PROCESSES FOR SYNTHESIZING PIPERAZINE-PIPERIDINE COMPOUNDS
[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 processes and methods for the synthesis of
piperazine-piperidinc compounds. These processes allow for safer and environmentally
tolerant production of these compounds, which are useful as 5-HT1A binding agents,
particularly as 5-HT1A receptor antagonists and agonists.
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-HTiA 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] Standard processes for the production of piperazine-piperadine derivatives
have disadvantages that include hazardous combinations of reaction materials and
reaction materials that pose environmental risks. In addition, certain processes utilize
chlorinated solvents such as dichloromethane during the production of piperazine-
piperadine derivatives. These solvents have undesired toxicity profiles. The processes
also produce byproducts that are potentially dangerous to the environment. Finally, the
chlorinated compounds used in these processes can produce certain side effects to patients
taking pharmaceutical compounds containing residual chlorinated solvents. Accordingly,
there remains a need to identify processes that are safer for individuals working with the
reaction materials, produce pharmaceutical compounds with decreased toxicity, and
generate fewer environmentally toxic byproducts.
DESCRIPTION OF THE INVENTION
Definitions
[0006] The term "(C1-C6)-alky]" 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 substituted with one or more of the following
groups: halogen, -N3, -NOz, -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 unsubstiruted (C1-C6)-alkyl.
[0007] The term "(C2-C6)-alkenyI" 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 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 unsubstiruted
(C1-C6)-alkyl.
[0008] The term "(C2-C6)-nlkynyl" 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 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'COjR', -NR'COR', -NR'CONR', or-CON(R')2, wherein
each R' is independently hydrogen or unsubstituted (Cl-C6)-alkyl.
[0009] "(Cl-C6)-haloalkyl" refers to a Cl-C6 alkyl group, as defined above, wherein
one or more of the Cl-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, -CCl3, -CF3, -CH2Cl, -CH2CH2Br, -CH2CH2l, -CH2CH2CH2F, -CH2CH2CH2Cl,
-CH2CH2CH2CH2Br, -CH2CH2CH2CH2I, -CH2CH2CH2CH2CH2Br,
-CH2CH2CH2CH2CH2I, -CH2CH(Br)CH3, -CH2CH(Cl)CH2CH3, -CH(F)CH2CH3,
-C(CH3)2(CH2Cl), -CH2CH2CH2CH2CH2CH2Br, and -CH2CH2CH2CH2CH2CH2l.
[0010] The term "(C1-C6)-alkyoxy," as used herein, means a functional group having
the formula L-O in which L is a linear or branched, saturated hydrocarbon having from I
to 6 carbon atoms. Representative (C1-C6)-alkyoxy groups include, but are not limited to,
methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy,
isopentyloxy, neopentoxy, hcxyloxy, isohcxyloxy, and neohexyloxy. In one embodiment,
the (C1-C6)-alkyl group is 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.
[0011] 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 substituted
with one or more of the following groups: C1-C6)-alkyl, -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.

[0012] 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.
[0013] 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
substituted with one or more of the following groups: C1-C6)-alkyl, -V-halogen, -V-N3, -
V-NOz, -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.
[0014] 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, cyclohcxyl,
and cycloheptyl. In one embodiment, the cycloalkyl group is substituted with one or
more of the following groups: C1-C6)-alkyl, -V-halogcn, -V-N3, -V-NO2, -V-CN, -V-OR',
-V-SR', -V-SOzR', -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.
[0015] The term "halogen" as used herein refers to fluorine, chlorine, bromine, and
iodine.
[0016] The term "heterocyclic group" as used herein refers to a monoclic, bicyclic or
tricyclic, 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
and the ring or each ring is three to seven-membered. 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, azctidinyl,
aziridinyl, furanyl, furazanyl, homopiperazinyl, imidazolidinyl, imidazolinyl, isothiazolyl,
isoxazolyl, morpholinyl, oxadiazolyll, 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 heterocyclic group is substituted with one or more of die following
groups: C1-C6)-alkyl, -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.
[0017] 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.
[0018] The term "pharmaceutically acceptable salt" as used herein refers to a salt of
an acid and one or more basic nitrogen atoms 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, gentisinatc, fumarate, gluconate,
glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonatc, camphorsulfonate, napthalenesulfonate, propionate,
succinate, fumarate, maleate, malonate, mandelate, malate, phthalate, and pamoate. The
term "pharmaccutically 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-hydroxyethy!)amine or tri-(2-hydroxycthyl)amine; N-methyl-
D-giucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such
as arginine, lysine, and the like. The term "pharmaceutically acceptable salt" also
includes a hydrate of a compound of the present invention.
[0019] The term "phenyl" as used herein refers to a substituted or unsubstituted
phenyl group. In one embodiment, the phenyl group is substituted with one or more of
the following groups: -V-halogen, -V-N,, -V-NO2, -V-CN, -V-OR', -V-SR', -V-SO2R', -
V-SO2N(R')2, -V-N(R')2, -V-COR', -V-CO2R-, -V-NRCO2R', -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.
[0020] The term "substantially free of its corresponding opposite enantiomer" as used
herein means that the compound contains no more than about ) 0% by weight of its
corresponding opposite enantiomer. In other embodiments, the compound that is
substantially free of its corresponding opposite entantiomer 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 enantiomer 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.
[0021] 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-Telated disorder is a condition for which
it would be beneficial to activate the 5-HT1A receptor. In one embodiment, a S-HT1A.-
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, 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, schizophreniform 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 Parkinsons 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 infcluding, 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-induccd 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; and sexual dysfunction when used in combination with an SSRI,
sexual dysfunction associated with drug treatment (e.g., treatment with SSRl's).
Methods for Making the Compounds of the Invention
[0022] The methods of the present invention can be utilized to generate piperazine-
pipcridine derivatives and pharmaceutically acceptable salts thereof. The present
invention provides methods used in the synthesis of compounds of Formula (V):
and pharmaceutically acceptable salts and hydrates thereof,
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, -NR2sCON(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.
[0023] The present invention provides methods for the synthesis of compounds of
Formula (Va):
and pharmaceutically acceptable salts and hydrates thereof,
wherein R5 and R9 are each independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl,
(C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen, -CF3 -NO2, -CN, -OR25, -OSO2R25, -SR23, -
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.
(0024] In some embodiments, the compound of Formula (Va) is optionally
substituted such that R5 and R9 are each independently hydrogen, halogen, (C1-C6)-alkyl,
(C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, -CF3, -NO2, -CN, or -OR25. In
other embodiments, Rs is hydrogen or -OR25 such that R25 is (C1-C6)-alkyl, and R9 is a
halogen such as fluorine, chlorine, or bromine. In more specific embodiments, the
process of the present invention is used to synthesize a compound of Formula (Vb):
[0025] Generally, the methods of the present invention allow the production of
compounds of Formulas (V), (Va), and (Vb) with increased safety during production and
decreased toxicity after production of the compound. The present invention provides
methods by which compounds of Formula (V), (Va), and (Vb) are synthesized by
processes utilizing less volatile reaction steps. For instance, the processes of the present
inventions do not utilize m-nitrobenzene compounds at high temperatures, which can
create potentially volatile reactions leading to significant safety concerns.
[0026] Furthermore, the addition of nitrobenzenes or other nitro-containing
compounds is carried out in a series of steps to reduce the potential for volatile
exothermic reactions. In some embodiments, this is accomplished by premixing nitro-
containing compounds such as 4-nitrobenzenc with optionally substituted phenyl
intermediates at room temperature prior to the addition of such a mixture to hot sulfuric
acid. In certain embodiments, the addition of the mixture containing the optionally
substituted intermediate and the nitro-containing compound is added slowly to the hot
sulfuric acid, thereby allowing the nitro-containing compounds to be consumed during the
addition and to reduce the amount of nitro-containing compounds in the hot sulfuric acid.
[0027] The present invention further reduces the reliance of the process on the use of
chlorinated solvents such as dichloroethane during the production of the di-quinoline
compounds of Formula (V). The reduction in the use of certain chlorinated compounds
improves the toxicity profile of the resulting pharmaceutical compounds and decreases
the potential for environmentally hazardous byproducts produced during the production.
[0028] In further embodiments, organic solvents such as toluene are utilized to
produce compounds of Formulas (V), (Va), and (Vb). The use of toluene as opposed to
chlorinated compounds allows for the production of pharmaceutical compounds having
reduced levels of chlorinated byproducts in the final pharmaceutical product.
[0029] In certain embodiments, dichloromethane is used rather than dichloroethane to
reduce the potential pharmaceutical toxicity of the solvents used during production of the
piperazine-piperidine compounds. The Food and Drug Administration ("FDA") has
classified dichloromethane as a class 2 compound, whereas dichloroethane is a class 1
compound. FDA guidelines for pharmaceutical manufacturing state that Class 1 solvents

