of the present invention.
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Therapeutic Administration
[0410] When administered to an animal, the compounds or pharmaceutically
acceptable salts of the compounds can be administered neat or as a component of a
composition that comprises a physiologically acceptable carrier or vehicle. A
pharmaceutical composition of the invention can be prepared using a method
comprising admixing the compound or a pharmaceutically acceptable salt of the
compound and a physiologically acceptable carrier, excipient, or diluent. Admixing
can be accomplished using methods well known for admixing a compound or a
pharmaceutically acceptable salt of the compound and a physiologically acceptable
carrier, excipient, or diluent.
[0411] The present pharmaceutical compositions, comprising compounds or
pharmaceutically acceptable salts of the compounds of the invention, can be
administered orally. The compound of the invention can also be administered by any
other convenient route, for example, by infusion or bolus injection, by absorption
through epithelial or mucocutaneous linings (e.g., oral, rectal, vaginal, and intestinal
mucosa, etc.) and can be administered together with another therapeutic agent. ;
Administration can be systemic or local. Various known delivery systems, including
encapsulation in liposomes, microparticles, microcapsules, and capsules, can be used.
[0412] Methods of administration include, but are not limited to, intradermal,
intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral,
sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical,
particularly to the ears, nose, eyes, or skin. In some instances, administration will
result of release of the compound or a pharmaceutically acceptable salt of the
compound into the bloodstream. The mode of administration is left to the discretion
of the practitioner.
[0413] In one embodiment, the compound of the invention is administered orally.
[0414] In another embodiment, the compound of the invention is administered
intravenously,
[0415] In another embodiment, it may be desirable to administer the compound of
the invention locally. This can be achieved, for example, by local infusion during
surgery, topical application, e.g., in conjunction with a wound dressing after surgery,
by injection, by means of a catheter, by means of a suppository or edema, or by means
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of an implant, said implant being of a porous, non-porous, or gelatinous material,
including membranes, such as sialastic membranes, or fibers.
[0416] In certain embodiments, it can be desirable to introduce the compound of
the invention into the central nervous system, circulatory system or gastrointestinal
tract by any suitable route, including intraventricular, intrathecal injection, paraspinal
injection, epidural injection, enema, and by injection adjacent to the peripheral nerve.
Intraventricular injection can be facilitated by an intraventricular catheter, for
example, attached to a reservoir, such as an Ommaya reservoir.
[0417] Pulmonary administration can also be employed, e.g., by use of an inhaler
or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a
fluorocarbon or synthetic pulmonary surfactant. In certain embodiments, the
compound or a pharmaceutically acceptable salt of the compound can be formulated
as a suppository, with traditional binders and excipients such as triglycerides.
[0418] In another embodiment, the compound of the invention can be delivered in
a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990) and
Treat etal., Liposomes in the Therapy of Infectious Disease and Cancer 317-327 and
353-365 (1989)).
[0419] In yet another embodiment, the compound of the invention can be
delivered in a controlled-release system or sustained-release system (see, e.g.,
Goodson, in Medical Applications of Controlled R6lease, vol. 2, pp. 115-138 (1984)).
Other controlled or sustained-release systems discussed in the review by Langer,
Science 249:1527-1533 (1990) can be used. In one embodiment, a pump can be used
(Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. R6f. Biomed. Eng. 14:201
(1987); Buchwald et al, Surgery 88:507 (1980); and Saudek et al., N. Engl. JMed.
321:574 (1989)). In another embodiment, polymeric materials can be used (see
Medical Applications of Controlled R6lease (Langer and Wise eds., 1974); Controlled
Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds.,
1984); Ranger and Peppas, J. Macromol. Sci. R6v. Macromol. Chem. 2:61 (1983);
Levy etal, Science 228:190 (1935); During etal, Ann. Neural. 25:351 (1989); and
Howard et al, J. Neurosurg. 71:105 (1989)).
[0420] The present compositions can optionally comprise a suitable amount of a
physiologically acceptable excipient.
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[0421] Such physiologically acceptable excipients can be liquids, such as water
and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as
peanut oil, soybean oil, mineral oil, sesame oil and the like. The physiologically
acceptable excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin,
colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening,
lubricating, and coloring agents can be used. In one embodiment the physiologically
acceptable excipients are sterile when administered to an animal. The physiologically
acceptable excipient should be stable under the conditions of manufacture and storage
and should be preserved against the contaminating action of microorganisms. Water
is a particularly useful excipient when the compound or a pharmaceutically acceptable
salt of the compound is administered intravenously. Saline solutions and aqueous
dextrose and glycerol solutions can also be employed as liquid excipients, particularly
for injectable solutions. Suitable physiologically acceptable excipients also include
starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium
stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol,
propylene, glycol, water, ethanol and the like. The present compositions, if desired,
can also contain minor amounts of wetting or emulsifying agents, or pH buffering
agents.
[0422] Liquid carriers may be used in preparing solutions, suspensions, emulsions,
syrups, and elixirs. The compound or pharmaceutically acceptable salt of the
compound of this invention can be dissolved or suspended in a pharmaceutically
acceptable liquid carrier such as water, an organic solvent, a mixture of both, or
pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable
pharmaceutical additives including solubilizers, emulsifiers, buffers, preservatives,
sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity
regulators, stabilizers, or osmo-regulators. Suitable examples of liquid carriers for
oral and parenteral administration include water (particularly containing additives as
above, e.g., cellulose derivatives, including sodium caRboxymethyl cellulose solution),
alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and
their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For
parenteral administration the carrier can also be an oily ester such as ethyl oleate and
isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions
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WO 2006/135839 PCT/US2006/022719
for parenteral administration. The liquid carrier for pressurized compositions can be
halogenated hydrocarbon or other pharmaceutically acceptable propellant.
[0423] The present compositions can take the form of solutions, suspensions,
emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders,
sustained-release formulations, suppositories, emulsions, aerosols, sprays,
suspensions, or any other form suitable for use. In one embodiment, the composition
is in the form of a capsule. Other examples of suitable physiologically acceptable
excipients are described in R6mington's Pharmaceutical Sciences 1447-1676 (Alfonso
R. Gennaro, ed, 19th ed. 1995).
[0424] In one embodiment, the compound or a pharmaceutically acceptable salt of
the compound is formulated in accordance with routine procedures as a composition
adapted for oral administration to humans. Compositions for oral delivery can be in
the form of tablets, lozenges, buccal forms, troches, aqueous ov oily suspensions or
solutions, granules, powders, emulsions, capsules, syrups, or elixirs for example.
Orally administered compositions can contain one or more agents, for example,
sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as
peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to
provide a pharmaceutically palatable preparation. In powders, the carrier can be a
finely divided solid, which is an admixture with the finely divided compound or
pharmaceutically acceptable salt of the compound. In tablets, the compound or
pharmaceutically acceptable salt of the compound is mixed with a carrier having the
necessary compression properties in suitable proportions and compacted in the shape
and size desired. The powders and tablets can contain up to about 99% of the
compound or pharmaceutically acceptable salt of the compound.
[0425] Capsules may contain mixtures of the compounds or pharmaceutically
acceptable salts of the compounds with inert fillers and/or diluents such as
pharmaceutically acceptable starches (e.g., corn, potato, or tapioca starch), sugars,
artificial sweetening agents, powdered celluloses (such as crystalline and
microcrystalline celluloses), flours, gelatins, gums, etc.
[0426] Tablet formulations can be made by conventional compression, wet
granulation, or dry granulation methods and utilize pharmaceutically acceptable
diluents, binding agents, lubricants, disintegrants, surface modifying agents (including
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WO 2006/135839 PCT/US2006/022719
surfactants), suspending or stabilizing agents (including, but not limited to,
magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin,
starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium
caRboxymethyl cellulose, caRboxymethylcellulose calcium, polyvinylpyrrolidine,
alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium
carbonate, glycine, sucrose, soRbitol, dicalcium phosphate, calcium sulfate, lactose,
kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins.)
Surface modifying agents include nonionic and anionic surface modifying agents.
R6presentative examples of surface modifying agents include, but are not limited to,
poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol,
cetomacrogol emulsifying wax, soRbitan esters, colloidal silicon dioxide, phosphates,
sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine.
[0427] Moreover, when in a tablet or pill form, the compositions can be coated to
delay disintegration and absorption in the gastrointestinal tract, thereby providing a
sustained action over an extended period of time. Selectively permeable membranes
surrounding an osmotically active driving compound or a pharmaceutically acceptable
salt of the compound are also suitable for orally administered compositions. In these
latter platforms, fluid from the environment surrounding the capsule can be imbibed
by the driving compound, which swells to displace the agent or agent composition
through an aperture. These delivery platforms can provide an essentially zero order
delivery profile as opposed to the spiked profiles of immediate release formulations.
A time-delay material such as glycerol monostearate or glycerol stearate can also be
used. Oral compositions can include standard excipients such as mannitol, lactose,
starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate.
In one embodiment, the excipients are of pharmaceutical grade.
[0428] In another embodiment, the compound or a pharmaceutically acceptable
salt of the compound can be formulated for intravenous administration. Typically,
compositions for intravenous administration comprise sterile isotonic aqueous buffer.
Where necessary, the compositions can also include a solubilizing agent.
Compositions for intravenous administration can optionally include a local anesthetic
such as lignocaine to lessen pain at the site of the injection. Generally, the ingredients
are supplied either separately or mixed together in unit dosage form, for example, as a
dry lyophilized powder or water-free concentrate in a hermetically sealed container
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such as an ampule or sachette indicating the quantity of active agent. Where the
compound or a pharmaceutically acceptable salt of the compound is to be
administered by infusion, it can be dispensed, for example, with an infusion bottle
containing sterile pharmaceutical grade water or saline. Where the compound or a
pharmaceutically acceptable salt of the compound is administered by injection, an
ampule of sterile water for injection or saline can be provided so that the ingredients
can be mixed prior to administration.
[0429] In another embodiment, the compound or pharmaceutically acceptable salt
of the compound can be administered transdermally through the use of a transdermal
patch. Transdermal administrations include administrations across the surface of the
body and the inner linings of the bodily passages including epithelial and mucosal
tissues. Such administrations can be carried out using the present compounds or
pharmaceutically acceptable salts of the compounds, in lotions, creams, foams,
patches, suspensions, solutions, and suppositories (e.g., rectal or vaginal).
[0430] Transdermal administration can be accomplished through the use of a
transdermal patch containing the compound or pharmaceutically acceptable salt of the
compound and a carrier that is inert to the compound or pharmaceutically acceptable
salt of the compound, is non-toxic to the skin, and allows delivery of the agent for
systemic absorption into the blood stream via the skin. The carrier may take any
number of forms such as creams or ointments, pastes, gels, or occlusive devices. The
creams or ointments may be viscous liquid or semisolid emulsions of either the oil-in-
water or water-in-oil type. Pastes comprised of absorptive powders dispersed in
petroleum or hydrophilic petroleum containing the active ingredient may also be
suitable. A variety of occlusive devices may be used to release the compound or
pharmaceutically acceptable salt of the compound into the blood stream, such as a
semi-permeable membrane covering a reservoir containing the compound or
pharmaceutically acceptable salt of the compound with or without a carrier, or a
matrix containing the active ingredient.
[0431] The compounds or pharmaceutically acceptable salts of the compounds of
the invention may be administered rectally or vaginally in the form of a conventional
suppository. Suppository formulations may be made from traditional materials,
including cocoa butter, with or without the addition of waxes to alter the suppository's
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melting point, and glycerin. Water-soluble suppository bases, such as polyethylene
glycols of various molecular weights, may also be used.
[0432] The compound or a pharmaceutically acceptable salt of the compound can
be administered by controlled-release or sustained-release means or by delivery
devices that are known to those of ordinary skill in the art. Such dosage forms can be
used to provide controlled- or sustained-release of one or more active ingredients
using, for example, hydropropylmethyl cellulose, other polymer matrices, gels,
permeable membranes, osmotic systems, multilayer coatings, microparticles,
liposomes, microspheres, or a combination thereof to provide the desired release
profile in varying proportions. Suitable controlled- or sustained-release formulations
known to those skilled in the art, including those described herein, can be readily
selected for use with the active ingredients of the invention. The invention thus
encompasses single unit dosage forms suitable for oral administration such a . but not ■•
limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or
sustained-release.
[0433] In one embodiment a controlled- or sustained-release composition
comprises a minimal amount of the compound or a pharmaceutically acceptable salt of
the compound to treat or prevent a 5-HT1A-related disorder in a minimal amount of
time. Advantages of controlled- or sustained-release compositions include extended
activity of the drug, reduced dosage frequency, and increased compliance by the
animal being treated. In addition, controlled- or sustained-release compositions can
favorably affect the time of onset of action or other characteristics, such as blood
levels of the compound or a pharmaceutically acceptable salt of the compound, and
can thus reduce the occurrence of adverse side effects.
[0434] Controlled- or sustained-release compositions can initially release an
amount of the compound or a pharmaceutically acceptable salt of the compound that
promptly produces the desired therapeutic or prophylactic effect, and gradually and
continually release other amounts of the compound or a pharmaceutically acceptable
salt of the compound to maintain this level of therapeutic or prophylactic effect over
an extended period of time. To maintain a constant level of the compound or a
pharmaceutically acceptable salt of the compound in the body, the compound or a
pharmaceutically acceptable salt of the compound can be released from the dosage
form at a rate that will replace the amount of the compound or a pharmaceutically
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acceptable salt of the compound being metabolized and excreted from the body.
Controlled- or sustained-release of an active ingredient can be stimulated by various
conditions, including but not limited to, changes in pH, changes in temperature,
concentration or availability of enzymes, concentration or availability of water, or
other physiological conditions or compounds.
[0435] In certain embodiments, the present invention is directed to prodrugs of the
compounds or pharmaceutically acceptable salts of compounds of the present
invention. Various forms of prodrugs are known in the art, for example as discussed
in Bundgaard (ed.), Design of Prodrugs, Elsevier (1985); Widder et al. (ed.), Methods
in Enzymology, vol. 4, Academic Press (1985); Kgrogsgaard-Larsen et al. (ed.);
"Design and Application of Prodrugs", Textbook of Drug Design and Development,
Chapter 5, 113-191 (1991); Bundgaard et al., Journal of Drug Delivery R6views, 8:1-
38 (1992); Bundgaard et al, J. Pharmaceutical Sciences, 77:285 et seq. (1988); and
Higuchi and Stella (eds.), Prodrugs as Novel Drug Delivery Systems, American
Chemical Society (1975).
[0436] The amount of the compound or a pharmaceutically acceptable salt of the
compound delivered is an amount that is effective for treating or preventing a 5-HT1A-
related disorder. In addition, in vitro or in vivo assays can optionally be employed to
help identify optimal dosage ranges. The precise dose to be employed can also
depend on the route of administration, the condition, the seriousness of the condition
being treated, as well as various physical factors related to the individual being
treated, and can be decided according to the judgment of a health-care practitioner.
Equivalent dosages may be administered over various time periods including, but not
limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every
12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about
every 72 hours, about every week, about every two weeks, about every three weeks,
about every month, and about every two months. The number and frequency of
dosages corresponding to a completed course of therapy will be determined according
to the judgment of a health-care practitioner. The effective dosage amounts described
herein refer to total amounts administered; that is, if more than one compound or a
pharmaceutically acceptable salt of the compound is administered, the effective
dosage amounts correspond to the total amount administered.
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[0437] The amount of the compound or a pharmaceutically acceptable salt of the
compound that is effective for treating or preventing a 5-HT1A-related disorder will
typically range from about 0.001 mg/kg to about 600 mg/kg of body weight per day,
in one embodiment, from about 1 mg/kg to about 600 mg/kg body weight per day, in
another embodiment, from about 10 mg/kg to about 400 mg/kg body weight per day,
in another embodiment, from about 10 mg/kg to about 200 mg/kg of body weight per
day, in another embodiment, from about 10 mg/kg to about 100 mg/kg of body weight
per day, in another embodiment, from about 1 mg/kg to about 10 mg/kg body weight
per day, in another embodiment, from about 0.001 mg/kg to about 100 mg/kg of body
weight per day, in another embodiment, from about 0.001 mg/kg to about 10 mg/kg of
body weight per day, and in another embodiment, from about 0.001 mg/kg to about 1
mg/kg of body weight per day.
[0438] In one embodiment, the pharmaceutical composition is in unit dosage
form, e.g., as a tablet, capsule, powder, solution, suspension, emulsion, granule, or
suppository. In such form, the composition is sub-divided in unit dose containing
appropriate quantities of the active ingredient; the unit dosage form can be packaged
compositions, for example, packeted powders, vials, ampoules, prefilled syringes or
sachets containing liquids. The unit dosage form can be, for example, a capsule or
tablet itself, or it can be the appropriate number of any such compositions in package
form. Such unit dosage form may contain from about 0.01 mg/kg to about 250 mg/kg,
and may be given in a single dose or in two or more divided doses. Variations in the
dosage will necessarily occur depending upon the species, weight and condition of the
patient being treated and the patient's individual response to the medicament.
[0439] In one embodiment, the unit dosage form is about 0.01 to about 1000 mg.
In another embodiment, the unit dosage form is about 0.01 to about 500 mg; in
another embodiment, the unit dosage form is about 0.01 to about 250 mg; in another
embodiment, the unit dosage form is about 0.01 to about 100 mg; in another
embodiment, the unit dosage form is about 0.01 to about 50 mg; in another
embodiment, the unit dosage form is about 0.01 to about 25 mg; in another
embodiment, the unit dosage form is about 0.01 to about 10 mg; in another
embodiment, the unit dosage form is about 0.01 to about 5 mg; and in another
embodiment, the unit dosage form is about 0.01 to about 10 mg;
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WO 2006/135839 PCT/US2006/022719
[0440] The compound or a pharmaceutically acceptable salt of the compound can
be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior
to use in humans. Animal model systems can be used to demonstrate safety and
efficacy.
[0441] The present methods for treating or preventing a 5-HT1A-related disorder
can further comprise administering another therapeutic agent to the animal being
administered the compound or a pharmaceutically acceptable salt of the compound. In
one embodiment the other therapeutic agent is administered in an effective amount.
[0442] Effective amounts of the other therapeutic agents are well known to those
skilled in the art. However, it is well within the skilled artisan's purview to determine
the other therapeutic agent's optimal effective amount range. The compound or a
pharmaceutically acceptable salt of the compound and the other therapeutic agent can
act additively or, in one embodiment, synergistically. In one embodiment of the
invention, where another therapeutic agent is administered to an animal, the effective
amount of the compound or a pharmaceutically acceptable salt of the compound is less
than its effective amount would be where the other therapeutic agent is not
administered. In this case, without being bound by theory, it is believed that the
compound or a pharmaceutically acceptable salt of the compound and the other
therapeutic agent act synergistically. In some cases, the patient in need of treatment is
being treated with one or more other therapeutic agents. In some cases, the patient in
need of treatment is being treated with at least two other therapeutic agents.
[0443] In one embodiment, the other therapeutic agent is selected from the group
consisting of one or more anti-depressant agents, anti-anxiety agents, anti-psychotic
agents, or cognitive enhancers. Examples of classes of antidepressants that can be
used in combination with the active compounds of this invention include
norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs),
NK-1 receptor antagonists, monoamine oxidase inhibitors (MAOs), reversible
inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake
inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, a-adrenoreceptor
antagonists, and atypical antidepressants. Suitable norepinephrine reuptake inhibitors
include tertiary amine tricyclics and secondary amine tricyclics. Suitable tertiary
amine tricyclics and secondary amine tricyclics include amitriptyline, clomipramine,
doxepin, imipramine, trimipramine, dothiepin, butriptyline, iprindole, lofepramine,
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WO 2006/135839 PCT/US2006/022719
nortriptyline, protriptyline, amoxapine, desipramine and maprotiline. Suitable
selective serotonin reuptake inhibitors include fluoxetine, citolopram, escitalopram,
fluvoxamine, paroxetine and sertraline. Examples of monoamine oxidase inhibitors
include isocaRboxazid, phenelzine, and tranylcypromine. Suitable reversible inhibitors
of monoamine oxidase include moclobemide. Suitable serotonin and noradrenaline
reuptake inhibitors of use in the present invention include venlafaxine, nefazodone,
milnacipran, and duloxetine. Suitable CRF antagonists include those compounds
described in International Patent Publication Nos. WO 94/13643, WO 94/13644, WO
94/13661, WO 94/13676 and WO 94/13677. Suitable atypical anti-depressants include
bupropion, lithium, nefazodone, trazodone and viloxazine. Suitable NK-1 receptor
antagonists include those referred to in International Patent Publication WO 01/77100.
[0444] Anti-anxiety agents that can be used in combination with the active
compounds of this invention include without limitation benzodiazepines and serotonin
1A (5-HT1A) agonists or antagonists, especially 5-HT1A partial agonists, and
corticotropin releasing factor (CRF) antagonists. Exemplary suitable benzodiazepines
include alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam,
halazepam, lorazepam, oxazepam, and prazepam. Exemplary suitable 5-HT1A receptor,
agonists or antagonists include buspirone, flesinoxan, gepirone and ipsapirone.
[0445] Anti-psychotic agents that are used in combination with the active
compounds of this invention include without limitation aliphatic phethiazine, a
piperazine phenothiazine, a butyrophenone, a substituted benzamide, and a
thioxanthine. Additional examples of such drugs include without limitation
haloperidol, olanzapine, clozapine, risperidone, pimozide, aripiprazol, and
ziprasidone. In some cases, the drug is an anticonvulsant, e.g., phenobaRbital,
phenytoin, primidone, or caRbamazepine.
[0446] Cognitive enhancers that are co-administered with the 5-HT1A antagonist
compounds of this invention include, without limitation, drugs that modulate
neurotransmitter levels (e.g., acetylcholinesterase or cholinesterase inhibitors,
cholinergic receptor agonists or serotonin receptor antagonists), drugs that modulate
the level of soluble Aβ, amyloid fibril formation, or amyloid plaque burden (e.g., γ-
secretase inhibitors, p-secretase inhibitors, antibody therapies, and degradative
enzymes), and drugs that protect neuronal integrity (e.g., antioxidants, kinase
inhibitors, caspase inhibitors, and hormones). Other representative candidate drugs
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that are co-administered with the compounds of the invention include cholinesterase
inhibitors, (e.g., tacrine (COGNEX®), donepezil (ARICEPT®), rivastigmine
(EXELON®) galantamine (REMINYL®), metrifonate, physostigmine, and Huperzine
A), N-methyl-D-aspartate (NMDA) antagonists and agonists (e.g., dextromethorphan,
memantine, dizocilpine maleate (MK-801), xenon, remacemide, eliprodil, amantadine,
D-cycloserine, felbamate, ifenprodil, CP-101606 (Pfizer), Delucemine, and
compounds described in U.S. Patent Nos. 6,821,985 and 6,635,270), ampukines (e.g.,
cyclothiazide, aniracetam, CX-516 (Ampalex®), CX-717, CX-516, CX-614, and CX-
691 (Cortex Pharmaceuticals, Inc. Irvine, CA), 7-chloro-3-methyl-3-4-dihydro-2H-
1,2,4-benzothiadiazine S,S-dioxide (see Zivkovic etal., 1995,7. Pharmacol. Exp.
Therap., 272:300-309; Thompson et al, 1995, Proc. Natl. Acad. Sci. USA, 92:7667-
7671), 3-bicyclo[2,2,l]hept-5-en-2-yl-6-chloro-3,4-dihydro-2H-l,2,4-
benzothiadiazine-7-sulfonamide-1,1-dioxide (Yamada, etal., 1993, J. Neurosc.
13:3904-3915); 7-fluoro-3-methyl-5-ethyl-l,2,4-benzothiadiazine-S,S-dioxide; and
compounds described in U.S. Patent No. 6,620,808 and International Patent
Application Nos. WO 94/02475, WO 96/38414, WO 97/36907, WO 99/51240, and
WO 99/42456), benzodiazepine (BZD)/GABA receptor complex modulators (e.g.,
progabide, gengabine, zaleplon, and compounds described in U.S. Patent No.
5,538,956, 5,260,331, and 5,422,355); serotonin antagonists (e.g., 5-HT receptor
modulators, including other 5-HT1A antagonist compounds and 5-HT6 antagonists
(including without limitation compounds described in U.S. Patent Nos. 6,727,236,
6,825,212, 6,995,176, and 7,041,695)); nicotinics (e.g., niacin); muscarinics (e.g.,
xanomeline, CDD-0102, cevimeline, talsaclidine. oxybutin, tolterodine, propiverine,
tropsium chloride and darifenacin); monoamine oxidase type B (MAO B) inhibitors
(e.g., rasagiline, selegiline, deprenyl, lazabemide, safinamide, clorgyline, pargyline,
N-(2-aminoethyl)-4-chlorobenzamide hydrochloride, and N-(2-aminoethyl)-5(3-
fluorophenyl)-4-thiazolecaRboxamide hydrochloride); phosphodiesterase (PDE)
inhibitors (e.g., PDE IV inhibitors, roflumilast, arofylline, cilomilast, rolipram, RO-
20-1724, theophylline, denbufylline, ARIFLO, CDP-840 (a tri-aryl ethane) CP80633
(a pyrimidone), RP 73401 (R1,one-Poulenc Rorer), denbufylline (SmithKline
Beecham), arofylline (Almirall), CP-77,059 (Pfizer), pyrid[2,3d]pyridazin-5-ones
(Syntex), EP-685479 (Bayer), T-440 (Tanabe Seiyaku), and SDZ-ISQ-844
(Novartis)); G proteins; channel modulators; immunotherapeutics (e.g., compounds
described in U.S. Patent Application Publication No. US 2005/0197356 and US
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2005/0197379); anti-amyloid or amyloid lowering agents {e.g., bapineuzumab and
compounds described in U.S. Patent No. 6,878,742 or U.S. Patent Application
Publication Nos. US 2005/0282825 or US 2005/0282826); statins and peroxisome
proliferators activated receptor (PPARS) modulators (e.g., gemfibrozil (LOPE)®),
fenofibrate (TRICOR®), rosiglitazone maleate (AVANDIA®), pioglitazone (Actos™),
rosiglitazone (Avandia ), clofibrate and bezafibrate); cysteinyl protease inhibitors; an
inhibitor of receptor for advanced giycation endproduct (RAGE) (e.g.,
aminoguanidine, pyridoxaminem carnosine, phenazinediamine, OPB-9195, and
tenilsetam); direct or indirect neurotropic agents (e.g., Cerebrolysin®, piracetam,
oxiracetam, AIT-082 (Emilieu, 2000, Arch. Neurol. 57:454)); beta-secretase (BACE)
inhibitors, α-secretase, immunophilins, caspase-3 inhibitors, Src kinase inhibitors,
tissue plasminogen activator (TPA) activators, AMPA (alpha-amino-3-hydroxy-5-
methyl-4-isoxazolepropionic acid) modulators, M4 agonists, JNK3 inhibitors, LXR
agonists, H3 antagonists, and angiotensin IV antagonists. Other cognition enhancers
include, without limitation, acetyl-1-carnitine, citicholine, huperzine, DMAE
(dimethylaminoethanol), Bacopamonneiri extract, Sage extract, L-alpha glyceryl
phosphoryl choline, Ginko biloba and Ginko biloba extract, Vinpocetine, DHA,
nootropics including Phenyltropin, Pikatropin (from Creative Compounds, LLC, Scott
City, MO), besipirdine, linopirdine, sibopirdine, estrogen and estrogenic compounds,
idebenone, T-588 (Toyama Chemical, Japan), and FK960 (Fujisawa Pharmaceutical
Co. Ltd.). Compounds described in U.S. Patent Nos. 5,219,857,4,904,658,4,624,954
and 4,665,183 are also useful as cognitive enhancers as described herein. Cognitive
enhancers that act through one or more of the above mechanisms are also within the
scope of this invention.
[0447] In one embodiment, the compound or a pharmaceutically acceptable salt of
the compound of the invention and cognitive enhancer act additively or, in one
embodiment, synergistically. In one embodiment, where a cognitive enhancer and a
compound or a pharmaceutically acceptable salt of the compound of the invention are
co-administered to an animal, the effective amount of the compound or
pharmaceutically acceptable salt of the compound of the invention is less than its
effective amount would be where the cognitive enhancer agent is not administered. In
one embodiment, where a cognitive enhancer and a compound or a pharmaceutically
acceptable salt of the compound of the invention are co-administered to an animal, the
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effective amount of the cognitive enhancer is less than its effective amount would be
where the compound or pharmaceutically acceptable salt of the invention is not
administered. In one embodiment, a cognitive enhancer and a compound or a
pharmaceutically acceptable salt of the compound of the invention are co-
administered to an animal in doses that are less than their effective amounts would be
where they were no co-administered. In these cases, without being bound by theory, it
is believed that the compound or a pharmaceutically acceptable salt of the compound
and the cognitive enhancer act synergistically.
[0448] In one embodiment, the other therapeutic agent is an agent useful for
treating Alzheimer's disease or conditions associate with Alzheimer's disease, such as
dementia. Exemplary agents useful for treating Alzheimer's disease include, without
limitation, donepezil, rivastigmine, galantamine, memantine, and tacrine.
[3449] In one embodiment, the compound or a pharmaceutically acceptable salt of
the compound is administered concurrently with another therapeutic agent.
[0450] In one embodiment, a composition comprising an effective amount of the
compound or a pharmaceutically acceptable salt of the compound and an effective
amount of another therapeutic agent within the same composition can be administered.
[0451] In another embodiment, a composition comprising an effective amount of
the compound or a pharmaceutically acceptable salt of the compound and a separate
composition comprising an effective amount of another therapeutic agent can be
concurrently administered. In another embodiment, an effective amount of the
compound or a pharmaceutically acceptable salt of the compound is administered
prior to or subsequent to administration of an effective amount of another therapeutic
agent. In this embodiment, the compound or a pharmaceutically acceptable salt of the
compound is administered while the other therapeutic agent exerts its therapeutic
effect, or the other therapeutic agent is administered while the compound or a
pharmaceutically acceptable salt of the compound exerts its preventative or
therapeutic effect for treating or preventing a 5-HT1A-related disorder.
[0452] Thus, in one embodiment, the invention provides a composition
comprising an effective amount of the compound or a pharmaceutically acceptable salt
of the compound of the present invention and a pharmaceutically acceptable carrier.
In another embodiment, the composition further comprises a second therapeutic agent.
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[0453] In another embodiment, the composition further comprises a therapeutic
agent selected from the group consisting of one or more other antidepressants, anti-
anxiety agents, anti-psychotic agents or cognitive enhancers. Antidepressants, anti-
anxiety agents, anti-psychotic agents and cognitive enhancers suitable for use in the
composition include the antidepressants, anti-anxiety agents, anti-psychotic agents and
cognitive enhancers provided above.
[0454] In another embodiment, the pharmaceutically acceptable carrier is suitable
for oral administration and the composition comprises an oral dosage form.
Therapeutic or Prophylactic Uses
[0455] In one embodiment, the compounds or pharmaceutically acceptable salts of
the compounds of the present invention are useful as 5-HT1A receptor antagonists. In
another embodiment, the compounds or pharmaceutically acceptable salts of the
compounds of the present invention are useful as 5-HT1A receptor agonists.
Compounds that are 5-HT1A antagonists and/or agonists can readily be identified by
those skilled in the art using numerous art-recognized methods, including standard
pharmacological test procedures such as those described herein. Accordingly, the
compounds and pharmaceutically acceptable salts of the compounds of the present
invention are useful for treating a mammal with a 5-HT1A-related disorder. One non- .
limiting example of a disorder that 5-HT1A receptor antagonists are useful for treating
is cognition-related disorder, while a non-limiting example of a disorder that 5-HT1A
receptor agonists are useful for treating is anxiety-related disorder. In some
embodiments, the compounds and pharmaceutical salts of the invention are useful for
improving cognitive function or cognitive deficits. Examples of improvements in
cognitive function include, without limitation, memory improvement and retention of
learned information. Accordingly, the compounds and pharmaceutical salts of the
invention are useful for slowing the loss of memory and cognition and for maintaining
independent function for patients afflicted with a cognition-related disorder. Thus, in
one embodiment, the compounds and pharmaceutically acceptable salts of the
compounds of the present invention that act as 5-HT1A receptor antagonists are useful
for treating a mammal with a cognition-related disorder. In one embodiment, the
compounds and pharmaceutically acceptable salts of the compounds of the present
invention that act as 5-HT1A receptor antagonists are useful for improving the
cognitive function of a mammal. Similarly, in one embodiment, the compounds and
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phaxmaceutically acceptable salts of the compounds of the present invention that act
as 5-HT1A receptor agonists are useful for treating a mammal with an anxiety-related
disorder.
[0456] In one embodiment, the invention provides a method for treating a
5-HT1A-related disorder, comprising administering to a mammal in need thereof a
compound or a pharmaceutically acceptable salt of the compound of Formula (I),
Formula (I'), Formula (I"), Formula (I"a), Formula (II), Formula (III) or Formula (IV)
in an amount effective to treat a 5-HT1A-related disorder. In one embodiment, the
invention provides a method for treating a cognition-related disorder, comprising
administering to a mammal in need thereof a compound or a pharmaceutically
acceptable salt of the compound of Formula (I), Formula (I'), Formula (I"), Formula
(Fa), Formula (II), Formula (III) or Formula (IV) in an amount effective to treat a 5-
HT1A-related disorder. In one embodiment, the invention provides a. method for
treating an anxiety-related disorder, comprising administering to a mammal in need
thereof a compound or a pharmaceutically acceptable salt of the compound of
Formula (I), Formula (I'), Formula (I"), Formula (I"a), Formula (II), Formula (III) ox-
Formula (IV) in an amount effective to treat a 5-HT1A-related disorder.
[0457] In one embodiment, the invention provides a method for treating
Alzheimer's disease, comprising administering to a mammal in need thereof a
compound or a pharmaceutically acceptable salt of a compound of Formula (I),
Formula (I'), Formula (I"), Formula (Ia"), Formula (II), Formula (III), or Formula
(IV) in an amount effective to treat Alzheimer's disease. In one embodiment, the
method for treating Alzheimer's disease includes administering a second therapeutic
agent. In some embodiments, the second therapeutic agent is an anti-depressant agent,
an anti-anxiety agent, an anti-psychotic agent, or a cognitive enhancer.
[0458] In one embodiment, the invention provides a method for treating mild
cognitive impairment (MCI), comprising administering to a mammal in need thereof a
compound or a pharmaceutically acceptable salt of a compound of Formula (I),
Formula (I), Formula (I"), Formula (Ia"), Formula (II), Formula (III), or Formula
(IV) in an amount effective to treat mild cognitive impairment (MCI). In one
embodiment, the method for treating MCI includes administering a second therapeutic
agent. In some embodiments, the second therapeutic agent is an anti-depressant agent,
an anti-anxiety agent, an anti-psychotic agent, or a cognitive enhancer.
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[0459] In one embodiment, the invention provides a method for treating
depression, comprising administering to a mammal in need thereof a compound or a
pharmaceutically acceptable salt of a compound of Formula (I), Formula (I'), Formula
(I"), Formula (Ia"), Formula (II), Formula (III), or Formula (IV) in an amount
effective to treat depression. In one embodiment, the method for treating depression
includes administering a second therapeutic agent. In some embodiments, the second
therapeuuc agent is an anti-depressant agent, an anti-anxiety agent, an anti-psychotic
agent, or a cognitive enhancer.
[0460] In some embodiments, the invention provides a pharmaceutical
composition for treating a 5-HT1A-related disorder, the composition including a
compound or pharmaceutically acceptable salt of a compound of Formula (I), Formula
(I'), Formula (I"), Formula (I"a), Formula (II), Formula (III), or Formula (IV). In
some embodireents, the invention provides a pharmaceutical composition for treating
a cognition-related disorder, the composition including a compound or
pharmaceutically acceptable salt of a compound of Formula (I), Formula (I'), Formula
(I"), Formula (I"a), Formula (II), Formula (III), or Formula (IV). In some
embodiments, the invention provides a pharmaceutical composition for treating an
anxiety-related disorder, the composition including a compound or pharmaceutically
acceptable salt of a compound of Formula (I), Formula (I'), Formula (I"), Formula
(I"a), Formula (II), Formula (III), or Formula (IV).
[0461] In one embodiment, the invention provides a pharmaceutical composition
for treating Alzheimer's disease, the composition including a compound or a
pharmaceutically acceptable salt of a compound of Formula (I), Formula (I'), Formula
(I"), Formula (Ia"), Formula (II), Formula (III), or Formula (IV).
[0462] In one embodiment, the invention provides a pharmaceutical composition
for treating mild cognitive impairment (MCI), the composition including a compound
or a pharmaceutically acceptable salt of a compound of Formula (I), Formula (I'),
Formula (F), Formula (Ia"), Formula (II), Formula (III), or Formula (IV).
[0463] In one embodiment, the invention provides a pharmaceutical composition
for treating depression, the composition including a compound or a pharmaceutically
acceptable salt of a compound of Formula (I), Formula (I'), Formula (I"), Formula
(Ia"), Formula (II), Formula (III), or Formula (IV).
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[0464] In one embodiment, the compounds or pharmaceutically acceptable salts of
the compounds of the present invention are useful for treating sexual dysfunction, e.g.,
sexual dysfunction associated with drug treatment such as drug treatment with an
antidepressant, an antipsychotic, or an anticonvulsant. Accordingly, in one
embodiment, the invention provides a method for treating sexual dysfunction
associated with drug treatment in a patient in need thereof. The method includes
administering to the patient an effective amount of one or more of the compounds
disclosed herein. In some embodiments, the drug treatment is antidepressant drug
treatment, antipsychotic drug treatment, or anticonvulsant drug treatment. The
compound can be a compound or pharmaceutically acceptable salt of a compound of
Formula (I), Formula (I'), Formula (I"), Formula (Fa), Formula (II), Formula (IE), or
Formula (IV).
[0465] In certain embodiments, the drug associated with sexual dysfunction is a
selective serotonin reuptake inhibitor (SSRI) (for example, fluoxetine, citalopram,
escitalopram oxalate, fluvoxamine maleate, paroxetine, or sertraline), a tricyclic
antidepressant (for example, desipramine, amitriptyline, amoxipine, clomipramine,
doxepin, imipramine, nortriptyline, protriptyline, trimipramine, dothiepin,
butriptyline, iprindole, or lofepramine), an aminoketone class compound (for example,
bupropion). In some embodiments, the drug is a monoamine oxidase inhibitor
(MAOI) (for example, phenelzine, isocaRboxazid, or tranylcypromine), a serotonin and
norepinepherine reuptake inhibitor (SNRI) (for example, venlafaxine, nefazodone,
milnacipran, duloxetine), a norepinephrine reuptake inhibitor (NRI) (for example,
reboxetine), a partial 5-HT1A agonist (for example, buspirone), a 5-HT2A receptor
antagonist (for example, nefazodone), a typical antipsychotic drug, or an atypical
antipsychotic drug. Examples of such antipsychotic drugs include aliphatic
phethiazine, a piperazine phenothiazine, a butyrophenone, a substituted benzamide,
and a thioxanthine. Additional examples of such drugs include haloperidol,
olanzapine, clozapine, risperidone, pimozide, aripiprazol, and ziprasidone. In some
cases, the drug is an anticonvulsant, e.g., phenobaRbital, phenytoin, primidone, or
caRbamazepine. In some cases, the patient in need of treatment for sexual dysfunction
is being treated with at least two drugs that are antidepressant drugs, antipsychotic
drugs, anticonvulsant drugs, or a combination thereof.
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[0466] In some embodiments of the invention, the sexual dysfunction comprises a
deficiency in penile erection.
[0467] The invention also provides a method of improving sexual function in a
patient in need thereof. The method includes administering to the patient a
pharmaceutically effective amount of one or more of the compounds disclosed herein.
The compound can be a compound or pharmaceutically acceptable salt of a compound
of Formula (I), Formula (I5), Formula (I"), Formula (Fa), Formula (II), Formula (HI),
or Formula (IV).
[0468] In another embodiment, the invention provides a pharmaceutical
composition for treating sexual dysfunction associated with drug treatment, the
composition including a compound or pharmaceutically acceptable salt of a compound
of Formula (I), Formula (I'), Formula (I"), Formula (I"a), Formula (II), Formula (III),
or Formula (IV). In some embodiments, the drug is an antidepressant, an
antipsychotic, or an anticonvulsant. In other embodiments, the compound or
pharmaceutically acceptable salt of the compound is effective for ameliorating sexual
dysfunction in an animal model of sexual dysfunction associated with drug treatment,
for example, in an animal model of sexual dysfunction that is an antidepressant drug-
induced model of sexual dysfunction.
[0469] The compounds and pharmaceutically acceptable salts of the compounds of
Formula (I), Formula (I'), Formula (I"), Formula (I"a), Formula (II), Formula (III) or
Formula (IV) are also useful in the manufacture of medicaments for treating a 5-HT1A-
related disorder in a mammal. Similarly, the compounds and pharmaceutically
acceptable salts of the compounds of Formula (I), Formula (I'), Formula (I"), Formula
(I"a), Formula (II), Formula (III) or Formula (IV) are also useful in the manufacture of
medicaments for treating a cognition-related disorder in a mammal. Also, the
compounds and pharmaceutically acceptable salts of the compounds of Formula (I),
Formula (I'), Formula (I"), Formula (I"a), Formula (II), Formula (III) or Formula (IV)
are also useful in the manufacture of medicaments for treating an anxiety-related
disorder in a mammal.
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EXAMPLES
Preparation of Piperazine-Piperidine Compounds
A) Preparation of 6-Methoxy-8-{4-[l-(8-quinolinyl)-4-piperidinyl]-l-
piperazinyl}quinoline and Intermediates