should be avoided because of their unacceptable toxicity or their deleterious
environmental effect. (See ICH Guideline Q3C Impurities: Residual Solvents.) In
situations where Class 1 solvents must be used, their concentration is generally limited to
less than 1500 ppm, with most solvents in this group being limited to less than 10 ppm
(See id.). In particular, dichloroethane levels must be limited to 5 ppm (See id.). In
contrast, the guidelines state that dichrloromethane may be present in concentrations up to
600 ppm (See id.). Accordingly, by improving the synthesis of the compounds of
Formulas (V), (Va), and (Vb) by replacing dichloroethane with dichloromethanc the
toxicity profile of the resulting compounds is reduced and the environmental impact
decreased.
[0030| It should also be noted that the processes of the present invention allow for
more cost effective production of piperazine-piperidine compounds. In some
embodiments, the use of the cheaper intermediate bis(2-chloroethyl)amine hydrochloride
to form the piperazine component of the compounds of the present invention creates a
more cost effective synthesis.
[0031] In some embodiments, the toxicity profile of the present invention is improved
by eliminating the use of the highly toxic sodium cyanoborohydride compound in the
reductive amination step. The use of sodium cyanoborohydride represents a significantly
dangerous compound that requires must be removed completely from the synthesized
pharmaceutical compounds. Therefore, the present invention provides processes that do
not use this compound and improves the safety connected with the production and use of
the di-quinoline compounds.
[00321 In alternative embodiments, quinoline substituted piperazine intermediates are
prepared by way of an intermediate of Formula VIU:
wherein Y, Rc, Rd, Re, Rf, are each independently hydrogen, (C1-C6)Valkyl, (C1-
C6)-haloalkyl, (C1-C6)-alkcnyl, or (C2-C6)-alkynyl, halogen, -CF3, -NO2, -CM, -OR25, -
OSO2R25, -SR25, -SO2R2s, -SO2N(R25)2, -N(R25)2, C(0), -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 (C2-C6)-alkynyl; and Rg and Rh, are each independently -H or CH3.
[0033] In some embodiments, Y is hydrogen, (C1-C6)-alkyl, (C1-C6)-naloalkyl, (C2-
C6)-alkenyl, or (C2-C6)-alkynyl, and R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-
C6)-haIoalky1, (C2-C6)-a!kenyl, or (C2-C6)-alkynyl.
[0034] In other embodiments, Rc, Rd, Re, Rf, are each independently hydrogen, (C1-
C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)alkynyl, halogen, -CF3, -NO2,
and -CN.
[0035] In certain embodiments, Rc, Rd, Re, Rf, are each independently H.
[0036] In still other embodiments, Y is methoxy, and Rc, Rd, Re, Rf, are each
independently H.
[0037] In the alternative embodiments, the synthesis of compounds of Formula 1a,
described below, goes through a step of removal of the benzene group by hydrogen
transfer in the presence of l-methylcyclohexene, which decreases the environmental
impact of synthesizing piperazine-piperidine compounds. This is shown in the following
Scheme 1:
wherein Rc, Rd, Re, Rf, are each independently hydrogen, (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, -NR2SCO2R25,
-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 (C2-C6)-alkynyl; and Rg and Rh are each independently -H or CH3.
[0038] The reduction in environmental hazard is due to l-mcthylhexcne yielding the
less toxic byproduct toluene rather than benzene. Accordingly, the processes of the
present invention provide for environmentally less hazardous byproducts, requiring less
stringent disposal and containment of such byproducts.
[0039] The methods of the present invention also allow for the synthesis of the
compounds of Formula (V), (Va), and (Vb) by way of quinoline-substituted piperazine
compounds. The present invention provides processes by which quinolinc-substituted
piperazine compounds are isolated from a highly viscous state. In certain embodiments,
the optionally substituted quinoline substituted piperadines are isolated by first
introducing a dicarboxylic acid in conditions effective at yielding an acid addition salt of
the quinoline-substituted piperazine. In one embodiment, the dicarboxylic acid is a (C3-
Cl2)-alkyl dicarboxylic acid, i.e. malonic acid or a homologue thereof. In one
embodiment, the dicarboxylic acid is a straight chain alkyl dicarboxylic acid. In one
embodiment, the dicarboxylic acid is adipic acid, yielding the adipate salt of the
optionally substituted quinoline-substituted piperazine.
[0040] In some embodiments, the optionally substituted quinoline substituted
piperadines are 6-methoxy -8-( 1 -piperazinyl)quinoline.
[0041] In certain embodiments, the salt is further reacted in the presence of a base and
organic solvent in conditions effective at yielding a solution containing the isolated
quinoline substituted piperazine. Accordingly, the process of the present invention allows
for effective isolation of quinoline-substituted piperazine compounds, even from viscous
solutions not normally amendable to processing of the compounds.
[0042] The compounds and pharmaceutically acceptable salts of compounds can be
prepared using a variety of methods of the present invention 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 arc
described in PCT Publication No. WO04/024731 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
funcationality in the target molecule.
[0043] It should also be noted that a variety of intermediates can also be used to
produce the compounds of Formula (V), (V1a), and (V1b). For instance, the quinoline-
suhstituted compound of Formula lb is used to produce a portion of the compound of
Formula (V), (Va), and (Vb):
[0044] The intermediate of Formula lb can be optionally substituted. In some
embodiments, R5 is hydrogen, (C1-C6)-alkyl, (C1-C6) haloalkyl, (C2-C6)-alkenyl, or (C2-
C6)alkynyl, CF3, OR25, -OSO2 R25, -SR25, -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 (C2-C6)-
alkynyl. In some embodiments, R5 is hydrogen, (C1-C6)-alkyl, halogen, -CF3, or -OR25.
In other embodiments, Rs is OR25 and R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-
C6) haloalkyl, (C2-C6)-alkcnyl, or (C2-C6)-alkynyl. In curtain embodiments, R5 is a
methoxy. In the above embodiments, Ra and Rb are each independently hydrogen or
methyl. In some embodiments, R5 is methoxy and Raand Rbare hydrogen, which yields ;
compound of Formula Ic:
[0045] In addition, various intermediates can be utilized in the processes of the
present invention to produce the optionally substituted quinolines that serve as
intermediates of the quinoline-substiruted piperidine components of the compounds of
Formulas (V), (Va), and (Vb). In some embodiments, the compound of Formula 11a is
used:
wherein R9 is hydrogen, (C1-C6)-alkyl, halogen, -CF3, or -OR25; R9 is any halogen;
and D is any halogen.

[0046] In some embodiments, R9 is any halogen and D is any halogen. In other
embodiments, R9 is fluorine and D is chlorine or bromine. In certain embodiments, R.9 is
fluorine and D is bromine to yield the structure of Formula 11b:

[0047] The above Formula 11b can be used to produce the quinoline structure that is
used to synthesize the compounds of Formulas (V), (Va), and (Vb). In some
embodiments, the optionally substituted quinoline compounds used in the processes of the
present inventions have the structure of Formula Ilia:
[0048] The compound of Formula IIIa arc optionally substituted such that R9 is
hydrogen or any halogen and D is a good leaving group. In one embodiment, D is
halogen. In some embodiments, R9 is fluorine and D is bromine or chlorine. In other
embodiments, R9 is fluorine and D is bromine to yield the structure of Formula IIIb:
[0049] To further describe the methods and processes of the invention, the following
non-limiting schemes illustrate the various synthetic means that can be utilized to produce
pharmaceutically advantageous piperazine-piperidine compounds.
[0050] For instance, Scheme 1 illustrates the production of compounds of Formula
(I). As shown in Scheme 1, a compound of Formula I and a compound of Formula IVa
arc reacted under conditions effective to produce the di-quinoline substituted piperazine-
piperidine compound of Formula V, such as those described in Scheme I.
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, and R16, arc
each independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-
C8)-alkynyl, halogen, -CF3, -NO2, -CN, -OR25, -OSO2R25, -SR25, -SO7R25, -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)-alkcnyl,
or (C2-C6)-alkynyl.
[0051] Scheme 2 illustrates the production of compounds of Formula (I) and Formula
(IV) in which R1, R2, R3, R10, R11, R12, R13, R14, R15, and R16 are each hydrogen and Ra,
Rb, R4, R5, R6, R7, R8 and R9 are as defined above. An optionally substituted aniline
compound of Formula IIe is reacted with an appropriate reagent under conditions
effective to produce the quinoline compound of Formula IIIc. Numerous reagents and
conditions affect this transformation. Many of these can be found in a review by G. Jones
(Synthesis of the Quinoline Ring System, in Heterocyclic Compounds: Volume 32
(Quinoilines), Interscience, New York, New York, 1977, pp. 93-318). One such reagent
is glycerol, as originally described by Skxaup (Monatsh. (1880), 1,316). R4, R5 and R6 of
IIe are as above for I and W is a good leaving group, for example halogen , p-
tolucnesulfonyl (-OTs), methanesulfonyl (-OMs) or trifluoromethanesulfonyl -OTr. The
compound of Formula IIIc is then reacted with a protected -pipcrazine derivative under
conditions effective to provide a protected piperazino-quinoline of Formula X, wherein A
is a protecting group- Protecting groups arc 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 etal.,J. Am. Chem. Soc. 118:7217 (1996). The protected
piperazino-quinoline of Formula X 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 I. Separately, compounds of Formula IV are produced by
beginning with an optionally substituted aniline compound of Formula II and reacting it
with glycerol under conditions effective to produce the quinoline compound of Formula
III as described above. R7, Rg and R9 are as above for Formula IVa and W is a suitable

leaving group such as halogen, -OTs, -OMs or -OTr. The quinoline compound of
Formula III is then reacted with a piperidin-4-one derivative where the carbonyl group is
protected under conditions effective to provide the compound of Formula IX (e.g., a
palladium-catalyzed coupling such as that described above). Suitable protecting groups
are well known to those of skill in the art and include, without limitation, 1,4-dioxo-8-
azaspiro-4, 5-dccane. The compound of Formula IX is then reacted under conditions to
promote the removal of the protecting group {e.g., aqueous acid or a mixture of a water
miscible organic solvent and aqueous acid), providing the pipcridin-4-one compound of
Formula IV. The piperidin-4-one compound of Formula IV is then reacted with the
piperazino-quinoline compound of Formula I as described above in Schemes 1 and 2 to
produce the di-quinoline pipcrazine-piperidine compound of Formula Vc.
wherein R1, R2, R3, R4, R5, 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, -OSO2R25, -SR25, -SO2R25, -SO2N(R25)2, -N(K25)2,
C(O), -COR25, -CO2R25, -NR25CO2R25, -NR25COR2, -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.
[0052] Alternative syntheses for the quinoline compounds of Formulae IX and X are
provided in Scheme 3, shown below. The aniline compounds of Formulae XII and XIII
are reacted with an appropriate reagent under conditions effective to produce the
quinoline compounds of Formulae IX and X. Reagents 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- The
compounds of Formulae XIV and XV are then reacted with appropriate reagents to yield
the desired intermediate compounds of Formulae IX and X.
[0053] The methods of the present invention also provide means for more safely
synthesizing piperazine-piperidine compounds that have toxic and environmentally
damaging byproducts. The present invention provides the method of Scheme 2a in which

the components of certain steps in the process have been altered to allow for safer
synthesis of the compounds of interest. In certain embodiments, the reaction of
optionally substituted anilines in conditions effective to form optionally substituted
quinolincs is performed by the process of Scheme 2a:
wherein D is a good leaving group, and 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, -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)-haIoalkyl, (C2-C6)-alkenyl,
or (C2-C6)-alkynyl.
[0054] In one embodiment, D is halogen.
[0055] According to the synthesis of Scheme 2a, 4-nitrophcnol and optionally
substituted aniline compounds of Formulae II are mixed together prior to addition to or
the addition of acid to produce the quinoline compounds of Formula III. In certain
embodiments, the acid is a strong acid. In other embodiments, the acid is H2SO4 or HCl.
In one embodiment, glycerol is added to the reaction. By performing the present reaction
accordingly, the reaction is less likely to represent a hazardous increase in temperature
(e.g., thermal runaway). This reduces the possibility of a volatile reaction occurring,
thereby improving the safety of the production process.
[0056] In additional embodiments, Scheme 2 is further modified to allow for isolation
of piperazine-piperadine compounds without the use of potentially environmentally
hazardous materials. In particular, piperadine and piperazine compounds are reacted in
conditions in which toluene replaces chlorinated solvents to produce the following
reaction Scheme 2b:
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.
[0057] The production of the di-quinoline substituted piperazine-piperidine
compound of Formula V is accomplished by the reaction of the compounds of Formula I
and Formula IV in effective conditions for the reaction to be completed. In certain
embodiments, the use of toluene reduces the amount of chlorinated byproducts requiring
disposal, which reduces the amount of hazardous environmental byproducts produced
during synthesis of the piperazine-piperidine compounds. In addition, the use of toluene
rather than chlorinated compounds such as CH2Cl2 reduces the toxicity of me compounds.
Such decrease in toxicity is important due to the use of these compounds as
pharmaceutical agents.
[0058] The process shown in Scheme 2b also has the advantage of increasing the
yield of Formula V over processes utilizing CH2Cl2. In certain embodiments, the yield of
the di-quinoline substituted piperazine-piperidine compound of Formula V in processes
using toluene is between 2.5 times and 3 times greater than processes utilizing
dichloromethane. In certain other embodiments, the yield is increased by 1.5 times to 2
times over processes utilizing dichloromethane. In other embodiments, the yield is
increased by more than 3 times, and up to 10 times over processes using dichloromethane.
[0059] The isolation of quinoJine-substituted piperazine compounds of Formula I has
presented a problem during standard production procedures due to the generation of
highly viscous solutions that create difficulties in isolating intermediates for further
processing. Accordingly, the present invention provides methods of isolating the
compounds of Formula 1. In some embodiments, the reaction of Scheme 3 is modified to
allow for improved isolation of di-quinolinc substituted piperazine-piperidine compound
of Formula V by way of Scheme 2c:
wherein R1, R2, R3, R4, R5, and R6, are each independently -H, (C1-C6)-alkyl, (C1-
C6)-haloalkyl, (C2-C6)alkenyl, or (C2-C6)-alkyny], halogen, -CF3, -NO2, -CN, -OR25, -
OSO2R25, -SR25, -SO2R25, -SO2N(R25)2, -N(R25)2, C(O), -COR25, -CO2R25, -NR2SCO2R25,
-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.
[0060] The quinoline-substituted piperazine of Formula I is reacted with adipic acid
in conditions effective to yield the adipate salt of the quinoline-substituted piperazine of
Formula XVI. The reaction allows for further isolation of the quinoline-substituted
piperazine in the presence of NaOH, toluene, CH2Cl2, and EtOAc according toScheme
2d:
XVI I
[0061] Accordingly, the present invention provides a method For isolating quinoline-
substiruted piperazine compounds of Formula XVI and Formula 1.
[0062] In additional embodiments, Scheme 2 is modified to allow for isolation of
piperazine-piperadine compounds without the use of potentially environmentally
hazardous materials. In particular, piperadine and piperazine compounds are reacted in
conditions in which toluene replaces chlorinated solvents to produce the following
reaction Scheme 2e:
wherein R1, R2, R3, and R4, are each independently hydrogen, (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,
-NR25COR2S, -NR2sCON(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.
[0063] The production of the di-quinoline substituted piperazine-piperidine
compound of Formula (XXI) is accomplished as described above for compounds of
Formula (I), (1'), and (1").
[0064] In some embodiments, R1, R2, R3, and R4, arc each independently hydrogen,
(C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, halogen, -CF3,
-OR25 and R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-
alkenyl, or (C2-C6)-alkynyl. In certain embodiments, R1, and R3 are hydrogen, (C1-C6)-
alkyl and R2 is hydrogen or halogen (e.g., fluorine). In one embodiment, R4, is hydrogen
or -CF3.
[0065] In certain embodiments, the process shown in Scheme 2e has the advantage of
decreasing the amount of solvent found in the final compound. In some embodiments,
the amount of each individual solvent is less than 0.25 w% of the compound identified in
solution. In other embodiments, the amount of each solvent is less than 0.2 w% of the
compound identified in solution. In still other embodiments, the amount of each solvent
is less than 0.15 w% of the compound identified in solution. In further embodiments, the
amount of each solvent is less than 0.1 vv% of the compound identified in solution. In yet
more embodiments, the amount of each solvent is less than 0.05 w% of the compound
identified in solution. In still more embodiments, the amount of each solvent is less than
0.025 w% of the compound identified in solution. In additional embodiments, the amount
of each solvent is less than 0.02 w% of the compound identified in solution. In another
embodiment, the amount of each solvent is less than 0.01 w% of the compound identified
in solution. In one embodiment, the presence of chlorinated solvents is decreased
significantly from the final isolated compound.
[0066] In some embodiments, the process shown in Scheme 2e occurs in the presence
of organic compounds including, but not limited to, THF, acetone, dichloromethane, and
dichloroethane. In certain embodiments, the organic compounds are THF and acetone.
In one embodiment, the compounds of Formula XVII are mixed with THF prior to
addition to a solution of acetone and an organic acid. In another embodiment, the organic
acid is succinic acid.
wherein W is halogen, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12, are
each independently -H, (C1-C6)-alkyl, (C1-C6)-haloalky1, (C2-C6)-alkcny1, 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.
[0067] Schemes 1-4 illustrate the synthetic methodology used to prepare particular
compounds of the present invention. One of skill in the art will recognize that Schemes
1-4 can be adapted to produce the other compounds accordirig to the present invention
and that other methods may be used to produce the compounds of the present invention.
Compounds of the Invention
[0068] The processes of synthesis described above are used to produce novel
piperazine-piperidine compounds. In one embodiment, the process of the present
invention is directed to synthesizing compounds of the Formula (V):
and pharmaceutically acceptable salts and hydrates thereof,
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.
[0069] In one embodiment, R1 is (C1-C6)-alkyl, -OR25, halogen, or -CF3. Tn another
embodiment, R1 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13, R14, R15 and
R16 is (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R1, is (C1-C6)-alkyl,
-OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen,
and R7, R8, R9, R10, R11, and R12 are each hydrogen. In yet another embodiment, R1 is
(C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is (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, R1 is (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.
[0070] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3. In another
embodiment, Rs is (C1-C6)alkyl, -OR25, halogen, or -CF3 and one of R13, R14, R15, and
R16 is (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R5 is (C1-C6)-alkyl,
-OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, halogen or
-CF3, and R7, R8, R9, R10, R11, and R12 are each hydrogen. In yet another embodiment, R5
is(C1-C6)-alkyl, -OR25, halogen, or-CF3; one of R13, R14, R15, and R16 is (C1-C6)-alkyl,
-OR25, or halogen; and R1, R2, R3, R4, R6, R7, R8, R9, R10, R11, and R12 are each hydrogen.
In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen or -CF3 and R1, R2, R3, R4, R5, 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 (C1-C6)-alkyl, halogen, -CF3, or -OR25; R5 is
(C1-C6)-alkyl, -OR25, halogen, or -CF3; and the remaining substituents are each hydrogen.
[0071] In one embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3. In another
embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13, Rl4, R15, and
R16 is (C1-C6)-alkyl, -OR2S, or halogen. In a further embodiment, R4 is (C1-C6)-alkyl,
-OR25. halogen, or -CF3; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen,
and R7, R8, R9, R10, R11, and R12 are each hydrogen. In yet another embodiment, R4 is
(C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is (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 (C1-C6)-alkyl, -OR25, halogen or -CF3 and R1, R2, R3, R5, R6,
R7, R8, R9, Rio, R11, R12, R13, R14, R15, and R16 are each hydrogen.
[0072] In one embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In another embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of
R1, R2, R3, R4, R5 and R6 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; and Ra and Rb are each
independently -H or -CH3; and the remaining substituents are each hydrogen. In a further
embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3,
R4, R5 and R6 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is
(C1-C6)-alkyl, -OR25, or halogen, and the remaining substituents are each hydrogen. In
one embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN and one of R4 or
R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3, and the remaining substituents are each
hydrogen. In one embodiment R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
and all other R groups are each hydrogen. In one embodiment, R9 is (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25,
or halogen, and the remaining substituents are each hydrogen.
[0073] In one embodiment, R8 is (C]-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In another embodiment, R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of
R1, R2, R3, R4, R5 and R6 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; Ra and Rb arc each
independently -H or -CH3; and the remaining substituents are each hydrogen. In a further
embodiment, R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or CN; one of R,, R2, R3,
R4, R5 and R6 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is
(C1-C6)-alkyl, -OR25, or halogen, and the remaining substituents are each hydrogen. In
one embodiment, R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN and one of R4 or
R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3, and the remaining substituents are each
hydrogen. In one embodiment R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
35
and all other R groups are each hydrogen. In one embodiment, R8, is (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25,
or halogen, and the remaining substituents are each hydrogen.
[0074] In one embodiment, R7 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R7 is -OR25 and R25 is (C1-C6)-alkyl. In one embodiment, R7 is -
OCH3
[0075] In one embodiment, R10 is (C1-C6)alky], -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R10 is -OR25 and R25 is (C1-C6)-alkyl. In one embodiment, R10 is -
OCH3.
[0076] In one embodiment, R11 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R11 is -OR25 and R25 is (C1-C6)-alkyl. In one embodiment, R11 is —
OCH3
[00771 In one embodiment, R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R12 is -CF3.
[0078] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of
R7, Rg, R9, R10, R11 and R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN. In
another embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R7, R8, R9,
R10, R11, R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and the remaining
substituents are each hydrogen. In some embodiments, R5 is (C1-C6)-alkyl, -OR25,
halogen, or -CF3 and R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and the
remaining substituents are each hydrogen.
[0079] In a further embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of
R7, R8, R9, R10, R14, and R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of
R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen, and the remaining substituents
are each hydrogen.