[0470] In a 500 ml 3-necked flask equipped with a mechanical stirrer, a reflux
condenser, were added in order ferrous sulfate (2.0 g), 4-amino-3-chlorophenol
hydrochloride (6.4 g, commercially available), nitrobenzene (2.9 mL) and a solution
of boric acid (3.0 g) in glycerol (16 g). Then concentrated sulfuric acid (9 mL) was
added drop by drop with cooling. The ice bath was removed and replaced by an oil
bath and the mixture was heated cautiously to 120°C for 2 hours, then at 150°C and . .
kept stirring under this temperature for 20 hours. After cooling, the reaction was
poured on crushed ice and the resulting solution was neutralized with K2CO3. The
product separated as a light brown solid that was filtered off, washed with water and
hexanes and dried in a vacuum oven (35 °C) overnight giving 7 g (77 %) of the desired
product. MS (ES) m/z (relative intensity): 180 (M++-H, 100).

[0471] To a solution of 3.3 g of 8-chloro-6-hydroxyquinoline (Step 1, 3.3 g) in
dimethylformamide was added K2CO3 (3.8 g), followed by iodomethane (5.2 g). The
mixture was stirred at room temperature overnight. Water was then added and the
aqueous mixture was extracted with CH2Cl2. The combined organic layers were
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dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator. The
crude product was purified by flash chromatography on silica gel using 100% CH2Cl2,
to give 2.2 g of the desired product as a beige solid; MP = 74-75°C; MS (ES) m/z
(relative intensity): 194 (M+H)+ (100).