[0080]0 In a further embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; two of
R7, R8, R9, R10, R11, and R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of
R13, R14, R15, and R16 is (C1-C6)alkyl, -OR250, or halogen, and the remaining substituents
are each hydrogen.
|0081] In a further embodiment, R5 is (C1-C6)-alkyl, -QR25, halogen, or -CF3; three of
R7, R8, R9, R10, R11. and R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of
R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen, and the remaining substituents
are each hydrogen.
[0082] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is
(C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and two of R10, R11 and R12 are each
independently (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN. In another
embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; two of R10, R11, R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; and the remaining substituents are each hydrogen. In some embodiments,
R5 is -OR25; R9 is halogen; two of R10, R11, R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; and the remaining substituents are each hydrogen. In some embodiments,
R3 is -OCH3; R9 is halogen; two of R10, R11, R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; and the remaining substituents are each hydrogen. In some embodiments,
R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; R10 and R)2 are each independently (C1-C6)-alkyl, -ORjs, halogen, -CF3,
-NO2 or -CN; and the remaining substituents are each hydrogen. In some embodiments,
R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; R10 and R11 are each independently (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; and the remaining substituents are each hydrogen. In some embodiments,
R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3,

-NO2 or -CN; R11 and R12 are each independently (C1-C6)-alkyl, -OR23, halogen, -CF3,
-NO2 or -CN; and the remaining substituents are each hydrogen.
[00831 In one embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of
R7, R8, R9, R10, R11 and R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN. In
another embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R7, R7, R8, R10,
R11, and R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and the remaining
substituents are each hydrogen. In a further embodiment, R4 is (C1-C6)-alkyl, -OR25,
halogen, or -CF3; one of R7, R8, R9, R10, R11, R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; one of R13, R14, R15, and R16 is (C1 -C6)-alkyl, -OR25, or halogen, and the
remaining substituents are each hydrogen.
[0084] In one embodiment, one of R14, R14, R15, and R16 is (C1-C6)-alkyl, halogen,
-CF3, or -OR25. In one embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN. In another embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
one of R1, R2, R3, R4, R5 and R6 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; and Ra and Rb
are each independently -H or -CH3; and the remaining substituents are each hydrogen. In
a further embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1,
R2, R3, R4, R5 and R8, is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and
R16 is (C1-C6)-alkyl, -OR25, or halogen, and the remaining substituents are each hydrogen.
In one embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN and one of R4
or R5 is (C1-C5)-alkyl, -OR25, halogen, or -CF3, and the remaining substituents are each
hydrogen. In one embodiment R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
and all other R groups are each hydrogen. In one embodiment, R9 is (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25,
or halogen, and the remaining substituents are each hydrogen.
[0085] In one embodiment, R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In another embodiment, R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of
R1, R2, R3, R4, R5 and R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; R. and Rb are each
independently -H or -CH3;and the remaining substituents are each hydrogen. In a further
embodiment, R8, is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R7, R3,
R4, R5 and R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is
(C1-C6)-alkyl, -OR25, or halogen, and the remaining substituents are each hydrogen. In
one embodiment, R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN and one of R4 or
R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3, and the remaining substituents are each
hydrogen. In one embodiment R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
and all other R groups are each hydrogen. In one embodiment, R8 is (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25,
or halogen, and the remaining substituents are each hydrogen.
[0086] In one embodiment, R7 is (C1-C6)-alky1, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R7 is -OR25 and R25 is (C1-C6)-alkyl. In one embodiment, R7 is -
OCH3.
[0087] In one embodiment, R10 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R10 is -OR25 and R25 is (C1-C6)-alkyl. In one embodiment, R10 is -
OCH3.
[0088] In one embodiment, R,, is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R11 is -OR25 and R25 is (C1-C6)-alkyl. In one embodiment, R11 is -
OCH3
[0089] In one embodiment, R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R12 is -CF3.
[0090] In one embodiment, R1, R2, R3, R8, R7, R8, R9, R10, R11,R12, Rf3, R14, R15, and
R16 are each hydrogen.
[0091] In one embodiment, R1, R2, R3, R4, R7, R9, R10, R11, and R12 are each
hydrogen.
[0092] In one embodiment, R1, R2, R3, R4, R7, R8, R10, R11, and R12 are each
hydrogen.
[0093] In one embodiment, R1, R2, R3, R8, R7, R8, R9, R11, and R12 are each hydrogen.
[0094] In one embodiment, R1, R2, R3, R4, R7, R8, R9, R10, and R12 are each hydrogen.
[0095] In one embodiment, R1, R2, R3, R4, R7, R1, R9, R10, and R11 are each hydrogen.
[0096] In one embodiment, R1, R2, R3, R4, R7, R8, and R11 are each hydrogen.
[0097] In one embodiment, R1, R2, R3, R4, R7, R8, R9 and R11 are each hydrogen.
[0098] In one embodiment, R1, R2, R3, R4, R5, R8, R7, R8, R9, and R12 are each
hydrogen.
[0099] In another embodiment, R13, RM, R15, and Rl6 are each hydrogen.
[0100] In one embodiment, R3, R8, R7, R8, R9, R12, R15, R10, R15, and R16 are each
hydrogen.
[0101] 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,
R12, R13, R14, R15, R16, Ra and Rb are each hydrogen. In one embodiment, R1 is -H or -
CH3; R1, R8, and R9 are each -H or F; R4 is -H, F, -OCH3, or -CF3; R5 is -H, F, -OCH3;
and R3, R8, R7, R10, R11, R12, R13, R14, R15, R16, Ra and Rb are each hydrogen.
[0102] In one embodiment, Rt is -H, -CF3 or (C1-C6)-alkyl; R4 and R5 are each -H,
halogen, -OR25, or-CF3; R7, R1, R9, R10, R11,and R12 are each-H, halogen, -alkyl, -OR25,
-CF3, or -NO2; R16 is -H or -CH3.
[0103] In one embodiment, any one of R7, R8, R9, R10, R11, and R12 is (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2, or -CN; and any one of R13, R14, R15, and R16 is (C1-C6)-
alkyl, -OR25, halogen, -CF3.
[0104] In one embodiment, any one of R1, R2, R3, R4, R8, and R6 is (C1-C6)-alkyl,
-OR25, halogen or -CF3; and any one of R7, R8, R9, R10, R11, and R12 is (C1-C6)-alkyl,
-OR25, halogen, or -CF3, -NO2, or -CN.
[0105] In one embodiment, any one of R1, R2, R3, R4, R5, and R8, is (C1-C6)-alkyl,
-OR25, halogen or -CF3; and any one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25,
halogen or -CF3.
[0106] In one embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and any one
of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25. halogen or -CF3; and any one of R7, R8,
R9, R10, R11, and R12 is (C1-C6)-alkyl, -OR25, halogen, or -CF3, -NO2, or -CN.
[0107] In one embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and any one
of R13, R14, R15, and R16 is (C1-C6)-alkyl,-OR25, halogen or-CF3; and any two of R7, R8,
R9, R10, R14, and R12 is (C1-C6)-alkyl, -OR25, halogen, or -CF3, -NO2, or -CN; wherein the
any two of R7, R8, R9, R10, R14, and R12 can be cither on the same ring of thequinoline or
on different rings.
[0108] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and any one
of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, halogen or -CF3; and any one of R7, R8,
R9, R10, R11, and R12 is (C1-C6)-alkyl, -OR25, halogen, or -CF3, -NO2, or -CN.
[0109] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and any one
of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, halogen or -CF3; and any two of R7, R8,
R9, R10, R11, and R12 is (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 thequinoline or
on different rings.

[0110] In one embodiment, R25 is (C1-C6)-haloalkyl.
[0111] In another embodiment, R25 is (C1-C6)-fluoroalkyl.
[0112] In one embodiment, R25 is (C1-C6)-alkyl. In one embodiment, R25 is -CH3.
[0113] In one embodiment, the compounds of Formula (V) are antagonists of the 5-
HT1A receptor. In another embodiment, the compounds of Formula (V) are agonists of
the 5-HT1A receptor.
[0114] In another aspect, the processes for synthesizing piperazine-piperidine
compounds provides compounds of the Formula (Vc):
and pharmaceutically acceptable salts and hydrates thereof,
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R11, 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 n is an integer from I to 2.
[0115] In one embodiment, R1 is (C1-C6)-alkyl, -OR25, halogen, or -CF3. In another
embodiment, R1 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13, R14, R15, and
R16 is (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R1 is (C1-C6)-alkyl,
-OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen,
and R7, R8, R9, R10, R11, and R12 are each hydrogen. In yet another embodiment, R1 is
(C1-C6)-alkyl, -OR25, halogen, or-CF3; one of R13, R14, R15, and R16 is (C1-C6)-alkyl,
-OR25, or halogen, and R1, R2, R3, R5, R8, R7, R8, R9, R10, R11. and R12 are each hydrogen.
In one embodiment, R1, is (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.
[0116] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3. In another
embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13, R14, R15, and
R16 is (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R5 is (C1-C6)-alkyl,
-OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, halogen or
-CF3, and R7, R8, R9, R10, R14, and R12 are each hydrogen. In yet another embodiment, R5
is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is (C1-C6)-alkyl,
-OR25, or halogen; and R1, R2, R3, R4, R6, R7, R8, R9, R10, R11, and R12 are each hydrogen.
In one embodiment, R5 is (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 (C1-C6)-alkyl, halogen, -CF3, or -OR25; R5 is
(C1-C6)-alkyl, -OR25, halogen, or -CF3; and the remaining substituents are each hydrogen.
[0117] In one embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3. In another
embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13, R14, R15, and
R16 is (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R4 is (C1-C6)-alkyl,
-OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen,
and R7, R8, R9, R10, R11, and R12 are each hydrogen. In yet another embodiment, R4 is
(C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is (C1-C6)-alkyl,
-OR25, or halogen, and R1, R2, R3, R8, R8, R7, R8, R9, R10, R11, and R12 are each hydrogen.
43
In one embodiment, R4 is (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.
[0118] In one embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In another embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of
R1, R2, R3, R4, R5 and R6 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; and Ra and Rb are each
independently -H or -CH3; and the remaining substituents are each hydrogen. In a further
embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3,
R4, R5 and R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is
(C)-C6)-alkyl, -OR25, or halogen, and the remaining substituents are each hydrogen. In
one embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN and one of R4 or
R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3, and the remaining substituents are each
hydrogen. In one embodiment R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
and all other R groups are each hydrogen. In one embodiment, R9 is (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25,
or halogen, and the remaining substituents are each hydrogen.
[0119] In one embodiment, R8, is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In another embodiment, R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of
R1, R2, R3, R4, R5 and R8, is (C1-C6)-alkyl, -OR25, halogen, or -CF3; Ra and Rb are each
independently -H or -CH3; and the remaining substituents are each hydrogen. In a further
embodiment, R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3,
R4, R5 and R8, is (C1-C6)-alkyl, -OR25 halogen, or -CF3; one of R13, R14, R14, and R16 is
(C1-C6)-alkyl, -OR25, or halogen, and the remaining substituents are each hydrogen. In
one embodiment, R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN and one of R4 or
R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3, and the remaining substituents are each
hydrogen. In one embodiment R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;