[0472] To a mixture of 8-chloro-6-methoxyquinoline (Step 2, 2.7 g) in anhydrous
tetrahydrofuran, was added tris(dibenzylideneacetone)dipalladium(O) (Pd2(dba)3,
0.064 g), sodium tert-butoxide (1.9 g), 2-dicyclohexylphosphino-2'-(N,N-
dimethylamino)biphenyl (CYMAP, 0.08 g) and tert-butoxycarbonylpiperazine (3.4 g).
The mixture was refluxed for 5 hours under a nitrogen atmosphere. The reaction was
then cooled to room temperature, diluted with ether, filtered through celite and
concentrated on a rotary evaporator. The crude material was purified by flash
chromatography using 100% CH2Cl2 to give 4.0 g of the desired product as a beige
solid; mp = 92-93°C; MS (ES) m/z (relative intensity): 344 (M++H) (100).

[0473] To a solution of 6-methoxy-8-[l~(tert-butoxycarbonyl)-4-
piperazino]quinoline (Step 3,4.0 g) in 20 mL of Dioxane was added 10 mL of 4 N
HCl/Dioxane. The mixture was stirred at room temperature overnight. The resulting
precipitate was collected by vacuum filtration, dissolved in water, neutralized with
aqueous sodium hydroxide and extracted with CH2Cl2. The combined organic layers
were dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator to
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give 2.8 g of the desired product as a beige solid; MP = 105-107°C; MS (ES) m/z
(relative intensity): 244 (M+H)+ (100).

[0474] To a solution of 8-bromoquinoline (commercially available, 4.0 g) in 20
mL of anhydrous tetrahydrofuran, was added
tris(dibenzylideniacetone)dipalladium(0) (Pd2(dba)3,0.2 g), sodium tert-butoxide (2.6
g), 2,2'-bis(diphenylphosphino)-l,l'-binapthyl (BINAP, 0.1 g), tetrakis-
(triphenylphosphine)palladium(O) (0.1 g) and 1,4- dioxo-8-azaspiro-4,5-decane (3,3
g). The mixture was refluxed for 3 hours under a nitrogen atmosphere. The reaction
mixture was then cooled to room temperature, diluted with ether, filtered through
celite and concentrated on a rotary evaporator. The crude material was then purified
by flash chromatography on silica gel using hexane/ethyl acetate to give 3.0 g of the
desired product as a brown oil; MS (ES) m/z (relative intensity): 271 (M+H)+ (100).

[0475] To a solution of (4.0 g) 8-(l,4-Dioxa-8-azaspairo[4,5]dec-8-yl)quinoline
(Step 4,4.0 g) in 10 mL of tetrahydrofuran was added 10 mL of 2N HC1. The reaction
was stirred at room temperature overnight. The mixture was then diluted with water,
made basic with aqueous sodium hydroxide and extracted with CH2Cl. The combined
organic layers were dried over anhydrous and the product is extracted with CH2Cl2,
dried over Na2SO4, filtered and concentrated on a rotary evaporator and to give 3.2 g
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of the desired product as a sticky yellow oil; MS (ES) m/z (relative intensity): 227
(M+H)+ (100).

[0476] To a solution of 0.247 g of 6-methoxy-8-piperazmo-quinoline (Step 4) in
10 mL of dichloroethane, was added 0.226g of l-quinolin-8-yl-piperidin-4-one (Step
6) followed by 0.274 g of sodium triacetoxyborohydride and 0.1 mL acetic acid. The
reaction was stirred at room temperature overnight. It was quenched with 1N NaOH,
and the product was extracted with CH2Cl2. The organic phase was washed with
water and dried over magnesium sulfate. The product crystallized and filtered to give
0.200 g of the desired product. Mp.l94-197°C; MS (ES) m/z (relative intensity): 454
(M++-H, 100).

[0477] To a mixture of 2-bromo-4-fluoroaniline (commercially available, 7.0 g),
glycerol (7.0 g) and m-nitrobenzene sulfonic acid sodium salt (13.0 g) was added 20
ml of 70 % sulfuric acid dropwise. The reaction temperature was raised to 150° C for
4 hr. The mixture then was cooled to room temperature, poured on ice water and
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filtered through celite. The filtrate was neutralized with NaOH and the resulting
precipitate was collected by vacuum filtration to yield 3.47g of the title compound as a
light yellow solid; MP = 75-78°C; MS (ES) m/z (relative intensity): 227 (M+H)+
(100).

[0478] To a mixture of 6-fluoro-8-bromoquinoline (Step 1,2.2 g) in anhydrous
tetrahydrofuran, was added tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3,
0.045 g) sodium tert-butoxide (1.3 g), 2,2'-bis(diphenylphosphino)-1,1'-binapthyl
(BINAP, 0.044 g), 0.052g tetrakis(triphenylphosphine)-palladium (0) (0.052 g) and
tert-butoxycarbonyl-piperazine (2.2 g). The mixture was refluxed for 3 hours under a
nitrogen atmosphere. The reaction was then cooled to room temperature, diluted with
ether, filtered through, celite and concentrated on a rotary evaporator. The crude
material was purified by flash chromatography using 100% CH2Cl2 to give 3.0 g of
the desired product as a brown oil; MS (ES) m/z (relative intensity): 332 (M+H)+
(100).

[0479] To a solution of 6-fluoro-8-[l-(tert-butoxycarbonyl)-4-
piperazino]quinoline (Step 2, 3.0 g) in 10 mL Dioxane was added 10 mL of 4 N
HCl/Dioxane. The mixture was stirred at room temperature overnight. The resulting
precipitate was collected by vacuum filtration, dissolved in water, neutralized with
aqueous sodium hydroxide and extracted with CH2Cl2. The combined organic layers
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WO 2006/135839 PCT/US2006/022719
were dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator to
give 1.9 g of the desired product as an off-white solid. Mp. 101-103°C; MS (ES) m/z
(relative intensity): 233 (M+H)+ (100).

[0480] To a solution of 0.247 g of 6-fluoro-8-piperazino-quinoline (Step 3) in 10
mL of dichloroethane, was added 0.226g of l-quinolin-8-yl-piperidin-4-one (Example
A, Step 6, above) followed by 0.274 g of sodium triacetoxyborohydride and 0.1 mL
acetic acid. The reaction was sthred at room temperature overnight. It was quenched
with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was
washed with water and dried over magnesium sulfate. The product crystallized and
filtered to give .200 g of the desired product. Mp: 211 °C; MS (ES) m/z (relative
intensity): 442 (M++-H, 100).
[0481]

[0482] To a mixture of (5.0 g) 2-chloro-5-fluoroaniline (commercially available,
6.0 g), glycerol (6.0 g) and m-nitrobenzene sulfonic acid sodium salt (11.0 g), was
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WO 2006/135839 PCT/US2006/022719
added 20 ml of 70 % sulfuric acid dropwise. The reaction temperature was raised to
140°C for 2 hr. The mixture was then cooled, poured on ice water and filtered through
celite. The filtrate was neutralized with NaOH and extracted with CH2Cl2. The
combined organic layers were dried over anhydrous MgSO4 and concentrated on a
rotary evaporator. The crude product was purified by flash chromatography on silica
gel using 100% CH2Cl2 to give 3.7 g of the desired product of a yellow solid; MP =
74-76°C; MS (ES) m/z (relative intensity): 182 (M+H)+ (100).

[0483] To a solution of 5-fluoro-8-chloroquinoline (Step 1,1.12 g) in 20 mL of
anhydrous tetrahydrofuran, was added 0.085 g of
109
tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 0.085 g), sodium tert-butoxide
(0.83 g), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (CYMAP,
0.036 g), and l,4-dioxo-8-azaspiro-4,5-decane (1.05 g). The mixture was refluxed for
6 hours under a nitrogen atmosphere. The reaction mixture was then cooled to room
temperature, diluted with ether, filtered through celite and concentrated on a rotary
evaporator. The crude material was then purified by flash chromatography on silica
gel using hexane/ethyl acetate to give 0.700 g of the desired product as a brown oil;
MS (ES) m/z (relative intensity): 289 (M+H)+ (100).


WO 2006/135839 PCT/US2006/022719
[0484] A solution of 8-(l,4-dioxa-8-azaspiro[4,5]dec-5-yl)-5-fluoroquinoline
(Step 2,2.1 g)) in 10 mL of 1:1 tetrahydrofuran/2N aqueous HC1 was stirred at room
temperature overnight. The reaction mixture was diluted with water, made basic with
1N aqueous NaOH and extracted with CH2Cl2. The combined organic layers were
dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator to give
1.68 g of the desired product as a yellow solid, which was pure enough to use in
subsequent reactions; MS m/z = 245 [M+H]+.

[0485] To a solution of 0.120 g of l-(5-fluoro-quinolin-8-yl)-piperidin-4-one
(Step 3, 0.22g) and 8-piperazin-l-ylquinoline (Oruz, etal., J. Med. Chem. 45:4128
(2002), 0.19g) was added of 0.19 g sodium triacetoxyborohydride and 0.1 mL acetic
acid. The reaction was stirred at room temperature overnight. It was quenched with
1N NaOH, and the product was extracted with CH2Cl2. The organic phase was
washed with water and dried over magnesium sulfate. The product was filtered
through 75 ml of silica gel using 100% Ethyl acetate, to give .30 g of the desired
product. Mp: 224 °C; MS (ES) m/z (relative intensity): 442 (MVH, 100).

[0486] To a solution of 0.270 g of 1-quinolin-8-yl-piperidin-4-one (Example A,
Step 6, above) and 0.240 g of 4-piperazino-indole (commercially available) in 15 mL
CH2Cl2 was added 0.327 g of sodium triacetoxyborohydride and 0.2mL acetic acid.
The reaction was stirred at room temperature overnight. It was quenched with 1N
NaOH, and the product was extracted with CH2Cl2. The organic phase was washed
110

WO 2006/135839 PCT/US2006/022719
with water, dried over magnesium sulfate and evaporated. The product crystallized to
give 0.200g of the desired product. Mp: 256 °C; MS (ES) m/z (relative intensity): 412
(M++-H, 100).

[0487] To a solution of l-quinolin-8-yl-piperidin-4-one (Example A, Step 6,
above, 0.220 g) in 10 mL of dichloroethane, was added 0.226 g of 8-piperazino-l,3-
benzdioxane (Childers et al., J. Med. Chem. 48:3467 (2005), 0.226 g) followed by
0.274 g of sodium triacetoxyborohydride and 0.1 mL acetic acid. The reaction was
stirred at room temperature overnight. It was quenched with 1N NaOH, and the
product was extracted with CH2Cl2. The organic phase was washed with water, dried
over magnesium sulfate and evaporated. The product crystallized to give 0.140 g of
the desired product. Mp: 226 °C; MS (ES) m/z (relative intensity): 431 (M++-H, 100).

[0488] To a stirred solution of TiCl4 (1M solution in CH2C12,7 ml) and
5-fluoro-benzofuran-3-one (Cagniant, et al., Comptus R6ndus des Seances Acad. de
Set, Ser. C, 282:993 (1976), 3.0 g) (3.0 g, 19.7 mmol) in methylene chloride (200 ml)
at -10°C, ethyl-1-piperizine caRboxylate (commercially available) (3.9 g, 35 mmol)
was slowly added. After the addition, the reaction mixture was warmed to room
temperature and slowly refluxed for 24 hours. After cooling to room temperature, the
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WO 2006/135839 PCT/US2006/022719
reaction was quenched with 2 N aqueous HC1. The organic layer was separated and
the aqueous layer was extracted with chloroform. The combined organic layers were
washed well with water and dried over anhydrous MgSO4 then filtered and
concentrated resulting in a brown oil. Yield: 3.5 g, (60%); MS (ESI) m/z 293 [M+-
H]+.

[0489] 4-(5-fluorobenzofuran-3-yl)-piperazine-l-caRboxylic acid ethyl ester (Step
1, 3 g) was dissolved in 95% ethanol and 3N aqueous sodium hydroxide (25 mL) was
added. The reaction mixture was stirred at reflux for 24 hours. The mixture was then
cooled to room temperature, concentrated on a rotary evaporator to remove the ethanol
and extracted with chloroform. The combined organic layers were washed with brine,
dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator. The
desired product (0.8 g) was obtained as a brown oil and was used without further
purification; MS (ES) m/z (relative intensity): 221 (M+H)+ (100).

[0490] To a solution of 0.200 g of l-(5-fluoro-quinolin-8-yl)-piperidin-4-one
(Example C, Step 3, 0.20 g) and 5-fluoro-3-piperazino benzofuran (Step 2, 0.20g) in
CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (0.224 g) and 0.02 mL
acetic acid. The reaction was stirred at room temperature overnight. It was quenched
with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was
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WO 2006/135839 PCT/US2006/022719
washed with water and dried over magnesium sulfate. The product was filtered
through 100 ML of silica gel using 50% Ethyl acetate / Hexanes then 100% Ethyl
acetate to give .100 g of the desired product. Mp: 187-189°C; MS (ES) m/z (relative
intensity): 449 (M++-H, 100).

[0491] Sodium triacetoxyborohydride (21.2 g) was added portionwise to a stirred
solution of l-(2-methoxyphenyl)piperazine (commercially available, 19.23 g) and 1-
benzyl-4-piperidone (commercially available, 18.93 g) in CH2Cl2 (300 mL) at room
temperature, followed by glacial acetic acid (6 mL). The resulting mixture was stirred
at room temperature for 24 hours. The reaction was made basic by careful addition of .
saturated aqueous NaHCO3. The organic layer was separated, washed with brine,
dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator to give
the desired product (20.65 g) as an off-white solid which was used without further
purification. The compound was characterized as the dihydrochloride salt, which was
formed by dissolving the free base in ethanol and treating it with an excess of 1 N
HCl/Et2O to give a white solid, which was collected by vacuum filtration, washed
with Et2O and dried in vacuo; MP. 238 - 242°C; MS (ES) m/z (relative intensity) 366
(M+H)+ (100).

[0492] A solution of 4-(l-benzylpiperidine-4-yl)-l-(2-methoxyphenyl)piperazine
(Step 1,20.0 g) in ethanol (120 mL) containing acetic acid (12 mL) was hydrogenated
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WO 2006/135839 PCT/US2006/022719
over 10% palladium on carbon (1 g) at 50 psig on a Parr apparatus for 12 hours. The
catalyst was removed by filtration through Celite and the mixture was concentrated to
dryness on a rotary evaporator. The residue was partitioned between chloroform and
saturated aqueous NaHCC>3. The combined organic layers were dried over anhydrous
MgSO4, filtered and concentrated on a rotary evaporator to provide the desired
product (14.4 g) as a yellow oil which was used without further purification. The
compound was characterized as the dihydrochloriae salt, which was formed by
dissolving the oil in ethanol and treating it with an excess of 1N HCl/Et2O to give an
off-white precipitate, which was collected by vacuum filtration, washed with Et2O
and dried in vacuo; MP. 274 - 288°C; MS (ES) m/z (relative intensity): 276 (M+H)+
(100).

114
[0493] A solution of 3-bromo-benzothiophene (commercially available, 0.232 g)
and 4-(4-(2-methoxyphenyl)piperazin-l-yl)piperidine (Step 2,0.30 g) in
tetrahydrofuran was added sodium tert-butoxide (0.15 g), tris-
(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 0.10 g) and 2-
dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (CYMAP, 0.01 g). The
reaction was heated at reflux for 24 hours. It was then cooled and filtered through
celite. The filtrate was evaporated and purified by flash chromatography on silica gel
using ethyl acetate/hexanes to give 0.10g of the desired product. MP: 156-158°C; MS
(ES) m/z (relative intensity): 408 (M+H)+ (100).


WO 2006/135839 PCT/US2006/022719
[0494] To a cold solution (-15°C) of benzo-[D]-isoxazole-3-ol (2.0g) in CH2C12
(20 mL) and triethylamine (4.5g), was added a solution of trifluoromethanesulfonic
anhydride (5.0 g) in CH2Cl2 (10 mL) dropwise with. The reaction was stirred at 0°C
for one hour and then poured into ice water. The mixture was extracted with CH2Cl2.
The organic phase was dried over anhydrous MgSO2, filtered and concentrated on a
rotary evaporator to give 3.0 g of the desired product as a brown oil, which was used
immediately without characterization or further purification.

115
[0495] l,2-benz-isoxazole-3- trifluoromethyl sulfonate I (Step 1,0.50 g) and 4-(4-
(2-methoxyphenyl)piperazin-l-yl)piperidine (Example G, Step 2, above. 0.514g) were
added to a cold suspension of CsCO3 (0.92 g) in acetonitrile (6 mL) under vigorous
stirring. The reaction mixture was stirred at room temperature for 48 hours. The
mixture was then filtered and concentrated on a rotary evaporator. The residue was
dissolved in water extracted with CH2Cl2, dried over anhydrous MgSO4, filtered and ..
concentrated on a rotary evaporator. The desired product was purified by flash
chromatography on silica gel using ethyl acetate/hexane to give 0.34 g as an off-white
solid; MP 71-73°C; MS (ES) m/z (relative intensity): 393 (M+H)+ (100).


WO 2006/135839 PCT/US2006/022719
[0496] This compound was prepared from the known 8-bromo-6-chloroquinoline
(Lachowicz et al., Rocz. Chem., 40:1848 (1966)) using a synthetic sequence and
reagents identical to those described for the synthesis of l-quinolin-8-yl-piperidin-4-
one (Step 5, Example A, above). The compound was obtained as an off-white solid;
MP: 223-225°C; MS (ES) m/z (relative intensity): 261 (M+H)+ (100).

116
[0497] To a solution of l-(6-chloro-quinolin-8-yl)-piperidin-4-one (Step 1, 0.13 g)
and of 4-piperazino-indole (commercially available, 0.100g) in 15 mL CH2Cl2 in 10
mL of dichloroethane, was added 0.137 g of sodium triacetoxyborohydride and 0.1
mL acetic acid. The reaction was stirred at room temperature overnight. It was
quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic
phase was washed with water and dried over magnesium sulfate. The product was
filtered through 100 ml of silica gel using 100% Ethyl acetate, to give 0.070 g of the
desired product. Mp: 224 °C; MS (ES) m/z (relative intensity): 447 (M++-H, 100).


WO 2006/135839 PCT/US2006/022719
[0498] To a mixture of 2,3-difluoroaniline (commercially available, 3.57g),
glycerol (5.55 g) and m-nitrobenzene sulfonic acid sodium salt (10.12 g) was added
dropwise 70% H2SO4 (20 mL). The reaction was heated at 135°C for 3.5 hours and
then cooled to room temperature. It was poured over ice, made basic with 50%
aqueous NaOH and extracted with Et2O. The combined organic layers were washed
with brine, dried over anhydrous MgSO4 and concentrated on a rotary evaporator to
give 4.13 g of cna desired product as a light brown solid; MS (ES) m/z (relative
intensity); 166 (M+H)+ (100).

[0499] A mixture of 7,8-difluoroquinoline (Step 1,0.50g) and dioxa-8-azaspiro-
4.5-decane (5 mL) was heated at 120°C for 48 hours. The reaction was cooled to
room temperature, poured into water and extracted with Et2O. The combined organic .
layers were dried over anhydrous Na2SO4, filtered and concentrated on a rotary
evaporator. The crude residue was purified by flash chromatography on silica gel.
Eluting with 30% ethyl acetate in hexane provided 0.39 g of 8-(1.4-dioxa-8-
azaspiro[4.5]dec-8-yl)-7-fluoroquinoline as yellow oil; MS (ES) m/z (relative
intensity): 289 (M+H)+ (100).
[0500] The eluent was then switched to 50% ethyl acetate in hexane, which
provided 0.23 g of the regioisomeric 7-(1.4-dioxa-8-azaspirol[4.5]dec-8-yl)-8-
fluoroquinoline as a white solid; MS (ES) m/z (relative intensity): 289 (M+H)+ (100).
117

WO 2006/135839 PCT/US2006/022719

[0501] To a solution of 8-(l .4-dioxa-8-azaspiro[4.5]dec-8-yl)-7-fluoroquinoline
(Step 2,1.73 g) in tetrahydrofuran (50 mL) was added aq. 2N aqueous HC1 (10 mL).
The resulting mixture was stirred at 50°C for 3 hours. The reaction mixture was then
cooled to room temperature, poured into 2.5 N aqueous NaOH and extracted with
ethyl acetate. The combined organic layers were dried over anhydrous MgSO4,
filtered and concentrated on a rotary evaporator. The crude product was purified by
flash chromatography on silica gel using hexane/ethyl acetate to give 1.17 g of the
desired product as a yellow oil; MS (ES) m/z (relative intensity): 245 (M+H)+ (100).

[0502] To a solution of l-(7-fluoroquinolin-8-yl)piperidin-4-one (Step 3,0.26 g)
and 6-methyoxy-8-(l-piperazinyl)quinoline (Example A, Step 4; 0.26 g) in anhydrous
methanol (10 mL) was added sodium cyanoborohydride (0.11 g). The resulting
mixture was stirred at room temperature under nitrogen for 18 hours. An additional
aliquot of sodium cyanoborohydride (0.11 g) was added and stirring at room
temperature was continued for another 24 hours. The resulting reaction mixture was
poured into brine and extracted with ethyl acetate. The combined organic layers were
dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator. The
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WO 2006/135839 PCT/US2006/022719
crude product was purified by flash chromatography on silica gel using
hexane/acetone to give the desired product, which was converted to its
trihydrochloride salt in CH2Cl2 using 1M HCl/Et2O to provide 0.12 g of a yellow
solid; MS (ES) m/z (relative intensity): 472 (M+H)+ (100).

[0503] To a solution of 7-(1.4-dioxa-8-azaspiro[4.5]dec-8-yl)-8-fluoroquinoline
(Example J, Step 2; 1.30 g) in tetrahydrofuran (60 mL) was added aq. 2N aqueous
HC1 (10 mL). The resulting mixture was stirred at room temperature for 18 hours and
then heated at 60°C for 5 hours. The reaction mixture was cooled to room
temperature, poured into 1N aqueous NaOH and extracted with ethyl acetate. The
combined organic layers were dried over anhydrous MgSO4, filtered and concentrated
on a rotary evaporator. The crude product was purified by flash chromatography using
hexane/acetone to give 0.89 g of the desired product as a yellow solid; MS (ES) m/z
(relative intensity): 245 (M+H)+ (100).
2) 6-Fluoro-8-{4-[1-(8-fluoroquinolin-7-yl)piperidin-4-vnpiperazin-l-
yl]quinoline (Final product)
[0504] To a solution of l-(8-fluoroqumolin-7-yl)piperidin-4-one (Step 1,0.25 g)
and 6-fluoro-8-(l-piperazinyl)quinoline (Example B, Step 3; 0.25 g) in anhydrous
methanol (10 mL) was added sodium cyanoborohydride (0.11 g). The resulting
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WO 2006/135839 PCT/US2006/022719
mixture was stirred at room temperature for 18 hours. An additional aliquot of
sodium cyanoborohydride (0.10 g) was added and stirring at room temperature was
continued for another 24 hours. The reaction mixture was poured into brine and
extracted with ethyl acetate. The combined organic layers were dried over anhydrous
Na2SO4, filtered and concentrated on a rotary evaporator. The crude product was
isolated by flash chromatography on silica gel using hexane/acetone to give the
desired product as a off-white solid, which was converted to its trihydrochloride salt in
CH2Cl2/Et2O diethyl ether using 1M HCl/Et2O to provide 0.11 g as a yellow solid; MS
(ES) m/z (relative intensity): 460 (M+H)+ (100).

[0505] To a solution of 8-bromoquinoline (commercially available, 1.0 g) in
glacial acetic acid (6 mL) was added portionwise, N-iodosuccinimide (1.08 g). The
resulting mixture was stirred at 70°C for 18 hours. The reaction was cooled to room
temperature and concentrated on a rotary evaporator. The residue was taken up in
CH2C12 and washed with saturated aqueous NaHCO3 and brine. The organic layer
was dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator.
The crude product was purified by flash chromatography on silica using hexane/ethyl
acetate to give 0.74 g of the desired product as a white solid; MS (ES) m/z (relative
intensity): 334 (M+H)+ (100).
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WO 2006/135839 PCT/US2006/022719

[0506] A mixture of cuprous iodide (0.25 g) and potassium fluoride (0.077 g) was
placed under a high vacuum and heated until the solid assumed a sight green color.
The cooled solid mass was suspended in anhydrous N-methylpyrrolidinone (5 mL)
and then treated with 8-bromo-3-iodoquinoline (Step 1,0.40 g), followed by
trifluoromethyl-trimethylsilane (0.17g). The resulting mixture was stirred at 50°C for
18 hours. The mixture was then cooled to room temperature and poured into 15%
aqueous NH4OH and then extracted with Et2O. The organic layer was washed with
water and brine, dried over anhydrous Na2SO4, filtered and concentrated on a rotary
evaporator. The crude product was purified by flash chromatography on silica gel
using hexane/ethyl acetate to give 0.24 g of the desired product as a brown oil; MS
(ES) m/z (relative intensity); 277 (M+H)+ (100).

[0507] To a solution of mixture 8-bromo-3-(trifluoromethyl)quinoline (Step 2,
0.22 g) in anhydrous tetrahydrofuran was added tris
(dibenzylideneacetone)dipalladium(O) (Pd2(dba)3, 0.03 g), sodium tert-butoxide
(0.085 g), 2.2'-bis(diphenylphosphino)-1.1'-binapthyl (BBSfAP, 0.02 g), tetrakis-
(triphenylphosphine)palladium(O) (0.037) g) and 1.4-dioxo-8-azaspiro-4.5-decane
(0.14 g). The resulting mixture was stirred at 70°C for 18 hours under a nitrogen
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WO 2006/135839 PCT/US2006/022719
atmosphere. The reaction was then cooled to room temperature, diluted with CH2Cl2,
filtered through celite and concentrated on a rotary evaporator. The crude product was
purified by flash chromatography on silica gel using hexane/ethyl acetate to give 0.21
g of the desired product as a beige solid; MS (ES) m/z (relative intensity); 399
(M+H)+ (100).

[0508] A solution of 8-(1.4-dioxa-8-azaspiro[4.5]dec-8-yl)-3~
(trifluoromethyl)quinoline (Step 3,0.19 g) in tetrahydrofuran (3 mL) was treated with
2N aqueous HC1(1 mL) and then stirred at 40°C for 18 hours. The mixture was
cooled to room temperature and concentrated on a rotary evaporator. The residue was
taken up in CH2Cl2, washed with water and brine, dried over anhydrous Na2SO4,
filtered and concentrated on a rotary evaporator to give 0.11 g of the desired product ;
as a yellow oil; MS (ES) m/z (relative intensity); 295 (M+H)+ (100).
5) 8- {4- [4-(6-Methoxvquinolin-8-yl)piperazin-1 -ylipiperidin-1 -yl) -3-
(trifluoromethyl)quinoline
[0509] A mixture of 6-methoxy-8-piperazinoquinoline (Example A, Step 4;
0.0825 g) and l-[3-(trifluoromethyl)quinolin-8-yl]piperidin-4-one (0.1 g) in methanol
(5 mL) was treated with sodium cyanoborohydride (Step 4, 0.032 g). The resulting
mixture was stirred at room temperature for 18 hours and then concentrated on a
rotary evaporator. The residue was taken up in CH2C2, washed with water and brine,
dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator. The
crude product was purified by flash chromatography on silica gel using hexane/ethyl
acetate to give the desired product, which, was converted to its dihydrochloride salt in
using 1N HCl/Et2O to yield 0.035 g as a yellow solid; MS (ES) m/z (relative
intensity): 522 (M+H)+ (100).
122


[0510] To a stirred mixture of 6-methoxy-8-piperazinoquinoline (Example A, Step
4, 0.24 g) and 4-benzyl-l-piperidinone (0.20 mL) in methanol (12 mL) was added
glacial acetic acid (0.06 g), followed by sodium cyanoborohydride (0.123 g). The
resulting mixture was stirred at room temperature for 18 hours. The reaction was then
concentrated on a rotary evaporator and re-dissolved in CH2Cl2. The solution was
washed with water and brine and then dried over anhydrous Na2SO4, filtered and
concentrated on a rotary evaporator. The crude product was purified by flash
chromatography on silica gel using hexane/ethyl acetate to give 0.23 g of the desired
product as an off-white solid; MS (ES) m/z (relative intensity); 417 (M+H)+ (100).
123


[0511] A solution of 8-[4-(l-benzylpiperidin-4-yl)piperazin-l-yl]~6-
methoxyquinoline (Step 1,0.22 g) and vinylchlorofonnate (0.067 mL) in anhydrous
CH2Cl2 (5 mL) was stirred at reflux for 1 hour. The reaction was cooled to room
temperature and then concentrated on a rotary evaporator. The residue was taken up
in dioxane (5mL), treated with concentrated HC1 (0.35 mL) and stirred at room
temperature for 1 hour. The resulting reaction was concentrated on a rotary
evaporator, taken up in ethanol (1 mL) and stirred at 50°C for 30 minutes. The
reaction was again concentrated on a rotary evaporator and partitioned between
CH2Cl2 and 1N aqueous NaOH. The organic layer was washed with water and then
brine and was then dried over anhydrous Na2SO4, filtered and concentrated on a rotary
evaporator. The crude product was purified by flash chromatography on silica gel
using ethyl acetate/methanol/conc, NH4OH to give 0.14 g of the desired product as a
yellow oil; MS (ES) m/z (relative intensity); 326 (M+H)+ (100).
3) 6-Methoxy-8-{4-[1-(quinoIin-8-ylmethyl)piperidin-4-vnpiperazin-l-
yl}quinoline (final product)
[0512] To a mixture of 6-methoxy-8-(4-piperidin-4-ylpiperazin-l-yl)quinoline
(Step 2,0.06 g) and 8-(bromo)methylquinoline (commercially available, 0.055 g) in
anhydrous dimethylsulfoxide (5 mL) was added anhydrous K2CO3 (0.051 g). The
resulting mixture was stirred at 70°C for 18 hours. The reaction mixture was cooled
to room temperature and partitioned between ethyl acetate and water. The organic
layer was washed with water and brine and was then dried over anhydrous Na2SO4,
filtered and concentrated on a rotary evaporator to give the desired product, which was
converted to its dihydrochloride salt in CH2Cl2 using 1N HCl/Et2O to give 0.31 g of a
light yellow solid; MS (ES) m/z (relative intensity); 468 (M+H)+ (100).
124


[0513] Using the synthetic methods described in previous examples, 8-(piperazin-
l-yl)quinoline (Oruz et al, J. Med. Chem. 45:4128 (2002)) and l-quinolin-8-yl-
piperidin-4-one (Example A, Step 5, above) were reacted with sodium
triacetoxyborohydride to give the desired product as a light yellow solid; MP. 194 -
196°C; MS (ES) m/z (relative intensity) 424 (M+H)+ (100).

[0514] To a hot suspension of 6-chloro-8-nitroquinoline (Mosher, et al., Org. Syn.
27:48 (1947), 0.8 g) in a mixture of ethanol/glacial acetic acid/water (2:2:1, 25 mL)
was added iron powder (0.5 g) portionwise. The resulting mixture was stirred at
reflux for 1.5 hours. The reaction was the cooled to room temperature, filtered
through celite and made basic by addition of solid Na2CO3. The aqueous mixture was
extracted with Et2O. The combined organic layers were dried over anhydrous MgSO4,
filtered and concentrated on a rotary evaporator to give the desired product (0.5 g) as a
yellow solid; MP. 70 - 73°C; MS (ES) m/z (relative intensity) 179 (M+H)+ (100).
125


[0515] 8-amino-6-chloroquinoline (Step 1, 0.49 g) and bis(chloroethyl)amine
hydrochloride (0.49 g) were dissolved in chlorobenzene (13 mL) and heated with
vigorous stirring at 135°C for 5 days. The reaction was cooled to room temperature,
diluted with water and extracted with Et2O. The aqueous phase was made basic by
addition of solid Na2CO3 and then extracted with Et2O. The combined organic layers
were dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator to
give the desired compound (0.20 g) as a yellow semi-solid; MS (ES) m/z (relative
intensity) 248 (M+H)+ (100).

[0516] Using the synthetic methods described in previous examples, 6-chloro-8-
(piperazin-l-yl)quinoline (Step 2) and l-quinolin-8-yl-piperidin-4-one (Example I,
Step 1, above) were reacted with sodium triacetoxyborohydride to give the desired
product as an off-white solid; MP. 269 - 271°C; MS (ES) m/z (relative intensity) 493
(M+H)+ (100).

[0517] Using the synthetic methods described in previous examples, 6-fluoro-8-
(piperazin-l-yl)quinoline (Example B, Step 3, above) and l-quinolin-8-yl-piperidin-4-
one (Example I, Step 1, above) were reacted with sodium triacetoxyborohydride to
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WO 2006/135839 PCT/US2006/022719
give the desired product as a white solid; MP. 256 - 258°C; MS (ES) m/z (relative
intensity) 477 (M+H)+(100).

[0518] To a suspension of 5-chloro, 8-hydroxy-quinoline (commercially available,
8.95 g) in 100 ml CH2Cl2, TEA is added (20 ml). The mixture becomes homogeneous
and is then cooled to -15°C. The suspension dissolved, then cooled to -15°C. A
solution of 21.1 g of triflic anhydride in 50 ml of CH2Cl2, is added drop by drop with
cooling. After complete addition, the reaction was stirred at -15°C for 1/2 hour; The
reaction was diluted with CH2C12, washed with a solution of NaHCO3, then with water
dried and the solvent was removed to give 15.0 g of product. MP: 80-83 °C. MS (ES)
m/z (relative intensity): 312 (MVH, 100

[0519] To a mixture of 5-chloro-8-(trifluoromethylsulfonyloxy)quinoline (Step 1,
4.0 g) in tetrahydrofuran (30 mL), was added 5.9 g of cesium carbonate (5.9 g), 2,2'-
bis(diphenylphosphino)-1,1'-binapthyl (B1NAP, 0.36 g), palladium acetate (0.12 g)
and tert-butoxycarbonylpiperazine (2.8 g). The mixture was refluxed for 5 hours. The
reaction mixture was then cooled to room temperature, diluted with Et2O, filtered
through celite and concentrated on a rotary evaporator. The crude material was
purified by flash chromatography on silica gel using CH2C12 to give 2.4 g of the
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WO 2006/135839 PCT/US2006/022719

[0520] To a solution of 5-chloro- 8-[(4-tert-butoxycarbonyr)-piperazin-l-
yl]quinoline (Step 2,2.2 g) in dioxane (10 mL), was added 4 N HCl/dioxane (5 mL).
The mixture was stirred at room temperature overnight. The formed precipitate was
collected by vacuum filtration, dissolved in water, made basic with solid NaHCO3 and
extracted with CH2Cl2. The combined organic layers were dried over anhydrous
Na2SO4, filtered and concentrated on a rotary evaporator to give 1.0 g of the,, desired
product as a brown semi-solid; MS (ES) m/z (relative intensity): 248 (M+H)+ (100).

[0521] Using the synthetic methods described in previous examples, 5-chloro-8-
(piperazin-l-yl)quinoline (Step 3) and l-quinolin-8-yl-piperidin-4-one (Example A,
Step 5, above) were reacted with sodium triacetoxyborohydride to give the desired
product as a beige solid; MP. 201 - 203°C; MS (ES) m/z (relative intensity) 459
(M+H)+ (100).

[0522] Using the synthetic methods described in previous examples, 2-methyl-8-
(piperazin-l-yl)quinoline (Oruz, etal., J. Med. Chem. 45:4128 (2002)) and 1-quinolin-
8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium
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triacetoxyborohydride to give the desired product as a light brown semi-solid; MS
(ES) m/z (relative intensity) 438 (M+H)+ (100).

[0523] Using the synthetic methods described in previous examples, 6-chloro-8-
(piperazin-l-yl)quinoline (Example O, step 2, above) and l-quinolin-8-yl-piperidin-4-
one (Example A, Step 5, above) were reacted with sodium triacetoxyborohydride to
give the desired product as a white solid; MP. 209 - 211°C; MS (ES) m/z (relative
intensity) 459 (M+H)+(100).

[0524] To a mixture of 2-bromo-4-(trifluoromethyl)aniline (commercially
available, 5.0 g), glycerol (3.8 g) and m-nitrobenzene sulfonic acid sodium salt 7.0 g)
was added 18 ml of 70 % sulfuric acid dropwise. The reaction temperature was raised
to 150° C for 4 hours. The mixture then was cooled to room temperature, poured on
ice water and filtered through celite. The filtrate was neutralized with NaOH and the
resulting precipitate was collected by vacuum filtration to yield 3.00 g of the title
compound as a brown solid that was used without further purification; MS (ES) m/z
(relative intensity): 277 (M+H)+ (100).
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WO 2006/135839 PCT/US2006/022719

[0525] To a mixture of 5-bromo-8-trifluoromethylsulfonyloxy)quinoline (Step 1,
2.83 g) in anhydrous tetrahydrofuran (38 mL), was added
tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 0.04 g) sodium tert-butoxide
(5.1 g), 2,2'-bis(diphenylphosphino)-l,l'-binapthyl (B1NAP, 0.04 g),
tetrakis(triphenylphosphine)-palladium (0) (0.04 g) and tert-butoxycarbonyl-
piperazine (2.33 g). The mixture was refluxed for 3 hours under a nitrogen
atmosphere. The reaction was then cooled to room temperature, diluted with ether,
filtered through celite and concentrated on a rotary evaporator. The crude material was
purified by flash chromatography on slilca gel using 100% CH2Cl2 to give 0.85 g of
the desired product as an off-white solid; MP. 105 - 107°C; MS (ES) m/z (relative
intensity): 332 (M+H)+(100).

[0526] To a solution of tert-butyl 4-[5-(trifluoromethyi)-8-quinolinyl]-l-
piperazine-caRboxylate(Step 2, 0.85 g) in 5 mL dioxane was added 5 mL of 4 N
HCl/dioxane. The mixture was stirred at room temperature overnight. The reaction
was concentrated on a rotary evaporator, dissolved in water, neutralized with aqueous
sodium hydroxide and extracted with CH2Cl2. The combined organic layers were
dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator to give
0.65 g of the desired product as an off-white solid; MP. 155-157°C; MS (ES) m/z
(relative intensity): 282 (M+H)+ (100).
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WO 2006/135839 PCT/US2006/022719

[0527] Using the synthetic methods described in preview; examples, 5-
(trifluoromethyl)-8-(piperazin-l-yl)quinoline (Step 3) and l-quinolin-8-yl-piperidin-4-
one (Example A, Step 5, above) were reacted with sodium triacetoxyborohydride to
give the desired product as a white solid; MP. 202 - 204°C; MS (ES) m/z (relative
intensity) 492 (M+H)+ (100).

[0528] Using the synthetic methods described in previous examples, 5-methoxy-;8-
(piperazin-l-yl)quinoline (prepared from 2-chloro-5-methoxyaniline using the
methodology described for the preparation of Example N, Step 3, above) and 1-
quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium
triacetoxyborohydride to give the desired product as a beige solid; MP. 218 - 220°C;
MS (ES) m/z (relative intensity) 454 (M+H)+ (100).

WO 2006/135839 PCT/US2006/022719
hydroxyquinoline using the methodology described for Example R, step 3, above) and
l-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium
triacetoxyborohydride to give the desired product as a yellow solid; MP. 222 - 224°C;
MS (ES) m/z (relative intensity) 442 (M+H)+ (100).

[0530] Using the synthetic methods described in previous examples, 1-(1-
benzofuran-3-yl)piperazine (Prepared from commercially available benzofuran-3-one
using the methodology described for Example F, step 2, above) and l-quinolin-8-yl-
piperidin-4-one (Example A, Step 5, above) were reacted with sodium
triacetoxyborohydride to give the desired product as a yellow solid; MP. 86 - 88°C;
MS (ES) m/z (relative intensity) 447 (M+H)+ (100).


WO 2006/135839 PCT/US2006/022719
[0531] A solution of ethyl 4,4,4-trifluoroacetoacetate (commercially available, 4
mL, 27.3 mmol, 1.05 eq.) in polyphosphoric acid (22 mL) was heated to 100°C. 2-
chloro-5-fluoroaniline (3.78 g, 26.0 mmol, 1 eq.) was added slowly to the stirred hot
solution. The resulting reaction mixture was further heated to 150°C and then stirred
at that temperature overnight (approximately 18 hours). The reaction was cooled to
room temperature and water was added carefully. The resulting light brown
precipitate was collected by vacuum filtration, washeu with water and dissolved in
ethyl acetate. The ethyl acetate solution was washed with brine, dried over anhydrous
MgSO4 and concentrated on a rotary evaporator. The crude product was purified by
flash chromatography on silica gel using hexane/ethyl acetate to give 3.54 g (51%
yield) of the desired product as an off-white solid; MP = 141-142; MS (ES) m/z
(relative intensity): 266 (M+H)+ (100).

[0532] To a solution of 8-Chloro-5-fluoro-2-(trifluoromethyl)quinolin-4-ol (Step
1, 3.54 g, 13.3 mmol, 1 eq.) in acetone (75 mL) was added anhydrous K2CO3 (3.88 g,
28.0 mmol, 2.1 eq.), followed by iodomethane (1.8 mL, 28.9 mmol, 2.17 eq.). The
resulting mixture was stirred at reflux for 1.5 hours. An additional aliquot of
iodomethane (1.8 mL, 28.9 mmol, 2.17 eq.) was added and reflux was continued for
an additional 1 hour. The reaction was cooled to room temperature, poured onto ice
and extracted with ethyl acetate. The combined organic layers were dried over
anhydrous MgSO4, filtered and concentrated on a rotary evaporator to give 3.72 g
(100% yield) of the desired product as a yellow solid, which was used in subsequent
reactions without further purification. An analytical sample was prepared by
recrystallization from hexane/ethyl acetate; MP = 198-200°C; MS (ES) m/z (relative
intensity): 280 (M+H)+ (100).
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[0533] To a solution of 8-chloro-5-fluoro-4-methoxy-2-(trifluoromethyl)quinoline
(Step 2,1.24 g, 4.45 mmol, 1 eq.) in anhydrous tetrahydrofuran (44 mL) was added
tris(dibenzylideneacetone)-dipalladium(0) (Pd2(dba)3, 0.125 g, 0.14 mmol, 0.03 eq.),
sodium tert-butoxide (0.69 g, 7.18 mmol, 1.61 eq.), 2-dicyclohexyl-phosphino-2'-
(N,N-dimethylamino)biphenyl (CYMAP, 0.054 g, 0.14 mmol, 0.03 eq.), and 1,4-
dioxo-8-azaspiro-4,5-decane (0.8 mL, 6.24 mmol, 1.4 eq.). The resulting mixture was
stirred at 70°C overnight (approximately 18 hours)under a nitrogen atmosphere. The
reaction was then cooled to room temperature, diluted with ether, filtered through a
plug of silica gel and concentrated on a rotary evaporator. The crude product was
purified by flash chromatography on silica gel using hexane/ethyl acetate to give 1.09
g (64% yield) of the desired product as a beige solid; MP = 101-103°C; MS (ES) m/z
(relative intensity): 387 (M+H)+ (100).