and all other R groups are each hydrogen. In one embodiment, R5 is (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25,
or halogen, and the remaining substituents are each hydrogen.
[0120] In one embodiment, R7 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R7 is -OR25 and R25 is (C1-C6)-alkyl. In one embodiment, R7 is -
OCH3
[0121] In one embodiment, R10 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R10 is -OR25 and R25 is (C1-C6)-alkyl. In one embodiment, R10 is -
OCH3.
[0122] In one embodiment, R13 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R11 is -OR25 and R25 is (C1-C6)-alkyl. In one embodiment, R11 is -
OCH3
[0123] In one embodiment, R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R12 is -CF3.
[0124] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of
R7, R8, R9, R10, R11 and R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN. In
another embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R7, R8, R9,
R10, R11, R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and the remaining
substituents are each hydrogen. In some embodiments, R5 is (C1-C6)-alkyl, -OR25,
halogen, or -CF3 and R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and the
remaining substituents are each hydrogen.
[0125] In a further embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of
R7, R8, R9, R10, R11, and R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of
R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen, and the remaining substituents
are each hydrogen.

[0126] In a further embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen; or -CF3; two of
R7, R8, R9, R10, R11, and R12, is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of
R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen, and the remaining substituents
are each hydrogen.
[0127] In a further embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; three of
R7, R8, R9, R10, R11, and R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of
R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen, and the remaining substituents
are each hydrogen.
[0128] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is
(C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and two of R10, R11and R12 are each
independently (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN. In another
embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or -CN; two of R10, R11, R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; and the remaining substituents are each hydrogen. In some embodiments,
R5 is -OR25; R9 is halogen; two of R10, R11, R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; and the remaining substituents are each hydrogen. In some embodiments,
R5 is -OCH3; R9 is halogen; two of R10, R11, R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; and the remaining substituents are each hydrogen. In some embodiments,
R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or-CN; R10 and R12 are each independently (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; and the remaining substituents are each hydrogen. In some embodiments,
R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; R10 and R11 are each independently (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; and the remaining substituents are each hydrogen. In some embodiments,
R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3,

-NO2 or -CN; R11 and R12 are each independently (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; and the remaining substituents are each hydrogen.
[0129] In one embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of
R7, R8, R9, R10, R11 and R12, is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN. In
another embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R7, R8, R9, R10,
R11, and R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and the remaining
substituents are each hydrogen. In a further embodiment, R4 is (C1-C6)-alkyl, -OR25,1
halogen, or -CF3; one of R7, R8, R9, R10, R11, R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; one of R13, R14, R15 and R16 is (C1-C6)-alkyl, -OR25, or halogen, and the
remaining substituents are each hydrogen.
[0130] In one embodiment, one of R13, R14, R15, and R16 is (C1-C6)-alkyl, halogen,
-CF3, or -OR25.
[0131] In one embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In another embodiment, R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of
R1, R2, R3, R4, R5 and R6 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; and Ra and Rb are each
independently -H or -CH3; and the remaining substituents are each hydrogen. In a further
embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3,
R4, R5 and R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is
(C1-C6)-alkyl, -OR25, or halogen, and the remaining substituents are each hydrogen. In
one embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN and one of R4
or R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3, and the remaining substituents are each
hydrogen. In one embodiment R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN;
and all other R groups are each hydrogen. In one embodiment, R9 is (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25,
or halogen, and the remaining substituents are each hydrogen.

[0132] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In another embodiment, R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of
R1, R2, R3, R4, R5 and R8, is {C1-C6)-alkyl, -OR25, halogen, or -CF3; Ra and Rb are each
independently -H or -CH3; and the remaining substituents are each hydrogen. In a further
embodiment, R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3,
R4, R5 and R6 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is
(C1-C6)-alkyl, -OR25, or halogen, and the remaining substituents are each hydrogen. In
one embodiment, R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN and one of R4 or
R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3, and the remaining substituents are each
hydrogen. In one embodiment R8 is (C1-C6)-a.lkyl, -OR25, halogen, -CF3, -NO2 or -CN;
and all other R groups are each hydrogen. In one embodiment, R8 is (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; one of R13, RM, R15, and R16 is (C1-C6)-alkyl, -OR25,
or halogen, and the remaining substituents are each hydrogen.
[0133] In one embodiment, R7 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R7 is -OR25 and R2S is (C1-C6)-alkyl. In one embodiment, R7 is -
OCH3
[0134] In one embodiment, R10 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R10 is -OR25 and R2S is (C1-C6)-alkyl. In one embodiment, R10 is -
OCH3.
[0135] In one embodiment, R1, is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R11 is -OR25 and R25 is (C1-C6)-alkyl. In one embodiment, Ra is —
OCH3
[0136] In one embodiment, R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R12 is -CF3.
[0137] In one embodiment, R1, R2, R3, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, and
R16 are each hydrogen.
[0138] In one embodiment, R1, R2, R1, R4, R7, R9, R10, R11, and R12 are each
hydrogen.
[0139] In one embodiment, R1, R2, R3, R4, R7, R8, R10, R11, and R12 are each
hydrogen.
[0140] In one embodiment, R1, R2, R3, R4, R7, R8, R9, R11, and R12 are each hydrogen.
[0141] In one embodiment, R1, R2, R3, R4, R7, Rg. R9. R10, and R12 are each hydrogen.
[0142] In one embodiment, R1, R2, R3, R4, R7, R8, R9, R10, and R11 are each hydrogen.
[0143] In one embodiment, R1, R2, R3, R4, R7, Rg. and R11 are each hydrogen.
[0144] In one embodiment, R1, R2, R3, R, R7, R8, R9 and R11 are each hydrogen.
[0145] In one embodiment, R1, R2, R3, R4, R8, R6, R7, R8, R9, and R12 are each
hydrogen.
[0146] In another embodiment, R14, R14, R14, and R16 are each hydrogen.
[0147] In one embodiment, R3, R6, R7, R8, R9, R12, R14, R14, R15, and R16 are each
hydrogen.
[0148] 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; R3 is -H, halogen, or -OR25; and R3, R6, R7,
R12. R13, R14, R15, R16, Ra, and Rb are each hydrogen. In one embodiment, R1 is -H or -
CH3; R2, R8, and R9 are each -H or F; R is -H, F, -OCH3, or -CF3; R5 is -II, F, -OCH3;
and R1, R8, R7, R10, R11, R12, R13, R14, R15, R16, Ra and Rb are each hydrogen.
[0149] In one embodiment, R1 is -H, -CF3 or (C1-C6)-alkyl; R8 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.
[0150] In one embodiment, any one of R7, R8, R9, R10, R11, and R12 is (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2, or -CN; and any one of R13, R14, R15, and R16 is (C1-C6)-
alkyl, -OR25, halogen, -CF3.
[0151] In one embodiment, any one of R1, R2, R3, R4, R5, and R6 is (C1-C6)-alkyl,
-OR25, halogen or -CF3; and any one of R7, R8, R9, R10, R11, and R12 is (C1-C6)-alkyl,
-OR25, halogen, or -CF3, -NO2, or -CN.
[0152] In one embodiment, any one of R1, R2, R3, R4, R5, and R6 is (C1-C6)-alkyl,
-OR25, halogen or -CF3; and any one of R14, R14, R14, and R16 is (C1-C6)-alkyl, -OR25,
halogen or -CF3.
[0153] In one embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and any one
of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, halogen or-CF3; and any one of R7, R8,
R9, R10, R11, and R12 is (C1-C6)-alkyl, -OR25, halogen, or -CF3, -NO2, or -CN.
[0154] In one embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and any one
of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, halogen or-CF3; and any two of R7, R8,
R9, R10, R11,and R12 is (C1-C6)-alkyl, -OR25, halogen, or -CF3, -NO2, or -CN; wherein the
any two of R7, R8, R9, R10, R14, and R12 can be either on the same ring of the quinoline or
on different rings.
[0155] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and any one
of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, halogen or -CF3; and any one of R7, R8,
R9, R10, R14, and R12 is (C1-C6)-alkyl, -OR25, halogen, or -CF3, -NO2, or -CN.
[0156] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and any one
of Rt3, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, halogen or -CF3; and any two of R7, R8,
R9, R10, R14, and R11 is (C1-C6)-alkyl, -OR25, halogen, or -CF3, -NO2, or -CN; wherein the
any two of R7, R8, R9, R10, R14, and R12 can be either on the same ring of the quinoline or
on different rings.