[0534] To a solution of 8-(l ,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5-fluoro-4~
methoxy-2-(trifluoro-methyl)quinoline (Step 3, 0.6 g, 1.56 mmol, 1 eq.) in
tetrahydrofuran (20 mL) was added 2N aqueous HC1 (6 mL). The resulting mixture
was stirred at 70°C for 5 hours. The reaction was cooled to room temperature, poured
into 1N aqueous sodium hydroxide and extracted with ethyl acetate. The combined
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organic layers were dried over anhydrous Na2SO4, and concentrated on a rotary
evaporator. The crude product was purified by flash chromatography on silica gel
using hexane/ethyl acetate to give 0.41 g of the desired product as a light yellow solid;
MP = 171-173C; MS (ES) m/z (relative intensity): 343 (M+H)+ (100).

[0535] To a solution of 1 -[5-fluoro-4-methoxy-2-(trifluoromethyl)quinolin-8-
yl]piperidin-4-one (Step 4, 0.31 g, 0.9 rxunol, 1 eq.) and 6-methoxy-8-(l-
piperazinyl)quinoline (Example A, Step 4,0.30 g, 1.23 mmol, 1.37 eq.) in anhydrous
methanol (20 mL) was added sodium cyanoborohydride (0.103 g, 1.64 mmol, 1.82
eq.). The resulting mixture was stirred overnight at room temperature under nitrogen
(app. 18 hr). An additional aliquot of sodium cyanoborohydride (0.10 g, 1.59 mmol,
1.76 eq.) was added and stirring at room temperature was continued overnight. The
resulting reaction mixture was poured into brine and extracted with ethyl acetate. The
organic layer was dried over anhydrous sodium sulfate and concentrated on a rotary
evaporator to a yellow oil. The desired product was isolated by chromatography on a
40 g silica column (1000 mL 20% acetone in hexane followed by 500 mL 30%
acetone in hexane) as a yellow solid (0.113 g, 22% yield). The free base was
converted to its trihydrochloride sesquihydrate salt by dissolving it in dichloromethane
(3 mL), adding diethyl ether (9 mL), cooling in an ice bath and adding 1M HCl/Et2O
(1 mL). The resulting yellow solid was collected by vacuum filtration, washed with
ether and dried in vacuo to give 0.152 g. MS (ES) m/z (relative intensity): 570
(M+H)+ (100).


[0536] 0.25 g (0.001mol) of l-(5-fluoro-quinolin-8-yl)-piperidin-4-one (Example
C, Step 3) and 0.25g (0.001mol) of 6-methoxy-8-piperazin-l-yl-quinoline (Example
A, Step 4) were stirred in 20 mL of anhydrous methanol. 1.1 eq, (0.07 gm) of sodium
cyanoborohydride was added and the reaction was stirred at room temperature for
eighteen hours. The reaction mixture was concentrated on a rotary evaporator and the
residue was taken up in ethyl acetate and washed with water. The organic layer was
dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator.
The desired product was obtained by flash chromatography on silica gel column using
ethyl acetate and converted to the trihydrochloride salt using methanolic HC1 to yield
0.15 gm (24%) of the title compound as a yellow solid. Mp: 200-202°C; MS (ES)
m/z (relative intensity): 472 (M+H)+ (100).


[0537] A mixture of 8-amino-6-methoxyquinoline (150.0 g, 0.862 mol) and bis(2-
chloroethyl)amine (219 g, 1.23 mol,) in 6 parts (volume of hexanol vs weight of 8-
amino-6-methoxyquinoline) of 1-hexanol (900 mL) was heated to 145°C and stirred
for 21 hours. Upon completion, the reaction mixture is cooled 50 - 60 °C, and 507 g
of aqueous NaOH solution was added slowly. The reaction mixture was cooled to 25
- 30°C and isopropyl acetate (750 mL) was added. The mixture was clarified through
a celite pad. The aqueous phase was then split off. The organic solution was treated
with a slurry of adipic acid (126 g, 0.862 mol) in isopropyl acetate (250 ml). The
resulting mixture was stirred for 16 hours to form 6-methoxy-8-(l-
piperazinyl)quinoline adipate salt. The adipate salt was filtered and washed with
isopropyl acetate (2x150 ml) and dried by nitrogen flow to give adipate of 6-Methoxy-
8-piperazin-l-yl-quinoline (186 g, 55% yield) with -97% HPLC area, 88% strength
purity in 51% yield.
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WO 2006/135839 PCT/US2006/022719
[0538] The salt can be recrystallized from a mixture of methanol and isopropyl
acetate if further purification is required. To purify the adipate salt, 580 g of the crude
adipate salt and 2.8 liter of methanol were mixed and heated to 65 °C and a dark
solution was obtained. To this solution was charged slowly 1.1 liter of isopropyl
acetate over 40 min at about 63 °C. The mixture was stirred at about 63 °C for about
1 h and cooled to 0-5°C. After stirring at 0-5 °C for 2 hours, the mixture was filtered
and washed with 300 ml of isopropyl acetate and dried with airflow. Yield, 395 g,
68.1% recovery yield.
[0539] To liberate 6-methoxy-8-(l-piperazinyl)quinoline from its adipate salt, 100
g (0.257 mol) of the adipate salt was added into a 2-L reactor followed by the addition
of 500 ml of dichloromethane. To this mixture was added 100 g of water followed by
the slow (in about 15 min) addition of 41 g of 50% sodium hydroxide solution to
maintain the pH in the 13-14 range, adding sodium hydroxide solution as necessary if
the pH is below 10. The organic bottom layer was separated and filtered through a
pad of activated basic aluminum oxide (100 g, 6.5 cm diameter x 3 cm depth). The
pad was washed with 100 ml of isopropyl acetate twice. The dichloromethane was
replaced by toluene by distillation under vacuum (450 to 500 mm Hg) while 3x150 ml
of toluene was added into the reactor until the final volume was about 135 ml. Some
white solid precipitated after distillation, the solid was removed by filtration, the filter
cake was washed with 50 ml of toluene. Final volume, 185 ml, purity 97.56%,
solution strength 27.4%)
2) 8-bromo-5-fluoroquinoline
[0540] To a 2-L reactor equipped with a mechanic agitator, a condenser, a
thermocouple, a baffle, and nitrogen inlet were charged 228 g of water, 200 g of 2-
bromo-5-fluoroaniline and 80 g of 4-nitrophenol. To this mixture was charged 96%
sulfuric acid in 10-30 min at 20-120°C. The mixture was heated to 135-140°C and
194 g of glycerol was charged into the reactor over two hours at 135-145°C. The
mixture was held at 135-145°C for 1 hour after the addition. The reaction mixture
was cooled to below 20-50°C and slowly transferred to a 5-L reactor containing 1100
g of water and 1210 g of toluene. The 2-L reactor was washed with 300 g of water
and the wash was combined into the 5-L reactor. The pH of the contents in the 5-L
reactor was adjusted to pH 8-10 by adding approximately 1233 g (1370 mL)
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WO 2006/135839 PCT/US2006/022719
ammonium hydroxide (28-30 % NH3) at 20-40°C. The mixture was stirred at room
temperature for 15 min and the solid by-product was filtered off while the filtrate was
retained. The filter cake was washed with 400 ml of toluene and the all the filtrate
was combined and charged a 3-L reactor. About 500 ml of 8.5% KOH solution was
charged into the 3-L reactor and stirred for 10 min and bottom aqueous layer was spit
off. A second portion of 500 ml of 8.5% KOH solution was added and the mixture
was stirred for 15 nun and the bottom aqueous layer was split off. Water 500 ml was
added and stirred for 15 min before the bottom aqueous layer was split off. The
organic layer was heated to distill off about 100-200 ml of toluene to azeotropically
remove water. A clear solution will be obtained. Typical yield 178g real 8-bromo-5-
fluoroquinoline, -75%.
[0541] Alternatively, 8-bromo-5-fluoroquinoline was prepared by adding a warm
mixture containing 2-bremo-5-fluoroaniline (100g, 1.0 eq), 4-nitrophenol (40g, 0.54 .
eq), and glycerol (97 g, 2.0 eq) over 1.5 hours to sulfuric acid (267 ml) and water (114 ,
mL) at 140-150°C. The initial mixture showed 37.8% 4-nitrophenol by relative HPLC
area%. Samples showed 4.7% 4-nitrophenol immediately after adding 50% of mixed
starting materials and 5.0% immediately after adding all of the materials. The yield
upon workup was 87.5%, with total impurities 0.29%. Addition of less (0.46 eq, 34 g) %
4-nitrophenol also successfully produced the intermediate of interest at acceptable
yield.
3) l-(5-fluoroquinolin-8-vl)piperidin-4-one
[0542] To a 5-L jacketed cylindrical reactor equipped with an impeller-style
agitator, condenser, thermocouple, and vacuum/nitrogen inlet was charged 2-L, 15%
toluene solution of 8-bromo-5-fmoroquinoline, 209 g of l,4-Dioxa-8-
azaspiro[4.5]decane. Meanwhile in a 500-mL Erlenmeyer flask, a suspension of 16.5
g (26.5 mmol) ±-[1,1-binaphthalene]-2,2'-diylbis[diphenyl-Phosphine, and 6.08 g
(6.64mmol)tris[μ-[(l,2-η:4,5-ri)-(1E,4E)-l,5-diphenyl-l,4-pentadien-3-
one]]dipalladium in 260 g of toluene was prepared. This freshly made suspension was
charged into the 5-L reactor followed by a rinse of 170 g of toluene. 166 g sodium
tert-butoxide was then charged into the reactor followed by a rinse with 430 g of
toluene. The reactor was degassed by vacuum to less than 125 mmHg and then filled
with nitrogen to atmosphere three times. The mixture was then heated to 50-60 °C
and stirred for 1 h and then heat to 65-75 ° and stirred at this temperature for about 10
139

WO 2006/135839 PCT/US2006/022719
hours. The mixture was cooled to 40-50°C and then quenched with 800 g of water.
The lower aqueous layer was split off and the volume of the organic layer was reduced
to about 1.5 L by vacuum distillation. To this residual was charged 2.28 kg of 20%
sulfuric acid at 25-30 °C. The mixture was stirred for an hour and was clarified by
filtration and a bi-phase filtrate was obtained. The aqueous phase was split and
retained. Toluene 870 g was added to the aqueous solution and the mixture was
neutralized by slowly adding 770 g 50% sodium hydroxide solution. The lower
aqueous layer was split off and extracted with 600 g of toluene. The organic layers
were combined and the volume of the reaction was reduced to about 1 L by vacuum
distillation. The residue was cooled to room temperature and 480 g of toluene was
charged. The mixture was heated to 45-55 °C to form a clear solution, which was
filtered through a celite/charcoal pad to remove palladium. The filtrate was
concentrated by vacuum distillation to about 0.7 L and diluted with 620 g heptane,
cooled to -15 to-5 °C to form a slurry. The solid was collected by filtration. The
product was dried by air flow at room temperature. Typical yield is about 70%.
4) 5-fluoro-8-{4-[4-(6-methoxvquinolin-8-yl)piperazin-l-yllpiperidin-l-
yl}quinoline
[0543] Toluene (118 g), sodium triacetoxyborohydride (44.5 g) were mixed at 0°G
to room temperature. To this mixture was charged a premixed toluene solution of 6-
methoxy-8-(l-piperazinyl)quinoline (Step 1, 160 g, 27.4wt% in toluene) and l-(5-
fluoroquinolin-8-yl)piperidin-4-one (Step 3,41 g). The resulting mixture was stirred
for 2 to 3 hours at about 30°C. KOH solution (443 g 9% in water) was charged to
quench the residual sodium triacetoxyborohydride. Heptane (118 g) was added to
further precipitate the product. The product was then filtered and washed with ethanol
(2x100 ml). Yield 68 g, 86%. This crude product (67 g) was dissolved in 586 g
dichloromethane and passed through a charcoal/celite pad to remove palladium. The
dichloromethane was distilled off while 400 g of ethanol was slowly added at the
same time. The resulting slurry was filtered and washed with ethanol twice (65 g
+100 g). The product was dried in oven at 55°C overnight. Purification recovery yield
59.9 g, 89.4%.
140


[0544] 6-methoxy-8-(l-piperazinyl)quinoline (Example P, Step 1) is also prepared
as shown in the reaction scheme above. To a 2 L reactor equipped with a mechanic
stirrer, an addition funnel, a thermocouple, nitrogen inlet and a bottom outlet was
added 442 g of .water, 134.5 g (0.5 mol) compound A and 177 g methyl tert-butyl
ether. To this mixture was slowly added 125 ml 5 N sodium hydroxide in 20 min. The
mixture was stirred for 10 min and the aqueous layer was split off. The organic layer
was washed with 20% aq sodium chloride solution twice (2x200 g). The methyl tert-
butyl ether was distilled off and the product was obtained as an oil, crude yield: 117
g~100% yield (still containing trace amount solvent).
[0545] To a 1-L reactor a mechanic stirrer, a thermocouple, and nitrogen inlet was
charged with 380 g of butanol, 42 g of 8-amino-6-methyoxyquinoline, and 97 g of
compound B (nor-mustard free amine). The mixture was heated to 100°C for 18 hours
before cooled to 0-5 °C. The solid was formed upon cooling and was filled with
nitrogen protection (solid is hygroscopic). The filter cake was washed with 100 g cold
butanol and 2x 200 g of MTBE. The solid was dissolved in 160 g of water to obtain
an orange solution. This orange solution was slowly charged into a 2-L reactor
containing a potassium hydroxide solution prepared with 537 g water and 60 g 45%
KOH. The product was precipitated upon addition into the base. The slurry was stirred
for 1 h and then filtered. The filter cake was washed with 100g water, 100g MeOH
and 100 g methyl tert-butyl ether. The product was dried under vacuum at 50°C.
Weight = 48.2 g, 60%
[0546] To a 100 ml flask equipped with a stirrer, a thermocouple, a condenser and
nitrogen inlet was charged ethanol (2B) 27 g, compound C (2 g), methylcyclohexene
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WO 2006/135839 PCT/US2006/022719
(10 g) and 0.6 g of dry 10% palladium on carbon. The mixture was heated to reflux for
30 h and cooled to ambient temperature. The palladium on carbon was filtered off, the
solvent was removed by rotavap, and the resulting compound isolated (weight 1.7 g
(>100%, the product contained small amount of solvent)).

[0547] l-(5-fluoroquinolin-8-yl)piperidin-4-one (Example P, Step 3) is also
prepared as shown in the reaction scheme above. To a 500 ml flask equipped with a
stirrer, a thermocouple, a condenser and nitrogen inlet were charged 50 g 2-bromo-5-
fluoroaniline and 60 g glycerol. The mixture was heated to 60°C and 55 g
nitrobenzene sulfonic acid was charged in portion. The mixture was then heated to
100-110 °C, started charge 200 ml 70% sulfuric acid. After sulfuric acid addition, the
mixture was heat to 130°C and stirred for 3 hours before cooled to room temperature.
Water (300 g) was added and a grayish by product was filtered off. The filtrate was
slowly added into a 2-L reactor containing a mix of 420 g 50% NaOH, 420 g of water,
352 g methyl tert-butyl ether. After filtering off small amount solid, the aqueous layer
was split off and the organic layer was washed with 10% NaOH (2x100 ml), 20%
NaCl (2x200 ml), the solvent was removed, weight 56 g, 89.8%.
[0548] To a 2-L reactor with a stirrer, a thermocouple, a condenser and nitrogen
inlet were charged 8-bromo-5fluoroquinoline (50 g), tetrahydrofuran (795 g),
Pd2(dba)3 (3.78 g), Cymap (1.6 g), and l,4-Dioxa-8-azaspiro[4.5]decane (47.3 g). the
mixture was heated to reflux (66°C) and the reaction was complete. The reaction
mixture was quenched into a 5 L reactor containing 1000 g of water and 640 g of
MTBE. The bottom aqueous layer was split off and the organic layer was washed with
5% NaOH (1120 g) and 20% NaCl (2x100 g). The solvent was evaporated, weight 87
g vs 79.4 g by theory.
[0549] The remaining steps are as described above in Example P, Step 3.
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DD) Preparation of 6-methoxy-8-[4-(l-(5-fluoro)-quinolin-8-yl-piperidin-4-yl)-
piperazin-l-yl]-quinoline trisuccinate salt (Polymorph Form A)
[0550] 6-Methoxy-8-[4-(l-(5-fluoro)-quinolia-8-yl-piperidin-4-yl)-piperazin-l-
yl]-quinoline (1.5089 g) was slurried in 100 mL of dichloromethane (99.8% HPLC) to
obtain a clear light yellow solution of free base. Succinic acid (99%; 258.6 mg) was
dissolved in 17 mL of acetone (99% HPLC). Then 15.275 mL of the succinic acid
solution was added to 20 mL of the free base solution slow, No immediate
precipitation was observed. The resulting solution was allowed to evaporate to dryness
at room temperature. The solid was analyzed by powder X-ray diffraction and found
to be crystalline having Form A.
EE) Preparation of 5-Fluoro-4-methoxy-8-(4-(4-(6-methoxy-quinoIin-8-yl)-
piperazin-l-yl)-piperidin-l-yl)-2-trifluoromethyl-quinoline disuccinate
salt

[0551] The free base of 5-fluoro-4-methoxy-8-(4-(4-(6-methoxy-quinolin-8-yl)-
piperazin-l-yl)-piperidin-l-yl)-2-trifluoromethyl-quinoline was prepared as described.
in Example Z. This compound was further isolated by conversion to a disuccinic acid.
To a 12-L reactor equipped with heating mantle, thermocouple and nitrogen inlet were
charged 124 g of succinic acid and 2470 g of acetone. The mixture was heated to 50°C
and a colorless solution was formed. Meanwhile, in a 3-L flask were charged 240 g of
5-fluoro-4-methoxy-8-(4-(4-(6-methoxy-quinolin-8-yl)-piperazin-l-yl)-piperidin-l-
yl)-2-trifluoromethyl-quinoline and 2250 g of tetrahydrofuran (THF). 5-Fluoro-4-
methoxy-8-(4-(4-(6-methoxy-quinolin-8-yl)-piperazin-l-yl)-piperidin-]-yl)-2-
trifluoromethyl-quinoline in THF mixture was heated to 50°C and a yellow solution
was achieved. This yellow solution was slowly (over the course of about 3 hours)
charged into the 12-L reactor while maintaining both solutions at a temperature of
about 50°C. The resulting slurry was stirred over night at room temperature, and then
cooled to 5-10°C. After stirring at 5-10 °C for 2 hours, the slurry was filtered and the
product was washed with acetone 3x600 ml. The product was dried with airflow at
room temperature for 3 hours.
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[00100] The weight of the resulting product was 311 g, or about 91.6% yield.
NMR analysis indicated that the compound was the disuccinate salt form of 5-fluoro-
4-methoxy-8-(4-(4-(6-methoxy-quinolin-8-yl)-piperazin-l-yl)-piperidin-l-yl)-2-
trifluoromethyl-quinoline. In addition, residual solvents were found at concentrations
of 0.047% for acetone, 0.027% for THF, and 0.14% for water.
BIOLOGICAL ASSAYS AND PROCEDURES
Novel Object R6cognition Model
[0552] Male Long-Evans hooded rats (~200g at the time of testing) were
individually housed with ad libitum access to food and water. Novel object
recognition (NOR) training and testing was performed in a circular field (diameter
~70cm, 30cm high) constructed out of plastic and containing soiled bedding (without
feces). The field was surrounded by black curtains to mask extra-field cues and was
located in a dimly lit room (-10 lux at the level of the area) in the presence of white
noise (-65 dB). Animal performance was tracked by video and monitored by an
experimenter located outside of the testing room. Objects, constructed with Duplo®
(Lego), could be affixed to the floor in one of four locations spaced evenly around the'
field approximately 10 cm from the field's edge. To avoid possible olfactory cues,
multiple copies of the objects were used throughout the study and were cleaned with a-
30% ethanol solution between animals.
[0553] The visual recognition task was divided into 3 sessions - habituation, a
sample trial and a choice trial. During habituation the animals were placed into the
field containing 2 identical yellow cubes (~10cm x 10cm x 10cm) and were allowed to
explore the field for ten minutes. Following habituation, rats were returned to their
home cage. One day after habituation, animals were dosed with a test compound and
following the pretreatment interval the sample trial was initiated. During the sample
trial, rats were allowed to explore the field, now containing two identical stimuli
(complex, multicolored, Duplo objects; -10cm x 10cm x 10 cm) located at opposing
compass points, for 5 minutes. The amount of time investigating the objects was
recorded for the entire trial. Investigation was defined as orientation toward the object
with the nose of the rat within <2cm of the object. Following the sample trial rats
were returned to their home cages for the 48 hour inter-trial interval and then tested in
the choice trial for recognition memory. The choice trial consisted of a 5 minute
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exploration of the field containing both a familiar, previously explored, object and a
novel object with an investigator again recording contact time. The location of the
objects, counteRbalanced across treatment groups, remained constant for each animal
during the habituation, sample and choice trials.
[0554] The effect of treatment on object exploration during trial one was
examined using a one-way ANOVA on total contact time followed by Fisher's LSD
group mean pair-wise comparisons. The amount of time exploring the novel and
familiar objects across treatment groups was analyzed using a repeated measures
ANOVA followed by Fisher's LSD post-hoc comparisons. Significantly more time
spent exploring the novel object than the familiar one represents intact recognition
memory for that treatment group. Control and untreated animals show no significant
differences between familiar and novel object exploration following the 48 hour delay
indicating no memory for the sample trial (significant differences are evident with
shorter delays).
[0555] Treatments: Animals were treated with a compound of the invention 60
minutes prior to the sample trials. Each candidate compound was dissolved in the
appropriate vehicle and administered orally at 1 ml/kg.
[0556] R6presentative compounds of the invention were tested according to the
protocol described. In these experiments, a positive effect of a compound on
recognition memory is demonstrated by animals spending significantly more time
exploring the novel object than the familiar one. It was found that the tested
compounds had a positive effect on recognition memory. Doses of the representative
compounds of the invention that were identified as having a positive effect in this
assay were dosed at 0.3 - 10 mg/kg p.o., with 10 mg/kg p.o. being the highest dose
tested. These data demonstrate that selected compounds of the invention are useful
for improving recognition memory, and that the protocol is suitable for identifying
compounds that have a positive effect on recognition memory.
Synergy of Test Compounds with Acetylcholinesterase Inhibitors
[0557] Acetylcholinesterase inhibitors are currently used to treat mild cognitive
deficits resulting from Alzheimer's disease. However, the use of acetylcholinesterase
inhibitors is hindered by the side effects often seen with this class of therapeutic agent,
and have limited efficacy. R6presentative compounds of the invention were shown to
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have a synergistic effect on the cognitive enhancing properties of a representative
acetylcholinesterase inhibitor, Aricept®, lowering the dose of both agents required to
obtain efficacy in the Novel Object R6cognition Model.
[0558] Novel Object R6cognition Model: The Novel Object R6cognition Model
was employed as described above. Sub-threshold doses (doses that did not provide a
positive effect on recognition memory) of Aricept® and representative compounds of
this invention were administered to test animals and their effects on recognition
memory were recorded as described above.
[0559] Treatments: Animals were treated with a compound of the invention 60
minutes prior to the sample trials. Each candidate compound was dissolved in an
appropriate vehicle and administered orally. The same animals were then treated with
Aricept® 30 minutes prior to the sample trials. Aricept® was dissolved in an
appropriate vehicle and administered intraperitoneally.
[0560] Animals were separately administered sub-threshold doses of Aricept® (0.5
mg/kg i.p.) or a representative compound of the invention (0.1 mg/kg p.o.). When
administered separately, the contact times for the animals in the familiar and novel
environments were not statistically different (P<0.05). Co-administration of Aricept®
and the each of candidate compounds at the same doses used in the separate
administration test for each agent resulted in a statistically significant decrease in the .
contact time for the familiar environment compared to the novel environment
(P<0.05). The decrease in contact time averaged more than 10 seconds. These data
suggest co-administration of a representative compound of the invention and a
cognitive enhancer resulted in a positive effect of recognition memory, as
demonstrated by the animals spending significantly more time exploring the novel
object than the familiar one. These data demonstrate that this test is effective in
identifying a synergistic effect between representative compounds and cognitive
enhancers to enhance cognition.
Treatment of Sexual Dysfunction
[0561] An animal model was used to demonstrate the utility of treating or
preventing sexual dysfunction, e.g., sexual dysfunction associated with SSRI
treatment, with compounds of this invention. The animal model is based on the
finding that sexually experienced rats that are administered an SSRI, a drug used to
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treat certain conditions such as depression, display a reduction in the number of non-
contact penile erections. SSRI treatment is associated with sexual dysfunction in
human subjects. In general, the animal model exposes sexually experienced male rats
(Sprague-Dawley rats) to female rats in estrous in a novel testing arena that is not the
regular housing environment. The number of non-contact penile erections is assayed
over a specified test period, e.g., 30 minutes (Sukoff, R1zzo, et ah, 2006, Society for
Neurosci. Abstr. 559.4; United States Application Serial No. 60/682,3379, filed May
19,2005). In the experiments described herein, animals were generally treated either
with 0.9% saline (vehicle) or a drug (i.e., a compound of the invention) in the vehicle.
[0562] The ability of fluoxetine, an SSRI associated with sexual dysfunction in
humans, to cause sexual dysfunction in the animal model was tested by examining a
10 mg/kg dose of fluoxetine or vehicle alone (0.9% saline), each administered
intraperitoneally, once daily for 14 days, on the number of non-contact penile. .-•,
erections over a 30 minute trial period. Fluoxetine produced a decrease in sexual
function under these experimental conditions compared to treatment with vehicle
alone. These data demonstrate that sexual dysfunction is induced in the animal model
using SSRIs, thereby providing support for the validity of using the animal model.
[0563] To examine the time course of the effects of a drug that causes sexual
dysfunction, rats that were handled and tested as described above were treated acutely:
rats were treated with vehicle for 6 days, and on the test day (day 7) instead of vehicle,
the animals received a single dose of fluoxetine in vehicle (i.p.). For a subchronic (7
day) study, fluoxetine was administered each day for 7 days and the animals were
evaluated on test day 7. For the chronic 14 day study, fluoxetine was administered
each day for 14 days and the animals were tested on day 14. Each fluoxetine dose was
10 mg/kg in vehicle and was delivered i.p. on each of the test days as described above.
The testing session for each section of the study was begun immediately following
compound administration and the behavior observed for 30 minutes immediately
following the drug administration.
[0564] It was found that both a sub-chronic and chronic administration of
fluoxetine were associated with a significant increase in sexual dysfunction, further
demonstrating the utility of the animal model for sexual dysfunction testing.
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[0565] To test the ability of the compounds of this invention to ameliorate the
effects of sexual dysfunction, sexually experienced rats were administered fluoxetine
using a subchronic (7 day) or chronic (14 day) schedule and then tested for sexual
function as described above. A single acute dose of a test compound given
intraperitoneally after 7 or 14 days of fluoxetine ameliorated sexual dysfunction as
demonstrated by the compound's ability to significantly reverse the fluoxetine-
induccd decrease in non-contact penile erections. Doses of selected tea-, compounds of
the invention that were effective in this model were 0.1-1 mg/kg i.p., with 1 mg/kg
i.p. being the highest dose tested.
[0566] To further test the ability of compounds described herein to ameliorate the
effects of sexual dysfunction, sexually experienced rats were co-administered
fluoxetine (10 mg/kg i.p.) and selected compounds of the invention once daily for 14
days and then tested for sexual function as described above. Chronic dosing of the
selected compounds of this invention ameliorated the sexual dysfunction induced by
chronic dosing of fluoxetine, as demonstrated by the compound's ability to
significantly reverse the fluoxetine-induced decrease in non-contact penile erections.
Doses of the selected test compounds that were effective in this model were 0.3 - 1
mg/kg i.p., with 1 mg/kg i.p. being the highest dose tested.
[0567] These data demonstrate this test is successful in identifying compounds
that can be used to treat sexual dysfunction associated with treatment with
antidepressants (e.g., SSRI's). Moreover, these data demonstrate the test is useful for
identifying compounds that are efficacious for treating sexual dysfunction, e.g., that is
associated with antidepressant treatment, whether the treatment with the test
compound is initiated at the same time as antidepressant treatment (e.g., SSRI
treatment) or when the treatment with the test compound is provided after initiation of
treatment with the antidepressant. Further, these data demonstrate that the candidate
compounds tested ameliorated sexual dysfunction associated with treatment with
antidepressants (e.g., SSRI'S) and suggest the candidate compounds are efficacious
for treating sexual dysfunction.
Enhancement of SSRI Activity
[0568] SSRIs are currently used to treat depression in humans. They are thought
to exert their antidepressant effect by increasing serotonin levels in the brain. One
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liability of SSRIs is a delay between initiation of drug treatment and onset of
antidepressant action, which can be 2-4 weeks. This delay in onset of action is
thought to be associated with an acute stimulation of pre-synaptic 5-HT1A
autoreceptors induced by the elevated levels in serotonin (which result from inhibition
of serotonin re-uptake). These autoreceptors are responsible for controlling serotonin
release, responding to elevated serotonin levels by inhibiting neurotransmitter release.
The 2-4 week delay is thought to be the time required for these autoreceptors to
become desensitized. A 5-HT1A antagonist that acts to block the pre-synaptic
autoreceptor would be expected to inhibit the contribution of these autoreceptors to
acute serotonin levels. The result should be an acute, sustained increase in serotonin
levels and a reduction in the onset of SSRI drug action.
[0569] The ability of the compounds of this invention to reduce time for onset of
action of the representative SSRI fluoxetine was assessed using in vivo microdialysis.
Using 2-3% halothane anesthesia (Fluothane; Zeneca, Cheshire, UK), male Sprague-
Dawley rats (280-350 g; Charles R1ver, Wilmington, MA) were secured in a
stereotaxic frame with ear and incisor bars (David Kopf, Tujunga, CA) while a
microdialysis guide cannula (CMA/12, CMA Microdialysis, Sweden) was directed
above the dorsal lateral frontal cortex (A/P +3.2 mm, M/L -3.5 mm, D/L -1.3 mm).
Coordinates were taken with a flat skull using the rat brain atlas of Paxinos and
Watson (1986). The guide cannula was secured to the skull with two stainless-steel
screws (Small Parts, Roanoke, VA) and dental acrylic (Plastics One, Roanoke, VA).
Following a 24 h post-operative recovery, animals were individually housed in
Plexigias cages (45 cm2) where they had free access to water and standard rat chow.
[0570] For in vivo neurochemical experiments, a microdialysis probe (CMA/12;
active membrane length 2mm; OD 0.5 mm; 20 kD cut-off) was pre-washed with
artificial CSF (aCSF; 125mM NaCl, 3mM KC1,0.75mM MgSO4 and 1.2mM CaCl2,
pH 7.4) according to the manufacturers specifications. On the morning of the study,
probes were inserted, via the guide cannula, into the frontal cortex and perfused with
aCSF at 1 μl/min. Following a 3 hour stabilization period, three control samples (20
μ1) were collected to establish a steady baseline. Immediately following the last
baseline sample, animals were treated with the compound of the invention (10 mg/kg
p.o. in 2% Tween™, 0.5% methyl cellulose, using a dose volume of 1 ml/kg). Thirty
minutes later rats were dosed with vehicle or fluoxetine (30 mg/kg s.c). Subsequent
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microdialysis samples were collected for 3 h post-injection and analyzed for 5-HT
content by high performance liquid chromatography (HPLC). The HPLC conditions
have been described previously (Beyer etal, J Psychopharmacol. 16(4): 297-304
(2002)). All neurochemical data were acquired using the Atlas software package
(Thermo Labsystems, Beverly, MA) and compared to an external standard curve. The
fmol concentrations of all neurotransmitters during the baseline samples were
averaged and this value denoted as 100%. Subsequent sample values were expressed
as a percent change from this preinjection baseline value (or % change from baseline).
Neurochemical data, excluding preinjection values, were analyzed by a two-way
analysis of variance (ANOVA) with repeated measures (time). Post-hoc analyses
were made using the Bonferroni / Dunns adjustment for multiple comparisons.
[0571] Acute treatment with fluoxetine did not increase serotonin levels in the
fromal cortex of text animals. However, co-administration of representative
compounds of the invention caused a significant increase in fronatal cortex serotonin
levels. R6presentative compounds of this invention had no effect on frontal cortex
serotonin levels when administered. Doses of representative compounds of this
invention that were effective in enhancing the effect of acute fluoxetine treatment
were 3-10 mg/kg p.o., with 10 mg/kg p.o. being the highest dose tested. These data
demonstrate this test is effective in identifying compounds of the invention that are
able to shorten the time to onset of action for SSRIs.
Cell line
[0572] The PCR cloning of the human 5-HT1A receptor subtype from a human
genomic library has been described previously (Chanda et al., Mol. Pharmacol.,
43:516 (1993)). A stable Chinese hamster ovary cell line expressing the human 5-
HT1A receptor subtype (h5-HT1A.CHO cells) was employed throughout this study.
Cells were maintained in DMEM supplemented with 10% fetal calf serum, non-
essential ammo acids and penicillin/ streptomycin.
Radioligand binding
[0573] Radioligand binding assays were performed as described in Dunlop, J. et
al., J. Pharmacol, and Toxicol. Methods 40: 47-55 (1998), which is incorporated by
reference. Cells were grown to 95-100% confluency as a monolayer before
membranes were harvested for binding studies. Cells were gently scraped from the
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culture plates, transferred to centrifuge tubes, and washed twice by centrifugation
(2000 rpm for 10 min., 4°C) in buffer (50 mM Tris; pH 7.5). The resulting pellets
were aliquoted and placed at -80°C. On the day of assay, the cells were thawed on ice,
and resuspended in buffer. Studies were conducted using [3H]8-OH-DPAT as the
radioligand. The binding assay was performed in 96 well microtiter plates in a final
total volume of 250 μL of buffer. Competition experiments were performed by using
seven different concentrations of unlabelled drug and a final ligand concentration of
1.5 nM. Non-specific binding was determined in the presence of 10 μM 5HT.
Saturation analysis was conducted by using [3H]8-OH-DPAT at concentrations
ranging from 0.3-30 nM. Following a 30 minute incubation at room temperature, the
reaction was terminated by the addition of ice cold buffer and rapid filtration using a
M-96 Brandel Cell Harvester (Gaithersburg, MD) through a GF/B filter presoaked for
30 minutes in 0.5% polyethyleneimine. Table 1 provides Ki values for the tested
compounds.
cAMP measurements
[0574] Measurements were performed as described in Dunlop, J. et al., supra.
Assays were performed by incubating the cells with DMEM containing 25 mM
HEPES, 5 mM theophylline and 10 μM pargyline for a period of 20 minutes at 37°C.
Functional activity was assessed by treating the cells with forskolin (1 uM final
concentration) followed immediately by test compound (6 different concentrations)
for an additional 10 minutes at 37°C. In separate experiments, 6 concentrations of
antagonist were preincubated for 20 min prior to the addition of 10 nM 8-OH-DPAT
and forskolin. The reaction was terminated by removal of the media and addition of
0.5 ml ice cold assay buffer. Plates were stored at -20°C prior to assessment of cAMP
formation by a cAMP SPA assay (Amersham).
[0575] Compounds of the invention were tested according to the protocol
described. The data demonstrate the protocol is effective for identifying compounds
that have 5-HT1A agonist activity and 5-HT1A antagonist activity. 5-HT1A agonist
activity is demonstrated by inhibiting the forskolin-induced increase in cAMP levels
and the results reported as EC50 values (Table 1, "Agonist Activity EC50").
Compounds having 5-HT1A antagonist activity show no effect on forskolin-induced
increases in cAMP levels on their own, but block the 8-OH-DPAT-induced inhibition
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of forskolin-stimulated increases in cAMP levels. R6sults are required as IC50 values
(Table 1, "Antagonist Activity IC50")

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CLAIMS
What is claimed is:
1. A compound of Formula (F):

and pharmaceutically acceptable salts and hydrates thereof,
wherein
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14,, R1s. and R16,
are each independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
aJkenyl, or (C2-C6)-alkynyl, halogen, -CF3, -NO2, -CN, -OR25, -
OSO2R25, -SR25, -SO2R25, -SO2N(R25)2, -N(R-25)2, -C(O), -COR25,
-CO2R25, -NR25CO2R25, -NR25COR25, -NR25CONOR25, or
-CON(R25)2;
Ra and Rb are each independently -H or -CH3;
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-
C6)-alkenyl, or (C2-C6)-alkynyl; and
n is 0, 1 or 2.
2. The compound or pharmaceutically acceptable salt of the compound of
claim 1, wherein R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3.
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3. The compound or pharmaceutically acceptable salt of the compound of
claim 1 or claim 2, wherein R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -
NO2,or-CN.
4. The compound or pharmaceutically acceptable salt of the compound of
any one of claims 1 to 3, wherein R10 is -H, (C1-C6)-alkyl, -OR25, halogen or
-CF3)-NO2,or-CN.
5. The compound or pharmaceutically acceptable salt of the compound of
any one of claims 1 to 4, wherein R12 is -H, (C1-C6)-alkyl, -OR25, halogen or
-CF3, -NO2,or-CN.
6. The compound or pharmaceutically acceptable salt of the compound of
claim 1, wherein R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and R9 is -
H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2, or -CN.
7. The compound or pharmaceutically acceptable salt of the compound of
claim 1, wherein R9 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
one of R1, R2, R3, R4, R5 and R6 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3;
Ra and Rb are each independently -H or -CH3; and the remaining substituents
are each hydrogen.
8. The compound or pharmaceutically acceptable salt of the compound of
claim 1, wherein R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of
R7, R8, R9, R10, R11, and R12 is -H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2
or-CN.
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WO 2006/135839 PCT/US2006/022719
9. The compound or pharmaceutically acceptable salt of the compound of
claim 1, wherein R1 is -H, -CF3 or (C1-C6)-alkyl; R4 and R5 are each
independently ~H, halogen, -OR25, or -CF3; and R7, R8, R9, R10, R11, and R12
are each independently -H, halogen, -alkyl, -OR25, -CF3, or -NO2; R16 is -H or
-CH3.
10. The compound or pharmaceutically acceptable salt of the compound of
claim 1, wherein any one of R1, R2, R3, R4, R5, and R6 is -H, (C1-C6)-alkyl,
-OR25, halogen or -CF3; and any one of R7, R8, R9, R10, R11, and R12 is -H,
(C1-C6)-alkyl, -OR25, halogen, or -CF3, -NO2, or -CN.
11. The compound or pharmaceutically acceptable salt of the compound of
claim 1, wherein any one of R1, R2, R3, R4, R5, and R6 is -H, (C1-C6)-alkyl,
-OR25, halogen or -CF3; and any two of R7, R8, R9, R10, R11, and R12 are each
independently ~H, (C1-C6)-alkyl, -OR25, halogen, or -CF3, -N02, or -CN.
12. The compound or pharmaceutically acceptable salt of the compound of
claim 1, wherein any one of R1, R2, R3, R4, R5, and R25 is -H, (C1-C6)-alkyl,
-OR25, halogen or -CF3; and any three of R7, R8, R9, R10, R11, and R12are each
independently is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3, -NO2, or -CN.
13. The compound or pharmaceutically acceptable salt of the compound of
any one of claims 1 to 12, wherein R25 is (C1-C6)-alkyl.
14. The compound or pharmaceutically acceptable salt of the compound of
any one of claims 1 to 13, wherein n is 1.
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15. A compound of Formula (I"):

wherein R1, R2, R3, R4, R5. Rs, R7, R7', R8, R9, R10, R11, R12,
R13, R14,, R15, and R16, are each independently -H, (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen, -CF3,
-NO2, -CN, -OR25, -OSO2R25, -SR25, -SO2R25, -SO2N(R25)2! -N(R25)2,
C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25, -NR25CON(R25)2,
or-CON(R25)2;
Ra and Rb are each independently -H or -CH3;
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl; and
where the piperidine group can be attached to the non-hetero
atom containing ring of the quinoline through positions R7, R7', R8, or
R9.
16. The compound or pharmaceutically acceptable salt of the compound of
claim 15, wherein any one of R1, R2, R3, R4, R5, and R6 is -H, (C1-C6)-alkyl,
-OR25, halogen or -CF3; and any one of R7, R7', R8, R9, R10, R11, and R12 is -H,
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WO 2006/135839 PCT/US2006/022719
(C1-C6)-alkyl, -OR25, halogen or -CF3, -NO2, or -CN, except for the R group
through which the piperidine is connected.
17. The compound or pharmaceutically acceptable salt of the compound of
claim 15, wherein R5 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and any
one of R7, R7', R8, R9, R10, R11; and R12is -H, (C1-C6)-alkyl, -OR25, halogen, or
-CF3, -NO2, or -CN, except for the R group through which the piperidine is
connected.
18. The compound or pharmaceutically acceptable salt of the compound of
claim 15, wherein R5 is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3; and any
two of R7, R7', R8, R9, R10, R11, and R12 are each independently -H, (C1-C6)-
alkyl, -OR25, halogen, or -CF3, -NO2, or -CN, except for the R group through
which the piperidine is connected.
19. The compound or pharmaceutically acceptable salt of the compound of
claim 15, wherein R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and any
three of R7, RT, R8, R9, R10> R11, and R12 are each independently -H, (C1-C6)-
alkyl, -OR25, halogen, or -CF3, -NO2, or -CN, except for the R group through
which the piperidine is connected.
20. The compound or pharmaceutically acceptable salt of the compound of
claim 15, wherein R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and R7' is
-H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN, and the remaining
substituents are each hydrogen except for the R group through which the
piperidine is connected.
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21. The compound or pharmaceutically acceptable salt of the compound of
any one of claims 15 to 20, wherein R25 is (C1-C6)-alkyl.
22. The compound or pharmaceutically acceptable salt of the compound of
any one of claims 15 to 21, wherein the piperidine is connected through R7.
23. The compound or pharmaceutically acceptable salt of the compound of
any one of claims 15 to 21, wherein the piperidine is connected through R7'.
24. The compound or pharmaceutically acceptable salt of the compound of
any one of claims 15 to 21, wherein the piperidine is connected through R8.
25. The compound or pharmaceutically acceptable salt of the compound of
any one of claims 15 to 21, wherein the piperidine is connected through R9.
26. A compound of Formula (I"a):

wherein R1, R2, R3, R4, R5, R6, R7', R8, R9, R10, R11, R12, R13,
R11, R15, and R16, are each independently -H, (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen, -CF3,
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-NO2, -CN, -OR25, -OSO2R25, -SR25, -SO2R25, -SO2N(R25)2, -N(R25)2, -
C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25, -NR25CON(R25)2,
or-CON(R25)2;
Ra and Rb are each independently -H or -CH3; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl.
27. The compound or pharmaceutically acceptable salt of the compound of
claim 26, wherein R5, is -H, (C1-C6)-alkyl, -OR25, halogen or -CF3.
28. The compound or pharmaceutically acceptable salt of the compound of
claim 26, wherein any one of R1, R2, R3, R4, R5, and R6 is -H, (C1-C6)-alkyl,
-OR25, halogen or -CF3; and any one of R7', R6, R9, R10, R11, and R12 is -H,
(C1-C6)-alkyl, -OR25, halogen or -CF3, -NO2, or -CN.
29. The compound or pharmaceutically acceptable salt of the compound of
claim 26, wherein R4 is —H, (C1-C6)-alkyl, -OR25, halogen or -CF3 and any one
of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen; and any two
of R7S R8, R9, R10, R11, and R12is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3,
-NO2, or -CN.
30. The compound or pharmaceutically acceptable salt of the compound of
claim 26, wherein R5 is —H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and any
one of R13, R14, R15, and R16 is -H, (C1-C6)-alkyl, -OR25, or halogen; and any
two of R7', R8, R9, R10, R11, and R12 are each independently -H, (C1-C6)-alkyl,
-OR25, halogen, or -CF3, -NO2, or -CN.
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31. The compound or pharmaceutically acceptable salt of the compound of
claim 26, wherein R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and R7- is -
H, (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and the remaining
substituents are each hydrogen.
32. The compound or pharmaceutically acceptable salt of the compound of
any one of claims 26 to 31, wherein R25 is (C1-C6)-alkyl.
33. A compound of Formula (II):