[0157] In one embodiment, R25 is (C1-C6)-haloalkyl.
[0158] In another embodiment, R25 is (C1-C6)-fluoroalkyl.
[0159] In one embodiment, R25 is (C1-C6)-alkyl. In one embodiment, R25 is -CH3.
[0160] In one embodiment, the compounds of Formula V are antagonists of the 5-
HT1A receptor. In another embodiment, the compounds of Formula V are agonists of the
5-HT1A receptor.
[0161] In another aspect, the compounds of the Formula Vd are synthesized by the
methods of the present invention:
and pharmaceutically acceptable salts thereof,
wherein R1, R2, R1, R4, R1, R5, R7, R7, R8, R9, R10, R14, 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), -COR2S, -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; 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.
[0162] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3. In another
embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13, R14, R15, and
R16 is (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R5 is (C1-C6)-alkyl,
-OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, halogen or
-CF3; the piperdine 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 (C1-C6)-alkyl, -OR25. halogen, or -CF3; one of R13, R14, R15, and R16 is
(C1-C6)-alkyl, -OR25, or halogen; the piperidine is connected through R7-; and the
remaining R groups are each hydrogen. In yet another embodiment, R1 is (C1-C6)-alkyl,
-OR25, halogen, or -CF3; one of R14, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen;
the piperidine is connected through R7; and the remaining R groups are each hydrogen.
In yet another embodiment, R5 is (C1-C6)alkyl, -OR25, halogen, or -CF3; one of R13, R14,
R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen; the piperidine is connected through Rg;
and the remaining R groups are each hydrogen. In yet another embodiment, R5 is (Cp
C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R14, and R,6 is (C1-C6)-alkyl, -OR25,
or halogen; the piperidine is connected through R9; and the remaining R groups are each
hydrogen. In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen or -CF3, the piperidine
is connected through R7', and the remaining R groups are each hydrogen. In one
embodiment, R1 is (C1-C6)-alkyl, -OR25, halogen or -CF3, the piperidine is connected
through R7, and the remaining R groups are each hydrogen. In one embodiment, R5 is
(C1-C6)alkyl, -OR25, halogen or -CF3, the piperidine is connected through R8, and the
remaining R groups are each hydrogen. In one embodiment, R5 is (C1-C6)-alkyl, -OR25,
halogen or -CF3, the piperidine is connected through R9, and the remaining R groups are

each hydrogen. In a further embodiment, one of R14, R14, R14, and R16 is (C1-C6)-alkyl,
halogen, -CF3, or -OR25; R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; and the remaining
substituents are each hydrogen.
[0163] In one embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3. In another
embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R13, R14, R15, and
R16 is (C1-C6)-alkyl, -OR25, halogen, or -CF3. In a further embodiment, R4 is (C1-C6)-
alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25,
halogen or -CF3; the piperdine 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 (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14,
R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen; the piperidine is connected through R7';
and the remaining R groups are each hydrogen. In yet another embodiment, R4 is (C1-
C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25,
or halogen; the piperidine is connected through R7; and the remaining R groups are each
hydrogen. In yet another embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one
of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen; the piperidine is connected
through R8; and the remaining R groups are each hydrogen. In yet another embodiment,
R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is (C1-C6)-alkyl,
-OR25, or halogen; the piperidine is connected through R9; and the remaining R groups
are each hydrogen. In one embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen or -CF3, the
piperidine is connected through R7', and the remaining R groups are each hydrogen. In
one embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen or -CF3, the piperidine is connected
through R7, and the remaining R groups are each hydrogen. In one embodiment, R4 is
(C1-C6)-alkyl, -OR25, halogen or -CF3. the piperidine is connected through R8, and the
remaining R groups are each hydrogen. In one embodiment, R4 is (C1-C6)-alkyl, -OR25,

halogen or -CF3, the piperidinc is connected through R9, and the remaining R groups are
each hydrogen.
[0164] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of
R7, R8, R9, R10, R11 and R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN. In
another embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of R7, R8, R9,
R10, R11, or R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and the remaining
substiruents are each hydrogen. In some embodiments, R5 is -OR25 and R9 is (C1-C6)-
alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and the remaining substiruents are each
hydrogen. In some embodiments, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3, R9 is
halogen and the remaining substiruents are each hydrogen.
[0165] In a further embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of
R7, R8, R9, R10, R11; R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R13,
R14, R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen, and the remaining substituenls are
each hydrogen.
[0166] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; two of R7,
R8, R9, R10, R11; R12 are each independently (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; one of R13, R14, R15, and R16, is (C1-C6)-alkyl, -OR25, or halogen, and the remaining
substiruents are each hydrogen.
[0167] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; three of R7,
R8, R9, R10, R11, R12 are each independently (C1-C6)-alkyl, -OR25, haloyen, -CF3, -NO2 or
-CN; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen, and the remaining
substituents are each hydrogen.
[0168] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; R9 is
(C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and two of R10, R11 and R12 are each
independently (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN. In another

embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; Ra is (C1-C6)-alkyl, -OR25,
halogen, -CF3, -NO2 or-CN; two of R10, R11, R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3,
-NO2 or -CN; and the remaining substituents are each hydrogen. In some embodiments,
In some embodiments, R5 is -(C1-C6)-alkyl, -OR25, halogen, or -CF3; R8 is (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or-CN; R10 and R12 are each independently (C1-C6)-alkyl,
-OR25, halogen, -CF3, -NO2 or -CN; and the remaining substituents are each hydrogen. In
some embodiments, In some embodiments, R5 is -(C1-C6)-alkyl, -OR25, halogen, or -CF3;
R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; R10 and R11 are each
independently (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and the remaining
substituents are each hydrogen. In some embodiments, In some embodiments, R5 is -(C1-
C6)-alkyl, -OR25, halogen, or -CF3; R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3. -NO2 or
-CN; R11 and R12 are each independently (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or
-CN; and the remaining substituents are each hydrogen.
[0169] In one embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of
R7', R7, R8, R9, R10, R11 and R12, is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN. In
another embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R7-, R7, R8, R9,
R10, R11, and R12 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; and the remaining
substituents are each hydrogen. In a further embodiment, R4 is (C1-C6)-alkyl, -OR25,
halogen, or -CF3; one of R7-, R7, R8, R9, R10, R11, R12 is (C1-C6)-alkyl, -OR25, halogen,
-CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen, and
the remaining substituents are each hydrogen.
[0170] In one embodiment, one of R13, R14, R15, and R16 is (C1-C6)-alkyl, halogen,
-CF3, or-OR25.
[0171] In one embodiment, R9 is (C1-C6}-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In another embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of
R1, R2, R3, R4, and R8, is (C1-C6)-alkyl, -OR25, halogen, or -CF3; Ra and Rb are each
independently -H or -CH3; and the remaining substituents are each hydrogen except for
the R group through which the piperidine is connected. In a further embodiment, R9 is
(C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R1, R2, R3, R4, and R8, is (C1-
C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25,
or halogen; Ra and Rb are each independently -H or -CH3; and the remaining substituents
are each hydrogen except for the R group through which the piperidine is connected. In
one embodiment, R9 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN and one of R4 or
R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3. In one embodiment R9 is (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 (C1-
C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is (C1-C6)-
alkyl, -OR25, or halogen, and the remaining substituents are each hydrogen except for the
R group through which the piperidine is connected.
[0172] In one embodiment, R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In another embodiment, R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN; one of
R1, R2, R3, R, and R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; Ra and Rb are each
independently-H or -CH3; and the remaining substituents are each hydrogen except for
the R group through which the piperidine is connected. In a further embodiment, R8 is
(C1-C6)-alkyl, -OR25, halogen, CF3, -NO2 or -CN; one of R1, R2, R1, R4, and R8, is (C1-
C6)-alkyl, -OR25, halogen, or -CF3; one of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25,
or halogen, Ra and Rb are each independently -H or -CH3; and the remaining substituents
are each hydrogen except for the R group through which the piperidine is connected. In
one embodiment, R8 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN and one of R4
or R5 is (C1-C6)-alkyl, -OR25, halogen, or-CF3. In one embodiment R8 is (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, R8 is (C1-
C6)-a]kyl, -OR25, halogen, -CF3, -NO2 or -CN; one of R13, R14, R15, and R16 is (C1-C6)-
alkyl, -OR25, or halogen, Ra and Rb are each independently -H or -CH3; and the remaining
substituents are each hydrogen except for the R group through which the piperidine is
connected.
[0173] In one embodiment, R7 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R7 is -OR25 and R25 is (C1-C6)-alkyl.
[0174] In one embodiment, R10 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R10 is -OR25 and R25 is (C1-C6)-alkyl.
|0175] In one embodiment, R11, is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R11 is -OR25 and R25 is (C1-C6)-alkyl.
[0176] In one embodiment, Rl2 is (C1-C6)-alkyl, -OR25, halogen, -CF3, -NO2 or -CN.
In one embodiment, R12 is -CF3.
[0177] 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.
[0178] In one embodiment, R1, R2, R3, R4, R7, R7', R8, K10, 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, R7, R7', R8, R9, R11, and R12, are each
hydrogen except for the R group through which the piperidine is connected.
[0180] In one embodiment, R1, R2, R3, R4, R7, R7', R8', R9, R10, and R11, are each
hydrogen except for the R group through which the piperidine is connected.
[0181] In one embodiment, R1, R2, R3, R4, R7, R7', R8, and R14, are each hydrogen
except for the R group through which the piperidine is connected.
[0182] In one embodiment, R1, R2, R3, R4, R7, R7, R8, R9, and R11, are each hydrogen
except for the R group through which the piperidine is connected.
[0183] 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.
[0184] In one embodiment, R1, R2, R3, R6, R7, 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, 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.
[0186] 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.
[0187] In one embodiment, R1, R2, R3, R4, R5, R6, R7, R7', R10, R11, and R12 are each
hydrogen.
[0188] In another embodiment, R13, R14, R15, and R16 are each hydrogen.
[0189] 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.
[0190] In one embodiment, R1 is -H or (C1-C6)-alkyl; R4 and R5 are each
independently -H, halogen, -OR7.5, or -CF3, R7, R7', R8, R9, R10, R11, and R12 are each
independently -H, halogen, (C1-C6)-alkyl , -OR24, -CF3, NO2 or CN; 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.
[0191] 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, R, R7, R8, R9, R12, R13, R14,
R is, and R16 are each hydrogen except for the R group through which the pipcridine is
connected.
[0192] In one embodiment, Rt 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, Ra is -H or (C1-C6)-alkyl; R2, R8',
and R9 are each -H or F; R4 is -II, F, -OR25, or -CF3; R5 is -H, F, or -OR25: and R3, R6, R7, R8, R9, R10, R11, R14, R15, and R16 are each hydrogen except for the R group through
which the pipcridine is connected.
[0193] In one embodiment, any one of R7, R7', R8, R9, R10, R11, and R12 is (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 (C1-C6)-alkyl, -OR25,
halogen or -CF3.
[0194] In one embodiment, any one of R1, R2, R3, R4, R5, and R6 is (C1-C6)-alkyl,
-OR25, halogen; and anyone of R7, R7', R8, R9, R10, R11, and R12, is (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, any one of R1, R2, R3, R4, R5, and R6, is (C1-C6)-alkyl.
-OR25, halogen; and any one of R13, R14, R15 and R16 is (C1-C6)-alkyl, -OR25 or halogen.
[0196] In one embodiment R4 is (C1-C6)-alkyl, -OR25, halogen or -CF3 and any one
of R13, R14, R15, and Rl6 is (C1-C6)-alkyl, -OR25. or halogen; and any one of R7, R7', R8,
R9, R10, R11, and R12, isa (C1-C6)-alkyl, -OR25, halogen, or -CF3, -NO or -CN except for
the R group through which the piperidine is connected.
[0197] tn one embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and any one
of R11, R14, Rl5, and R16 is (C1-C6)-alkyl, -OR25. or halogen; and any two of Rr, R7, R1,

R9, R10, R11,and R12 are each independently (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.
[0198] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and any one
of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen; and any one of R7, R7', R8,
R9, R10, R11, and R]2 is (C1-C6)-alky], -OR25, halogen, or -CF3, -NO3, or-CN except for
the R group through which the piperidine is connected
[0199] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and any one
of R13, R14, R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen; and any three of R7', R7, R8,
R9, R10, R11, and R12 are each independently (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 Rr, R7, R8, R9, R10, R11, and R12 can be either on the same ring of the
quinoline or on different rings.
[0200] 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.
[0201] In one embodiment, R25 is (C1-C6)-haloalkyl.
[0202] In another embodiment, R25 is (C1-C6)-fluoroalkyl.
[0203] In one embodiment, R25 is (C1-C6)-alkyl. In one embodiment, R25 is -CH3.
[0204] In one embodiment, the compounds of Formula Vb are antagonists of the 5-
HT1a receptor. In another embodiment, the compounds of Formula Vb are agonists of the
5-HT1a receptor.