R4, R5, R15, R16, R17, R18 and R19 are each independently -H, (C1-C6)-
alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl,
halogen, -CF3, -NO2, -CN, -OR25, -OSO2R25, -SR25, -SO2R25, -
SO2N(R25)2, -N(R25)2, -C(O), -COR25, -CO2R25, -NR25CO2R25,
-NR25COR25, -NR25CON(R25)2, or -CON(R25)2; Ra and Rb are each
independently -H or -CH3; R25 is -H; or linear or branched (C1-C6)-
alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6-alkynyl); and
R4 and R5 cannot both be hydrogen.
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34. The compound or pharmaceutically acceptable salt of the compound of
claim 33, wherein R4 and R5 are each independently -H, -OR25, halogen, or
(C1-C6)-alkyl; R15 and R16 are each independently -H or -CH3; and R11, R18,
and R19 are each independently -H, -OR25, halogen, (C1-C6)-alkyl, -CF3, -NO2,
-CN.
35. The compound or pharmaceutically acceptable salt of the compound of
claim 33, wherein R4 and R5 are each independently -H, -OCH3, F, or -CH3;
R15, and R16 are each independently -H or -CH3; and R17, R18, and R19 are each
independently -H, F, -CH3, -CF3, -NO2, -CN or Br.
36. The compound or pharmaceutically acceptable salt of the compound of
claim 33, wherein R4 and R5 are each independently -H, or -OR25; and R17,
R18, and R19 are each independently -H, -OR25, halogen, (C1-C6)-alkyl, or -CF3.
37. The compound or pharmaceutically acceptable salt of the compound of
claim 33, wherein R4 and R5 are each independently -H, or -OR25; R17, R18,
and R19 are each independently -H, -OR25, halogen, (C1-C6)-alkyl, -CF3; and
the remaining R groups are hydrogen.
38. The compound or pharmaceutically acceptable salt of the compound of
claim 33, wherein R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of
R11, R18, and R19is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3.
39. The compound or pharmaceutically acceptable salt of the compound of
claim 33, wherein R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and two of
R17, R1s, and R19 are each independently -H, (C1-C6)alkyl, -OR25, halogen, or
-CF3.
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40. The compound or pharmaceutically acceptable salt of the compound of
claim 33, wherein R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and R11,
R18, and R19 are each independently -H, (C1-C6)-alkyl, -OR25, halogen, or
-CF3.
41. The compound or pharmaceutically acceptable salt of the compound of
claim 33, wherein R5 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of
R17, R18, and R19 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; and the
remaining substituents are each hydrogen.
42. The compound or pharmaceutically acceptable salt of the compound of
any one of claims 33 to 41, wherein R19 is in the para position relative to the
nitrogen of the piperidine.
43. The compound or pharmaceutically acceptable salt of the compound of
any one of claims 33 to 42, wherein R17 and R18 are located at positions 2 and
4 of the quinoline ring.
44. A compound of claim 1 wherein the compound is one of the following
or a pharmaceutically acceptable salt thereof:
6-methoxy-8-[4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-quinoline;
6-fluoro-8-[4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-quinoline;
5-fluoro-8-[4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-quinoline;
7-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-l-
yl)quinoline;
6~fluoro-8- {4- [ 1 -(8-fluoroquinolin-7-yl)piperidin-4-yl]piperazin-1 -
yl} quinoline;
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3-trifluoromethyl-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-l-
yl)quinoline;
6-methoxy-8-(4-(l-(quinolin-8-ylmethyl)piperidin-4-yl)piperazin-l-
yl)quinoline;
5-fluoro-4-methoxy-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-
1 -yl)-2- (trifluoromethyl)quinoline;
5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-l-
yl)quinoline;
8-[4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-quinoline;
6-chloro-8-[4-(4-(6-chloro)-quinolin-8-yl-piperidin-l-yl)-piperazin-l-yI]-
quinoline;
6-fluoro-8-[4-(4-(6-chloro)-quinolin-8-yl-piperidin-l-yl)-piperazin-l-yl]-
quinoline;
5-chloro-8-[4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-quinoline;
2-methyl-8-[4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-quinoline;
6-chloro-8-t4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-quinoline;
8-[4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-5-trifluoromethyl-
quinoline;
5-methoxy-8-[4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yI]-quinoline;
5-fluoro-8-[4-(4-quinolin-8-yl-piperazin-l-yl)-piperidin-l-yl]-quinoline;
6-methoxy-8-[4-(2-methylquinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-
quinoline;
6-fluoro-8-(4-(l-(2-methylquinolin-8-yl)piperidin-4-yl)piperazin-l-
yl)quinoline;
6-methoxy-8-[4-(3-methylquinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-
quinoline;
6-methoxy-8-(4-(l-(4-methylquinolin-8-yl)piperidin-4-yl)piperazin-l-
yl)quinoline;
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6-methoxy-8-(4-(l -(2,4-dimethylquinolin-8-yl)piperidm-4-yl)piperazin-1 -
yl)quinoline;
6-methoxy-8-(4-(l-(2,4-dimethyl-5-fluoroquinolin-8-yl)piperidin-4-
yl)piperazin-1 -yl)quinoline;
6-methoxy-8-(4-(l-(2-(trifluoromethyl)quinolin-8-yl)piperidin-4-yl)piperazin-
l-yl)quinoline;
6-fluoro-8-(4-(l-(5-fluoroquinolin-8-yl)piperidin-4-yl)piperazin-
l-yl)quinoline;
6-methoxy-8-(4-(l-(6-bromoquinolin-8-yl)piperidin-4-yl)piperazin-
l-yl)quinoline;
6-methoxy-8-(4-(l-(6-fluoroquinolin-8-yl)piperidin-4-yl)piperazin-
l-yl)quinoline;
6-fluoro-8-(4-(l-(7-fluoroquinolin-8-yl)piperidin-4-yI)piperazin-
l-yl)quinoline;
6-methoxy-8- {4-[ l-(8-fluoroquinolin-7-yl)piperidin-4-yl]piperazin-1 -
yl}quinoline;
6-methoxy-8-{4-[l-(2-triiluoromethyl-4-methoxyquiaolin-7-yl)piperidin-4-
yl]piperazin-1 -yl} quinoline;
6-methoxy-8-(4-(l-(2-trifluoromethyl-4-methoxyquinolin-8-yl)piperidin-4-
yl)piperazin-l-yl)quinoline;
5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-l-yl)-
2-trifluoromethylquinoline;
5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-l-yl)-
3-trifluoromethylquinoline;
5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1 -yl)piperidin-1 -yl)-
4-trifluoromethylquinoline;
2,5-difluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-
l-yl)quinoline;
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3,5-difluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidm-
l-yl)quinoline;
or
4,5-difIuoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-
l-yl)quinoline.
45. A pharmaceutical formulation comprising a compound of any one of
claims 1 to 44 or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
46. The pharmaceutical formulation of claim 45, further comprising a
second therapeutic agent.
47. The pharmaceutical formulation of claim 46, wherein the second
therapeutic agent is a selective serotonin reuptake inhibitor or a cholinesterase
inhibitor.
48. The pharmaceutical formulation of any one of claims 45 to 47 wherein
the pharmaceutically acceptable carrier is suitable for oral administration and
the composition comprises an oral dosage form.
49. A compound of Formula (HI):

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and pharmaceutically acceptable salts thereof,
wherein
R99 is selected from:

R7, R8, R9, R10, R11, R12, R13, R14, R15. Rl6, R20. R21, R22, R23, R24, R26,
R27, R28, R29 and R30 are each independently -H, (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen, -CF3,
-NO2, -CN, -C(O), -OR25, -SRM, -SO2R25, -SC2N(R25)2, -N(R25)2, -
COR25, -CO2R25, -NR25CO2R25, -NR25COR25, -NR25CON(R25)2, or
-CON(R25)2;
Ra and Rb are each independently -H or -CH3; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-
Ce-alkynyl).
50. The compound of claim 49, wherein one of R7, R6, R9, R10, R11, and
R12are each independently -H, (C1-C6)alkyl, halogen, -CF3, -OR25, -NO2 or -
CN and the remaining R7, R8, R9, R10, R11, and R12 are each hydrogen.
51. The compound of claim 49 or claim 50, wherein R7 is -H, (C1-C6)-
alkyl, halogen, -CF3, -OR25, -NO2 or -CN.
52. The compound of any one of claims 40 to 51, wherein Rg is -H, (C1-
C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN.
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53. The compound of any one of claims 40 to 52, wherein R9 is -H, (C1-
C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN.
54. The compound of claim 49, wherein R7 is -H, (C1-C6)-alkyl, halogen,
-CF3, -OR25, -NO2 or -CN and R8, R9, R10, R11, and R12 are each hydrogen.
55. The compound of claim 49, wherein R8 is -H, (C1-C6)-alkyl, halogen,
-CF3, -OR25, -NO2 or -CN and R7, R9, R10, R11. and R12 are each hydrogen.
56. The compound of claim 49, wherein R9 is -H, (C1-C6)-alkyl, halogen,
-CF3, -OR25, -NO2 or -CN and R7, R8, R10, R11, and R12 are each hydrogen.
57. The compound and pharmaceutically acceptable salts of the compound
of claim 53,

and R20, R21, R22 and R23 are each independently -H, (C1-C6)-alkyl,
-OR25, halogen, -CF3, NO2 or CN.
58. The compound of claim 57, wherein R7, R8, R9, R10, R11, R12, R20, R21,
R22 and R23 are each independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25,
-NO2or-CN.
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59. The compound of claim 57, wherein one of R7, R8, R9, R10, R11, and
R12 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and the
remaining R groups are each hydrogen.
60. The compound of claim 57, wherein one of R20, R21, R22 and R23 is -H,
(C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and the remaining R groups
are each hydrogen.
61. The compound of claim 57, wherein one of R7, R8, R9, R10, R11, and
R12 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and one of R20,
R21, R22 and R23is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN.
62. The compound of claim 57, wherein one of R7, R8, R8, R10, R11, and
R12 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; one of R20, R21,
R22 and R23 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and the
remaining R groups are hydrogen.
63. The compound of claim 57, wherein R8 is -H, (C1-C6)-alkyl, halogen,
-CF3, -OR25, -NO2 or -CN; R7, R9, R10, R11, and R12are each independently -H,
(C1-C6)alkyl, halogen, -CF3, or -OCH3; and R13, R11, R15, and R16 are each
hydrogen.
64. The compound of claim 57, wherein Rg is -H, (C1-C6)-alkyl, halogen,
-CF3, -OR25, -NO2 or -CN; and R7, R9, R10, R11, R12, R20, R21, R22 and Ra are
each hydrogen.
65. The compound of claim 57, wherein R9 is -H, (C1-C6)-alkyl, halogen,
-CF3, -OR25, -NO2 or -CN; R7, R8, R10, R11, and R12 are each independently -H,
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(C1-C6)-alkyl, halogen, -CF3, or -OCH3; and R13, R14, R15, and R16 are each
hydrogen.
66. The compound of claim 57, wherein R9 is -H, (C1-C6)-alkyl, halogen,
-CF3, -OR25, -NO2 or -CN; and R7, R8, R10, R11, R12, R13, R14, R15, and R16 are
each hydrogen.
67. The compound of claim 57, wherein R9 and R22 are each independently
-H or (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and the remaining R
groups are each hydrogen.
68. The compound of claim 57, wherein R9 and R22 are each independently
-H or halogen and the remaining R groups are each hydrogen.
69. The compound and pharmaceutically acceptable salts of the compound
of claim 49, wherein R99 is

and R24, R26 and R27 are each independently -H, (C1-C6)-alkyl, halogen, -CF3,
-OR25, NO2 or CN.
70. The compound of claim 69, wherein R7, R8, R9, R10, R11, R12, R13, R14,
R15, and R16 are each independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25,
NO2 or -CN.
71. The compound of claim 69, wherein R7, R8, R9, R10, R11, R12, R13, R14,
R15, R16, R24, R26, and R27 are hydrogen.
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72. The compound and pharmaceutically acceptable salts of the compound
of claim 49, wherein R99 is

and R28, R29 and R30 are each independently -H, (C1-C6)-alkyl, halogen, -CF3,
-OR25, -NO2 or -CN.
73. The compound of claim 72, wherein R28, R29, and R30 are each -H.
74. The compound of claim 72 or 73, wherein R7, R6, R9, R10, R11, and R12
are each independently -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN;
and R13, R14, R15, and R16 are each hydrogen.
75. The compound of claim 72 or 73, wherein one of R7, R8, R9, R10, R11,
and R12 is -H, (C1-C6)-alkyl, halogen, -CF3, -OR25, -NO2 or -CN; and the
remaining substituents are each hydrogen.
76. The compound of claim 72, wherein R8 is -H, (C1-C6)-alkyl, halogen,
-CF3, -OR25, -NO2 or -CN; R7, R9, R10, R11, R12,R13, R11, R15, and R16are each
hydrogen.
77. The compound of claim 72, wherein R8 is halogen; R7, R9, R10, R11,
R12,R13, R14, R15, and R25are each hydrogen.
78. A pharmaceutical formulation comprising a compound of any one of
claims 49 to 77 or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
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79. A compound of Formula (IV):

and pharmaceutically acceptable salts thereof,
wherein
X is CR25, N, O or S;
Y is CR25, NR.25, O or S; with the proviso that when X is CR25, Y is not
NR25;
R13, R14, R15, R16, R31, R32, R33, R34, R35, R36, R37, R38 and R39 are each
independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or
(C2-C6)-alkynyl, halogen, -CF3, -NO2, -CN, -OR25, -SR25, -SO2R25,
-SO2N(R2s)2, -N(Ras)2, -COR25, -CO2R25, -NR25CO2R25, -NR25COR25,
-NR25CON(R25)2, or -CON(R25)2; Ra and Rb are each independently -H
or -CH3; R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-aIkenyl, or (C2-C6-alkynyl).
80. The compound and pharmaceutically acceptable salts of the compound
of claim 19, wherein
X is CR25 or N;
Y is O or S;
R13, R14, R45, and R16 are each independently -H, F, CH3, -CF3, -NO2,
-CN or Br; and
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R31, R32, R33, R34, R35, R36, R37, R38 and R39 are each independently -H,
-CR25, -OR25, halogen, or -CF3.
81. The compound of claim 79, wherein X is CR25 or N; Y is O or S; one
of R31, R32, R33, R34 and R35 is -H, (C1-C6)-alkyl, -OR25, halogen, or-CF3; and
the remaining substituents are each hydrogen.
82. The compound of claim 79, wherein X is CR25 or N; Y is O or S; one
of R31, R32, R33, R34 and R35 is -H, (C1-C6)-alkyl, -OR25, halogen, or -CF3; one
of R36, R37, R38 and R39 is -H, (C1-C6)-alkyl, -OR25, -CH3, halogen, or -CF3;
and the remaining substituents are each hydrogen.
83. The compound of claim 79, wherein X is CR25 or N; Y is O or S; R31 is
-H, (C1-C6)-alkyl, -OR25, halogen, or-CF3; and R13, R14, R15, R16, R32, R33,
R34, R35, R36, R37, R38, and R39 are each hydrogen.
84. The compound and pharmaceutically acceptable salts of the compound
of claim 49 or 79,
wherein the compound is
6-chloro-8- {4- [4-(lH-indole-4-yl)-piperazin-1 -yl]-piperidin-1 -yl} -
quinoline;
8-{4-[4-(lH-indole-4-yl)-piperazin-l-yl]-piperidin-l-yl}-quinoline;
8-{4-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-piperidin-
l-yl}-quinoline;
8-[4-(4-benzofuran-3yl-piperazin-l-yl)-piperidin-l-yl]-6-chloro-
quinoline;
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5-fluoro-8-{4-[4-(5-fluoro-benzofuran-3-yl)-piperazin-l-yl]-piperidin-
l-yl}-quinoline;
l-(l-benzo[b]thiophen-3-yl-piperidin-4-yl)-4-(2-methoxy-phenyl)-
piperazine; or
3-{4-[4-(2-methoxyphenyl)-piperazin-l-yl]-l-piperidinyl}-l,2-
benzisoxazole.
85. A pharmaceutical formulation comprising a compound of any one of
claims 79 to 84 or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
86. A method of synthesizing a compound comprising:
177
a) reacting a substituted piperazine compound of Formula (X):


WO 2006/135839 PCT/US2006/022719

R1, R2, R3, R4, R5, R6, R20, R21, R22, R23, R24, R26, R27, R28, R29, and
R30, are each independently -H, (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen,
-CF3, -NO2, -CN, -OR25, -SR25, -SO2R25, -SO2N(R25)2,
-N(R25)2, -C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25,
-NR25CON(R25)2, or -CON(R25)2;
Ra and Rb are each independently -H or -CH3; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6)-alkynyl);
with a substituted piperidin-4-one compound of Formula (XIV):
178

WO 2006/135839 PCT/US2006/022719

R7, R8, R8, R10, R11, R12, R13, R14, R15, and R16 are each
independently -H, (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-
alkynyl, halogen, -CF3, -NO2, -CN, -OR25, -SR25, -SO2R25,
-SO2N(R25)2, -N(R25)2, -C(O), -COR25, -CO2R25, -NRKCO2R25,
-NR25COR25, -NR25CON(R25)2, or -CON(R25)2; and
R25 is as above;
179
under conditions effective to bring about reductive animation at the
piperidine carbonyl, thereby providing a piperazine-piperidine
compound having the Formula (VI):


WO 2006/135839 PCT/US2006/022719
87. A method of synthesizing a compound comprising:
a) reacting an optionally substituted aniline compound of Formula

W is a leaving group;
R4, R5, and R6 are each independently -H, (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen,
-CF3) -NO2, -CN, -OR25, -SRzs, -SO2R25, -SO2N(R25)2,
-N(R25)2, -C(O), -CORM, -CO2R25, -NR25CO^s,
-NR25COR25, -NR25CON(R25)2, or -CON(R25)2;
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6)-alkynyl);
180
under conditions effective to produce an optionally substituted
quinoline of Formula (VIII):


WO 2006/135839 PCT/US2006/022719
wherein:
R1, R2, and R3 are each independently -H, (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-allcynyl, halogen,
-CF3, -NO& -CN, -OR25, -SR25, -SO2R25, -SO2N(R25)2,
-N(R25)2, -C(O), -COR25, -CO2R25, -NR25CO2R25,
-NR25COR25, -NR2sCON(R25)2, or -CON(R25)2;
b) reacting the leaving group of the quinoline of Formula (VIII) with a
protected piperazine derivative under conditions effective to
provide a protected piperazino-quinoline of Formula (IX):

Ra and Rb are each independently -H or -CH3 and
X1 is a protecting group
181
c) reacting the protected piperazino-quinoline of Formula (IX) under
conditions effective to provide a substituted piperazino-quinoline
compound of Formula (Kb):


WO 2006/135839 PCT/US2006/022719
d) reacting a second optionally substituted aniline compound of
Formula (XI):

R7, R8, and R9, are each independently -H, (C1-C6)-alkyl,
(C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl,
halogen, -CF3, -NO2, -CN, -OR25, -SR25, -SO2R25, -SO2N(R;>5)2,
-N(R25)2, -C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25,
-NRMCON(R25)2 or -CON(R25)2;
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6-alkynyl); and
W is a leaving group under conditions effective to produce a second
optionally substituted quinoline of Formula (XII):

wherein R10, R11, and R12, are each independentiy -H, (C1-C6)-
alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl,
halogen, -CF3, -NO2, -CN, -OR25, -SR25, -SO2R25, -SO2N(R25)2,
182

WO 2006/135839 PCT/US2006/022719
-N(R25)2, -C(O), -CORas, -CO2R25, -NR25CO2R25, -NR25COR25,
-NR25CON(R25)2, or -CON(R25)2;
R25 is as above; and
W is a leaving group
e) reacting the leaving group of the quinoline of Formula (XII) with a
protected piperidin-4-one derivative, under conditions effective to
provide the compound of Formula (XIII):

f) reacting the compound of Formula (X1H) under conditions effective
to provide the piperidin-4-one compound of (XIVa):

g) reacting the substituted piperazine compound of Formula (Xb) with
the substituted piperidin-4-one compound of Formula (XIVa) under
conditions effective to provide a piperazine-piperidine compound
having the Formula (XV):
183

WO 2006/135839 PCT/US2006/022719

88. A method of synthesizing a compound comprising:
a) reacting a substituted piperazine compound of Formula (X):

R1, R2, R3, R4, R5, R6, R20, R21, R22, R23, R24, R26, R27, R28, R29, and
R30, are each independently -H, (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2.C6)-alkenyl, or (C2-C6)-alkynyl, halogen,
-CF3, -NO2, -CN, -OR25, -SR25, -SO2R25, -SO2N(R25)2,
184

WO 2006/135839 PCT/US2006/022719
-N(R25)2, -C(O), -COR25, -CO2R25, -NR25CO2R25> -NR25COR25,
-NR25CON(R25)2, or -CONCR25;
Ra and Rb are each independently -H or -CH3; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6-alkynyl);
with a substituted piperidin-4-one compound of Formula (XlVb):