[0205] In another aspect, the invention provides methods and processes of
synthesizing compounds of the Formula Ve:
and pharmaceutically acceptably salts thereof,
wherein Ra, Rb, R4, R5, R15, R16, R17, R18 and R19 are defined as above for Formula
V; and
R4 and R5, cannot bath be hydrogen.
[0206] In one embodiment, R4, and R5 are each independently -H, -OR?5, halogen, or
(C1-C6)-alkyl; R1S and R16 are each independently -H or ~CH3; and R17, R18, 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, -CH,, -CF3, -NO2, -CN. or -Br.
[0207] In another embodiment, R19 is in the para position relative to the nitrogen of
the piperidine.
[0208] In one embodiment, Rl7 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
quinolinc ring).
[0209] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3.

[0210] In another embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one
of R15 and R16 is (C1-C6)-alkyl, -OR25, or halogen. In a further embodiment, R5 is (C1-
C6)-alkyl, -OR25, halogen, or -CF3; one of R15 and R16 is (C1-C6)-alkyl, -OR25, or halogen;
and R17, R18 and R19 are each hydrogen.
[0211] In yet another embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; R15 is
(C1-C6)-alkyl, -OR25, or halogen, and R4 and R16 are each hydrogen.
[0212] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; R16 is
(C1-C6)-alkyl, -OR25, or halogen, and R4 and R15 are each hydrogen.
[0213] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen or -CF3 and R4, R15,
R16, R17, R18 and R19 are each hydrogen. In one embodiment, R1 is (C1-C6)-alkyl, -OR25,
halogen, or -CF3 and one of R17, R18 and R19 is (C1-C6)-alkyl, -OR25, halogen, or -CF3. In
another embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R17, R18 and R19
is (C1-C6)-alkyl, -OR25, halogen, or -CF3; and the remaining substitucnts are each
hydrogen.
[0214] In one embodiment, R5, R17, R18, and R19 are each independently (C1-C6)-alkyl,
-OR25, halogen or -CF3 and R8, R15, and R16 are each hydrogen. In one embodiment, R5 is
-OR25 or halogen; R17 and R18 are each independently -OR25, halogen or -CF3; R19 is
halogen; and Ra, Rb, R4, R15, and R16 are each hydrogen.
[0215] In one embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3.
[0216] In another embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one
of R15, and R16 is (C1-C6)-alkyl, -OR25, or halogen.
[0217] In a further embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of
R15 and R18 is (C1-C6)-alkyl, -OR25, or halogen; and R17, R18 and R19 are each hydrogen.
[0218] In yet another embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; R15 is
(C1-C6)-alkyl, -OR25, or halogen, and R5 and R16 are each hydrogen.

[0219] In one embodiment, R4, is (C1-C6)-alkyl, -OR25, halogen, or -CF3; R16 is
(C1-C6)-alkyl, -OR25, or halogen, and R5 and R15 are each hydrogen.
[0220] In one embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen or -CF3 and R5, R15,
R16, R17, R18 and R19 are each hydrogen.
[0221] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of
R17, R18 and R19 is (C1-C6)-alkyl, -OR25, halogen, or -CF3.
[0222] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and two of
R17, R18 and R19 are each independently (C1-C6)-alkyl, -OR25, halogen, or -CF3.
[0223] In one embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and three of
R17, R18 and R19 are each independently (C1-C6)-alkyl, -OR25, halogen, or -CF3.
[0224] In another embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one
of R17, R18 and R19 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; and the remaining
substituents are each hydrogen.
[0225] In one embodiment, R8, R17, R11 and R19 are each independently (C1-C6)-alkyl,
-OR25, halogen, or -CF3 and the remaining substituents are each hydrogen.
[0226] In a further embodiment, R5 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of
R17, R18 and R19 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R15 and R16 is (C1-C6)-
alkyl, -OR25, or halogen; and the remaining substituents are each hydrogen.
[0227] In one embodiment, R1 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; and any two
of R17, R18 and R19 are each independently (C1-C6)-alkyl, -OR25, halogen, or ~CF3, and
one of R15, and R16 is (C1-C6)-alkyl, -OR25, halogen, or -CF3.
[0228] In one embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one of
R17, R18 and R19 is (C1-C6)-alkyl, -OR25, halogen, or -CF3.
[0229] In another embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3 and one
of R17, R18 and R19 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; and the remaining
substituents are each hydrogen.
[0230] In a further embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of
R17, R18 and R19 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; one of R15 and R16 is (C1-C6)-
alkyl, -OR25, or halogen; and the remaining substituents are each hydrogen.
[0231] In a further embodiment, R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; and any
two of R17, R18 and R19 are each independently (C1-C6)-alkyl, -OR25, halogen, or -CF3. In
one embodiment, R5, R17, R18 and R19 are each independently (C1-C6)-alkyl, -OR25,
halogen, or -CF3 and the remaining substituents are each hydrogen.
[0232] 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 (C1-C6)-alkyl, -OR25, halogen, or -CF3; and the remaining substituents are
each hydrogen. In one embodiment, R5, R17, R18 and R19 are each independently (C1-C6)-
alkyl, -OR25, halogen, or -CF3 and the remaining substituents are each hydrogen.
[0233] In a further embodiment, one of R15 and R16 is -H, (C1-C6)-alkyl, halogen,
-CF3, or -OR25; R4 is (C1-C6)-alkyl, -OR25, halogen, or -CF3; and the remaining
substituents are each hydrogen.
[0234] In one embodiment, R4, R15, R16, R17, R18 and R19 are each hydrogen.
[0235] In one embodiment, R4, R|$, R16, R17, and R15 are each hydrogen.
[0236] In one embodiment, R4, R14, and R16 are each hydrogen.
[0237] In one embodiment, R5, R15, R16, R17, R18 and R19 are each hydrogen.
[0238] In one embodiment, R5, R15, R16, R17, and R18 are each hydrogen.
[0239] In one embodiment, R5 is -OR25 or halogen; R4, R14, R16, R17, and R18 are each
hydrogen; and R19 is -H or halogen.

[0240] In one embodiment, R5 is -OCH3 or F; R4, R15, R16, R17, and R18 are each
hydrogen; and R19 is -H or F.
[0241] In one embodiment, R5 is -OCH3 or F; R4, R14, and R16 are each hydrogen;
and one of R18 or R19 is -H or F. In one embodiment, R5 is -OCH3 or F; R4, R15, R16 and
R17 are each hydrogen; and R18 and R19 are each independently —CH3 or halogen.
[0242] In one embodiment, R5 is -OR25 or halogen; R17 and R18 are each
independently -OR25, halogen or -CF3; R19 is halogen; and Ra, Rb, R4, R15, and R16 are
each hydrogen.
[0243] In one embodiment, R5 is -OCH3 or F; R17 is -OCH3; R18 is -CF3; R19 is F;
and Ra, Rb, R4, R15, and R16 are each hydrogen.
[0244] In one embodiment, R4 is -OR25 or halogen; R8, R15, R16, R17 and R15 are each
hydrogen; and R19 is -H or halogen. In one embodiment, R5 is -OCH3 or F; R4, R15, R16
and R19 are each hydrogen; and R11 and R18 are each -CH3 or halogen.
[0245] In one embodiment, R4 is -OCH3 or F; R5, R15, R16, R17 and R18 are each
hydrogen; and R19 is -H or F.
[0246] In one embodiment, R4 is -OCH3 or F; R5, R15, and R16 are each hydrogen;
and one of R18 or R19 is -H or F. In one embodiment, R4 is -OCH3 or F; R5, R15, R16 and
R17 are each hydrogen; and R18 and R19 are each -CH3 or halogen. In one embodiment,
R4 is -OCH3 or F; R4, R15, R16 and R19 are each hydrogen; and R17 and R18 are each -CH3
or halogen.
[0247] In one embodiment, the compounds of Formula Ve are antagonists of the 5-
HT1a receptor.
[0248] In another embodiment, the compounds of Formula Ve are agonists of the
5-HTia receptor.
[0249] Illustrative examples of compounds of Formula V and Formula Ve are set
forth below and include, without limitation:
6-methoxy-8-[4-( 1 -quinolin-8-yl-piperidin-4-yl)-piperazin-1 -yl]-quinoline;
6-fluoro-8-[4-(1-quinolin-8-yi-piperidin-4-yl)-piperazin-1-yl]-quinoline;
5-fluoro-8-[4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline;
7-fluoro-8-(4-(4-(6-meuioxyquinolin-8-yl)piperazin-1-yl)piperidin-1-yl)quinoline;
6-fluoro-8-{4-[1-(8-fluoroquinolin-7-yl)piperidin-4-yl]piperazin-1-
yl}quinoline;
3-trifluoromethyl-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-
yl)quinoline;
6-methoxy-8-(4-(1-(quinolin-8-ylmethyl)piperidin-4-yl)piperazin-1-
yl)quinolinc;
5-fluoro-4-methoxy-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-yl)-2-
(trifluoromethyl)quinoline;
5-fiuoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-
yl)quino!ine;
8-[4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinolinc;
6-chloro-8-[4-(4-(6-chloro)-quinolin-8-yl-piperidin-1-yl)-piperazin-1-yl]-
quinoline;
6-fIuoro-8-[4-(4-(6-chloro)-quinolin-8-yl-piperidin-l -yl)-piperazin-1-yl]-
quinoline;
5-ch1oro-8-[4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline;
2-methyl-8-[4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline;
6-chloro-8-(4-(I-quinolin-8-yl-piperidin-4-yl)-pipcrazin-1-yl]-quinoline;
8-[4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin-I-yl]-5-trifluoromethyl-quinoline;