R7, R8, R9, R10, R11, R12, R13, R14, R15, and R16 are each
independently -H, (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-
alkynyl, halogen, -CF3, -NO2) -CN, -OR25, -SR25, -SO2R25,
-SO2N(R25)2, -N(R25)2, -C(O), -COR25, -CO2R25, -NR25CO2R25,
-NR25COR25, -NR25CON(R25)2, or -CON(R25)2;
n is 1 or 2; and
R25 is as above;
under conditions effective to bring about reductive amination at the
piperidine carbonyl, thereby providing a piperazine-piperidine
compound having the Formula (I'):
185

WO 2006/135839
PCT/US2006/022719

Rb R2, R3, R4, R5, R8, R20, R21, R22, R23, R24, R26, R27, R28, R29, and
R30, are each independently -H, (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alk.ynyl, halogen,
186

WO 2006/135839
PCT/US2006/022719
-CF3, -NO2, -CN, -OR25, -SR25, -SO2R25, -SO2N(R25)2,
-N(R25)2, -C(O), -COR25> -CO2R25, -NR25CO2R25, -NR25COR25,
-NR25CON(R25)2, or -CON(R25)2;
Ra and Rb are each independently -H or -CH3; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6-alkynyl);
with an a compound of formula (XIVc):

R7, R8, R9, R10, R11, R12, R13, R14, R15, and R16 are each
independently -H, (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)~
alkynyl, halogen, -CF3, -NO2, -CN, -OR25, -SR25, -SO2R25,
-SO2N(R2s)2, -N(R25)2, -C(O), -COR25, -CO2R25, -NR25CO2R25,
-NR25COR25, -NR25CON(R25)2, or -CON(R25)2 except for the R
group through which the piperidine is connected; and
R25 is as above;
187

WO 2006/135839 PCT/US2006/022719
under conditions effective to bring about reductive animation at the
piperidine carbonyl, thereby providing a piperazine-piperidine
compound having the Formula (I"):

90. A method of synthesizing a compound comprising:
a) reacting an optionally substituted aniline compound of Formula

W is a leaving group;
R.7, R.8, and R9 are each independently -H, (C1-C6)-alkyl,
(C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl,
halogen, -CF3, -NO2, -CN, -OR25, -SR25, -SO2R25, -SO2N(R25)2,
-N(R25)2, -C(O), -COR25, -CO2R25, -NRzsCOaR25, -NR25COR25,
-NR25CON(R25)2, or -CON(R25)2; R25 is -H; or linear or
188

WO 2006/135839 PCT/US2006/022719
branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or
(C2-C6)-alkynyl;
under conditions effective to produce an optionally substituted

wherein R10, R11, and R12 are each independently -H, (C1-C6)-alkyl,
(C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl,
halogen, -CF3, -NO2, -CN, -OR25, -SR25, -SO2R25, -SO2N(R25)2,
-N(R25)2, -COR25, -CO2R25, -NR25CO2R25, -NR25COR25,
-NR25CON(R25)2, or -CON(R25)2; R25 is -H; or linear or
branched (C1-C6)-aIkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or
(C2-C6)-alkynyl;
b) reacting the leaving group of the optionally substituted quinoline of
Formula (XII) with a protected piperidin-4-one derivative under
conditions effective to provide the compound (XIII):

c) reacting the compound of Formula (XIII) under conditions effective
to provide the compound of (XIVa):
189

WO 2006/135839 PCT/US2006/022719

R28. R29, and R30 are each independently -H, (C1-C6)-alkyl,
(C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen,
-CF3, -NO2, -CN, -OR25, -SR25, -SO2R25, -SO2N(R25)2) -N(R25)2, -
C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25,
-NR25CON(R25)2, or -CON(R2s)2;
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6)-alkynyl;
with N,N-dimethylformamide dimethyl acetal and pyrrolidine under
conditions effective to bring about cyclization, thereby providing
an indole-4-ylamine having the Formula (XVII):


WO 2006/135839 PCT/US2006/022719
e) reacting the indole-4-ylamine of Formula (XVII) with bis(2-
chloroethyl)-benzylamine under conditions effective to produce the
compound of Formula (XVIII):

f) reacting the compound of Formula (XVIII) under conditions
effective to produce a 4-piperazin-l-yl-indole having the Formula
(XIX):

191
g) reacting the substituted 4-piperazin-l-yl-indole of Formula (XIX) with the
substituted piperidin-4-one compound of Formula (XIV) under conditions
effective to bring about reductive animation at the piperidine carbonyl, thereby
providing an piperazine-piperidine compound having the Formula (XX):


WO 2006/135839 PCT/US2006/022719
91. A method of synthesizing a compound comprising:
a) reacting the nitro-benzodioxane of Formula (XXI):

R24, R26, and R27 are each independently -H, (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen, -CF3,
-NO2, -CN, -OR25, -SR25, -SO2R25, -SO2N(R25)2> -NORas),, -C(O), -
COR25, -CO2R2S, -NR25CO2R25, -NRasCOR25, -NR25CON(R25)2, or
-CON(R25)2; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-
C6)-alkenyl, or (C2-C6)-alkynyl;
under conditions effective to produce the compound of Formula

b) reacting the compound of Formula (XXII) with bis(2-
chloroethyl)amine hydrochloride under conditions effective to
produce a benzodioxane-piperazine having the Formula (XXIII):
192

WO 2006/135839 PCT/US2006/022719

W is a leaving group;
R7, R8, and R9 are each independently -H, (C1-C6)-alkyl,
(C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen,
-CF3, -NO2, -CN, -ORzs, -SR25, -SO2R25, -SO2N(R25)2, -N(R25)2, -
C(O), -COR25, -CO2R25, -NR2sCO2R25, -NR25COR25,
-NR25CON(R23)2, or -CON(R25)2;
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6)-alkynyl; and
W is a leaving group
193

WO 2006/135839 PCT/US2006/022719

wherein R10, R11. and R25 are each independently -H, (C1-C6)-alkyl,
(C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen,
-CF3, -NO2, -CN, -OR25, -SR25, -SOfe -SO2N(R25)2, -N(R25)2, -
C(O), -COR25> -CO2R25, -NR25CO2R25, -NR25COR25,
-NR25CON(R25), or -CON(R25)2;
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6)-alkynyl;
194
d) reacting the leaving group of the optionally substituted quinoline of
Formula (XII) with a protected piperidin-4-one derivative under
conditions effective to provide the compound (XIII):


WO 2006/135839 PCT/US2006/022719
e) reacting the compound of Formula (XIII) under conditions effective
to provide the compound of (XIVa):

f) reacting the compound of Formula (XXIII) with the substituted piperidin-4-
one compound of Formula (XIV) under conditions effective to bring about
reductive animation at the piperidine carbonyl, thereby providing an
piperazine-piperidine compound having the Formula (XXIV):

92. A method of synthesizing a compound comprising:
195
a) reacting an optionally substituted aniline compound of Formula


WO 2006/135839 PCT/US2006/022719
W is halogen;
R7, R8, and R9 are each independently -H, (C1-C6)-alkyl,
(C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen,
-CF3, -NO2, -CN, -ORas, -SRas, -SO2R25, -SO2N(R25)2, -N(R25)2, -
C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25,
-NR25CON(R25)2, or -CON(R25)2; Ra and Rb are each independently
-H or -CH3; R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl; R25 is -H; or
linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-alkynyl; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6-alkynyl);
under condition effective to produce an optionally substituted quinoline
of Formula (XII):

wherein R10, R11, and R12 are each independently -H, (C1-C6)-alkyl,
(C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen,
-CF3, -NO2> -CN, -OR25, -SR25, -SO2R25, -SO2N(R25)2, -N(R25)2, -
C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25,
-NR25CON(R25)2, or -CON(R25)2; Ra and Rb are each independently
196

WO 2006/135839 PCT/US2006/022719
-H or -CH3; R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl; R25 is -H; or
linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-alkynyl;
and R25 is as above;
b) reacting the leaving group of the optionally substituted quinoline of
Formula (XII) with a protected piperidin-4-one derivative under
conditions effective to provide the compound (XIII):

wherein X2 is a protecting group;
c) reacting the compound of Formula (XIII) under conditions effective
to provide the compound of (XIVa):

d) reacting a compound of Formula (XXXI):
197

WO 2006/135839 PCT/US2006/022719

wherein R20, R21, R22, and R23 are each independently -H, (C1-C6)-
alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl,
halogen, -CF3, -NO2, -CN, -OR25, -SR25, -SO2R25, -SO2N(R25)2,
-N(R25)2, -C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25,
-NR25CON(R25)2, or -CON(R25)2; R25 is -H; or linear or branched
(C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-
alkynyl; R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl; and
R25 is as above;
with protected piperazine under conditions effective to produce a compound of
Formula (XXXII):

wherein Ra and Rb are each independently -H or -CH3; and
X1 is a protecting group;
198

WO 2006/135839 PCT/US2006/022719
e) deprotecting the N-protecting group of the compound of formula (XXXII)
under conditions effective to produce the compound of Formula (V):

f) reacting the compound of Formula (V) with the substituted piperidin-
4-one compound of Formula (XTVa) under conditions effective to
bring about reductive amination at the piperidine carbonyl, thereby
providing an piperazine-piperidine compound having the Formula
(XXV):

93. A method of synthesizing a compound comprising:
a) reacting an optionally substituted phenyl-piperazine compound of
Formula (XXVI):
199

WO 2006/135839 PCT/US2006/022719

R31, R32, R33, R34, and R35 are each independently -H, (C1-C6)-alkyl,
(C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen,
-CF3l -NO2, -CN, -OR25, -SR25, -SO2R25, -SO2N(R25)2) -N(R25)2, -
C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25,
-NR25C ON(R25)2, or -CON(R25)2; Ra and Rb are each independently \.
-H or -CH3; R25 is -H; or linear or branched (C1-C6)-alkyl, (C1
C6)-ha]oalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
Ra and Rb are each independently -H or -CH3; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6-alkynyl);
with an optionally substituted protected piperazine under conditions
effective to provide the compound of Formula (XXVII):

R13, R14, R15, and R16 are each independently -H, (C1-C6)-alkyl,
(C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen,
-CF3, -NO2, -CN, -OR25) -SR25, -SO2R25, -SO2N(R25)2, -N(R25)2, -
200

WO 2006/135839 PCT/US2006/022719
C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25,
-NR25CON(R25)2, or -CON(R25)2;
R25 is as above; and
X1 is a protecting group.
c) reacting the compound of Formula (XXVII) under conditions
effective to provide a compound of Formula (XXVIII):

X is CR25,N, O or S;
Y is CR25, NR25, O or S;
R36, R37, R38, and R39 are each independently -H, (C1-C6)-alkyl,
(C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen,
-CF3, -NO2, -CN, -OR25, -SR25, -SO2R25, -SO2N(R25)2, -N(R25)2, -
201

WO 2006/135839 PCT/US2006/022719
C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR25,
-NR25CON(R25)2, or -CON(R25)2;
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6)-alkynyl; and
W is a leaving group.
under conditions effective to provide the compound of Formula
(XXX):

R1, R2, R3, R4, R8, R6, R7, R8, R9, R10, R11 and R12 are each
independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-alkynyl, halogen, -CF3, -NO2, -CN, -OR25, -
SR25, -SO2R25, -SO2N(R25)2, -NO(R25)2 -COR25, -CO2R25,
202

WO 2006/135839 PCT/US2006/022719
-NR25CO2R25, -NR25COR25, -NRasCON(25)2, or -CON(R25)2;
Ra and Rb are each independently -H or -CH3; R25 is -H; or
linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6)-alkynyl;
Ra and Rb are each independently -H or -CH3; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6-alkynyl);
prepared by the method comprising:
a) reacting an optionally substituted aniline compound of Formula
(VII):


WO 2006/135839 PCT/US2006/022719
with a protected piperazine derivative under conditions effective to
provide a protected piperazino-quinoline of Formula (XI):

204
c) reacting the protected piperazino-quinoline of Formula (IX) under
conditions effective to provide a substituted piperazine compound
of Formula (Xb):


WO 2006/135839 PCT/US2006/022719
under conditions effective to produce a second optionally substituted
quinoline of Formula (XII):

e) reacting the leaving group of the second quinoline of Formula (XII)
with a protected piperidin-4-one derivative under conditions
effective to provide the compound (XIII):

f) reacting the compound of Formula (XIII) under conditions effective
to provide the compound of (XIVa):

g) reacting the substituted piperazine compound of Formula (X) with
the substituted piperidin-4-one compound of Formula (XIV) under
205

WO 2006/135839 PCT/US2006/022719
206
conditions effective to provide a piperazine-piperidine compound
having the Formula (XV):


WO 2006/135839 PCT/US2006/022719

R1, R2, R3, R4, R8, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16,
R20, R21, R22, R23, R24, R25, R26. R27, R28, R29, and R30, are each
independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-aIkynyl) halogen, -CF3, -NO2, -CN, -OR25, -
SR25, -SO2R25, -SO2N(R25)2, -N(R25)2. -COR25, -CO2R25,
-NR25CO2R25, -NR25COR25, -NR25CON(R25)2, or -CON(R25)2;
Ra and Rb are each independently -H or -CH3; R25 is -H; or
linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-alkynyl;
Ra and Rb are each independently -H or -CH3; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6-alkynyl);
prepared by the method comprising:
a) reacting a substituted piperazine compound of Formula (V):

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with a substituted piperidin-4-one compound of Formula (XIV):

208
under conditions effective to bring about reductive amination at the
piperidine carbonyl, thereby providing an piperazine-piperidine
compound having the Formula (VI):


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R1, R2, R3, R4, R5, R8, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16,
R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, and R30, are each
independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-alkynyl, halogen, -CF3, -NO2) -CN, -OR25, -
SR25, -SO2R25, -SO2N(R25)2, -N(R25)2, -COR25, -CO2R25,
-NR25CO2R25, -NR25COR25, -NR25CON(R25)2, or -CON(R25)2;
Ra and Rb are each independently -H or -CH3; R25 is -H; or
linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-alkynyl; and
n is 1 or 2;
prepared by the method comprising:
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210
a) reacting a substituted piperazine compound of Formula (X):


WO 2006/135839 PCT/US2006/022719

R1, R2, R3, R4, R5. R6. R7' R7', R8, R9, R10, R11, R12, R13, R14, R15,
R16, R20, R21. R22, R23, R24, R25, R26, R27, R28, R29, and R30, are
each independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-
C6)-alkenyl> or (C2-C6)-alkynyl, halogen, -CF3, -NO2, -CN,
-OR25, -SR25, -SO2R25, -SO2N(R25)2, -N(R25)2, -COR25,
- -CO2R25, -NR25CO2R25, -NR25COR25, -NR25CON(R25)2, or
-CON(R25)2 except for the R group through which the
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piperidine is connected; Ra and Rb are each independently -H or
-CH3; and R25 is -H; or linear or branched (C1-C6)-alkyl,
(C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
Ra and Rb are each independently -H or -CH3; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6-alkynyl);
prepared by the method comprising:
a) reacting a substituted piperazine compound of Formula (X):

under conditions effective to bring about reductive amination at the
piperidine carbonyl, thereby providing a piperazine-piperidine
compound having the Formula (I"):
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98. A method for treating a 5-HT1A-related disorder to a patient in need
thereof, the method comprising administering to the patient an effective
amount of a compound or pharmaceutically acceptable salt of the compound of
Formula (I), Formula (I'), Formula (I"), Formula (Ia"), Formula (II), Formula
(III), or Formula (IV) as claimed in any one of claims 1 to 44,49 to 77, 79 to
84 and 94 to 97.
99. The method of claim 98, wherein the 5-HT1A-related disorder is a
cognition-related disorder or an anxiety-related disorder.

100. The method of claim 99, wherein the cognition-related disorder is
dementia, Parkinson's disease, Huntington's disease, Alzheimer's disease,
cognitive deficits associated with Alzheimer's disease, cognitive deficits
associated with depression, mild cognitive impairment, or schizophrenia.
101. The method of claim 99, wherein the anxiety-related disorder is
attention deficit disorder, obsessive compulsive disorder, substance addiction,
withdrawal from substance addiction, premenstrual dysphoric disorder, social
anxiety disorder, anorexia nervosa, or bulimia nervosa.
102. A method for treating Alzheimer's disease to a patient in need thereof,
the method comprising administering to the patient an effective amount of a
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compound of Formula (I), Formula (I'), Formula (I"), Formula (Ia"), Formula
(II), Formula (III), or Formula (IV) as claimed in any one of claims 1 to 44,
49 to 77,79 to 84 and 94 to 97.
103. A method for treating mild cognitive impairment (MCI) to a patient in
need thereof, the method comprising administering to the patient an effective
amount of a compound of Formula (I), Formula (I'), Formula (I"), Formula
(Ia"), Formula (II), Formula (III), or Formula (IV) as claimed in any one of
claims 1 to 44,49 to 77, 79 to 84 and 94 to 97.
104. A method for treating depression to a patient in need thereof, the
method comprising administering to the patient an effective amount of a
compound of Formula (I), Formula (I'), Formula (I"), Formula (Ia"), Formula
(II), Formula (III), or Formula (IV) as claimed in any one of claims 1 to 44,
49 to 77, 79 to 84 and 94 to 97.
105. The method of any one of claims 98 to 104, further comprising
administering a second therapeutic agent.
106. The method of claim 105, wherein the second therapeutic agent is an
anti-depressant agent, an anti-anxiety agent, anti-psychotic agent, or a
cognitive enhancer.
107. The method of claim 105, wherein the second therapeutic agent is a
selective serotonin reuptake inhibitor.
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108. The method of claim 105, wherein the second therapeutic agent is
fluoxetine, fluvoxamine, paroxetine, sertaline, clonazepam, diazepam,
buspirone, haloperidol, olanzapine, or clozapine.
109. The method of claim 105, wherein the second therapeutic agent is a
cholinesterase inhibitor.
110. The method of claim 105, wherein the second therapeutic agent is
tacrine, donepezil, rivastigmine or galantamine.
111. A method for treating sexual dysfunction associated with drug
treatment in a patient in need thereof, the method comprising administering to ,
the patient an effective amount of a compound of Formula (I), Formula (I'),
Formula (I"), Formula (Ia"), Formula (II), Formula (III), or Formula (IV) as
claimed in any one of claims 1 to 44,49 to 77, 79 to 84 and 94 to 97.
112. The method of claim 108, wherein the drug treatment is antidepressant
drug treatment, antipsychotic drug treatment, or anticonvulsant drug treatment.
113. A method of improving sexual function in a patient in need thereof, the
method comprising administering to the patient a pharmaceutically effective
amount of a compound of Formula (I), Formula (I'), Formula (I"), Formula
(Ia"), Formula (II), Formula (III), or Formula (IV) as claimed in any one of
claims 1 to 44,49 to 77, 79 to 84 and 94 to 97.
114. A pharmaceutical composition for treating a 5-HT1A-related disorder,
the composition comprising a compound of any one of claims 1 to 44,49 to
77,79 to 84 and 94 to 97, or a pharmaceutically acceptable salt.
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115. A pharmaceutical composition for treating cognition-related disorder,
the composition comprising a compound of any one of claims 1 to 44,49 to
77,79 to 84 and 94 to 97, or a pharmaceutically acceptable salt.
116. A pharmaceutical composition for treating anxiety-related disorder, the
composition comprising a compound of any one of claims 1 to 44, 49 to 77, 79
to 84 and 94 to 97, or a pharmaceutically acceptable salt.
117. A pharmaceutical composition for treating sexual dysfunction
associated with drug treatment, the composition comprising a compound of
any one of claims 1 to 44, 49 to 77,79 to 84 and 94 to 97, or a
pharmaceutically acceptable salt.
118. The pharmaceutical composition of claim 114, wherein the drug is an
antidepressant, an antipsychotic, or an anticonvulsant.
119. A pharmaceutical composition for treating Alzheimer's disease to a
patient in need thereof, the composition comprising a compound of any one of
claims 1 to 44,49 to 77,79 to 84 and 94 to 97, or a pharmaceutically
acceptable salt.
120. A pharmaceutical composition for treating mild cognitive impairment
(MCI) to a patient in need thereof, the composition comprising a compound of
any one of claims 1 to 44,49 to 77, 79 to 84 and 94 to 97, or a
pharmaceutically acceptable salt.
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121. A pharmaceutical composition for treating depression to a patient in
need thereof, the composition comprising a compound of any one of claims 1
to 44,49 to 77,79 to 84 and 94 to 97, or a pharmaceutically acceptable salt.
122. A process for isolating a compound comprising:
a) mixing a compound of Formula A with a first organic solvent to make a first
solution:

wherein R1, R2, R3, and R4, are each independently -H, (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)~alkynyl, halogen, -CF3, -NO2, -CN, -OR25, -
OSO2R25, -SRzs, -SO2R25, -SO2N(R25)2, -N(R25)2, C(O), -COR25, -CO2R25,
-NR25CO2R25, -NR25COR25, -NR25CON(R25)2, or -CON(R25)2; and
R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C1-C6)-alkynyl;
b) mixing the first solution with a second solution, the second solution
comprising a second organic solvent and a dicaRboxylic acid; and
c) isolating the dicaRboxylic acid addition salt of the compound of Formula A
from the mixture, wherein the residual amount of the first organic solvent in
the acid addition salt of the compound of Formula A is less than about
0.25 w%
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123. The process of claim 122, wherein the residual amount of the second
organic solvent is less than about 0.25 w%.
218

The present invention relates to novel piperazine-piperidine compounds. The compounds are useful as 5-HT1A
binding agents, particularly as 5-HT1A receptor antagonists and agon fits. These compounds are useful in treating central nervous
system disorders, such as cognition disorders, anxiety disorders, depression and sexual dysfunction.