5-methoxy-8-[4-( 1 -quinolin-8-yl-piperidin-4-yl)-piperazin-1 -yl]-quinoline;
5-fluoro-8-[4-(4-quino]in-8-yl-piperazin-1-yl)-piperidin-1-yl3-quinoline;
6-methoxy-8-[4-{2-methylquinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-
quinolinc;
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-1-yl]-
quinoline;
6-methoxy-8-(4-(l -(4-methylquino!in-8-yl)piperidin-4-yl)piperazin-1 -yl)quinoline;
6-methoxy-8-(4-(1-(2,4-dimethylquinolin-8-yl)piperidin-4-yl)piperazin-1-
yl)quinoline;
6-methoxy-8-(4-(1-(2,4-dimethyl-5-fluoroquinolin-8-yl)piperidin-4-
yl)piperazin-1 -yl)quinoline;
6-methoxy-8-(4-(1-(2-(trifluoromethyl)quinolin-8-yl)piperidin-4-yl)pipera2in-
l-yl)quinoline;
6-fluoro-8-(4-(1-(5-fluoroquinolin-8-yl)piperidin-4-yl)piperazin-1-yl)quinoline;
6-methoxy-8-(4-(1-(6-bromoquinolin-8-yl)piperidin-4-yl)piperazin-
]-yl)quinoline;
6-methoxy-8-(4-(1-(6-fluoroquinolin-8-yl)piperidin-4-yl)pipera2in-1-yl)quinoline;
6-fluoro-8-(4-(1-(7-fluoroquinolin-8-yl)piperidin-4-yl)piperazin-
I-yl)quinolinc;
6-methoxy-8-{4-[1-(8-fluoroquinolin-7-yl)piperidin-4-yl]piperazin-1-yl}quinoline;
6-methoxy-8-{4-[1-(2-trifluoromethyl-4-mell)oxyquinolin-7-yl)piperidin-4-
yl]piperazin-1-yl}quinoline;
6-methoxy-8-(4-(1-(2-trifluoromethyl-4-methoxyquinolin-8-yl)piperidin-4-yl)piperazin-
1 -yl)quinoline;
5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-yl)-
2-trifluoromethylquinoline;
5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-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-1-yl)piperidin-
l-yl)quinoline;
3,5-difluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-
l-yl)quinoline;
4,5-difluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-
l-yl)quinoline;
and pharmaceutically acceptable salts thereof.
[0250] 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. These polymorphs are within the scope of the
present invention.
[0251] Prodrugs of the compounds or pharmaceutically acceptable salts of
compounds are also within the scope of the present invention.
[0252] Therapeutic or Prophylactic Uses
[0253] 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. 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-HT]a 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 pharmaceutically 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.
[0254] One nonlimiting example of a 5-HT1 A-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.
[0255] 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.
[0256] 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:weight; hexanol:8-amino-6-
methoxyquinoline) of 1-hexanol (900 mL) was heated to 145 °C and stirred for 21 hours.
Upon completion, the reaction mixture was cooled 50 - 60 °C, and 507 g of aqueous
NaOH solution (made from 300 g of water and 207 g of 50% NaOH) was added slowly.
The reaction mixture was cooled to 25 - 30 °C and isopropyl acetate (750 mL) wass
added.
[0257] The mixture was then clarified through a eclite pad. The aqueous phase was
subsequently split off, and discarded. 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-(1-piperazinyl)quinoline adipatc 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-1-yl-quinoline (186 g, 55% yield)
with ~97% HPLC area, 88% strength purity in 51% yield.
[0258] The salt was recrystallized from a mixture of methanol and isopropyl acetate.
This was done due to the need for further purification. However, if purification is not
required, the following procedure can be eliminated.
[0259] 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. The total yield was 395 g, or 68.1% recovery.
[0260] To liberate 6-methoxy-8-(1-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 (additional sodium hydroxide solution may be needed 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. This solution was used for reductive
animation.
|0261] White solid precipitated after distillation. The solid was removed by filtration,
and the resultant filter cake was washed with 50 ml of toluene. The final volume was 185
ml at a purity of 97.56%, and a solution strength of 27.4%.
2. Preparation of 8-bromo-5-fluoroquinoline via 2-bromo-5-fluoroaniline
Intermediate

[0262] To a 2-L reactor equipped with a mechanic agitator, a condenser, a
thermocouple, a baffle, and nitrogen inlet were charged with an aqueous solution of
sulfuric acid made from 267 ml concentrated sulfuric acid and 114 mL of water. The
sulfuric acid was heated to 140-150 °C. Prior to addition to the hot sulfuric acid, 228 g
of water, 200 g of 2-bromo-5-fluoroaniline, 97 g of glycerol, and 80 g of 4-nitrophcnol
were mixed at between 25-50 °C. The 2-bromo-5-fluoroaniline mixture was added
slowly over 1.5 hours to the diluted, hot (140-150 °C) sulfuric acid. The mixture was
incubated at 135-145 °C for 1 hour after the addition. The reaction mixture was cooled to
below 20-50 °C, and the reaction mixture was transferred slowly to a 5-L reactor
containing 1100 g of water and 1210 g of toluene.
[0263] 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) 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 split off. A second portion of 500 ml of 8.5% KOH solution was
added and the mixture was stirred for 15 min and the bottom aqueous layer was split off.
Water, at a volume of 500 ml, was added and stirred for 15 min before the bottom
aqueous layer was split off. The aqueous layers were subsequently discarded. The
organic layer was heated to distill off about 100-200 ml of toluene to azeotropically
remove water. A clear solution was obtained . This solution was used directly in the
following step.
[0264] During the typical reaction scheme, the yield is 178 g real 8-bromo-5-
fluoroquinoline, ~75%. The yield for the above reaction scheme was 87.5% at a product
purity of over 99%.
[0265] 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-fluoroquinoline produced in the step above, 209 g of 1,4-Dioxa-8-
azaspiro[4.5]decane. Meanwhile in a 500-mL Erlenmycr flask, a suspension of 16.5 g
(26.5 mmol) ±-[1,1'-binaphthalene]-2,2'-diylbis[diphenyl-Phosphine, and 6.08 g (6.64
mmol)tris[m-[(1,2-h:4,5-h)-(1E,4E)-1,5-diphenyl-1,4-pentadicn-3-one]]dipalladiumin
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 ºC and stirred for 1 hour and then
heated to 65-75 °C and stirred at this temperature for about 10 hours.
[0266] The mixture was subsequently 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 off and
retained. Toluene (870 g) was added to the aqueous solution and the mixture was
neutralized by slowly adding 770 g of a 50% sodium hydroxide solution.
[0267] 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 ºC to form a slurry. The solid was collected by filtration. The product was
dried by air-flow at room temperature.
[0268] The overall yield was about 70%.
[0269] Toluene (118 g), sodium triacetoxyborohydride (44.5 g) were mixed at 0 ºC to
room temperature. To this mixture was charged a premixed toluene solution of 160 g, or
27.4 wt% in toluene, of 6-methoxy-8-(1-piperazinyl)quinoline and 41 g of 1-(5-
Fluoroquinolin-8-yl)piperidin-4-one. 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). The yield
was 68 g, or approximately 86%.
[0270] 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. The recovery yield for the purification procedure was 59.9 g, or
approximately 89.4%.
[0271] Production of the trisuccinate salt of 5-Fluoro-8-(4-(4-(6-methoxyquinolin-8-
yl)piperazin-1-yl)piperidin-1-yl)-quinoline was accomplished as follows. Briefly, 55 g
(0.127 mol) of 5-Fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1 -yl)piperidin- 1-yl)-
quinoline was dissolved in 440 ml of dichloromethane. This solution was charged in 20
min into a 3-L reactor containing 42.7 g (0.361 mol) succinic acid and 1.5 L acetone at 30

- 35 °C. The product crystallized out of the solution and then dichloromethane was
distilled off while simultaneously 1.5 kg of 2-butanone was added. The resulting slurry
was filtered and the crystalline solid was collected.
[0272] The yield was 74.0 g at approximately 77%.

[0273] 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) nor-mustard and 177 g methyl tert-butyl ether. To this mixture was slowly added
125 ml, 5 N, sodium hydroxide over a period of 20 min. The mixture was stirred for 10
min and the aqueous layer was split off. The organic layer was washed with 20%
aqueous sodium chloride solution twice (2x200 g). The methyl tert-butyl ether was
distilled off and the product was obtained as an oil. The yield was 117 g at -100% yield.
The product still contained trace amount solvent.
2. Piperazine Formation
[0274] To a 1-L reactor a mechanic stirrer, a thermocouple, and nitrogen inlet was
charged 380 g of butanol, 42 g of 8-amino-6-methoxyquinoline and 97 g of nor-mustard
free amine. The mixture was heated to 100 °C for 18 hours before cooled to 0-5 °C. A
solid was formed upon cooling and was filled with nitrogen protection. The solid was
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.
[0275] 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 hour
and then filtered. The filter cake was washed with 100 g water, 100 g MeOH and 100 g
methyl tert-butyl ether. The product was dried under vacuum at 50°C. Weight = 48.2 g,
60%
[0276] To a 100 ml flask equipped with a stirrer, a thermocouple, a condenser and
nitrogen inlet was charged ethanol 27 g, 8-(4-Benzyl-piperazin-1-yl)-6-methoxy-
quinoline (2 g), methylcyclohexene (10 g), and 0.6 g of dry 10% palladium on carbon.
The mixture was heated to reflux for 30 hours, and cooled to ambient temperature. The
palladium on carbon was filtered off, and the solvent was removed by rotavap. The
weight of the product yield was 1.7 g. The product contained small amounts of solvent.
[0277] 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-S-
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, washed 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 hexanc/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).

[0278] 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).
[0279] To a solution of 8-ch1oro-5-fluoro-4-methoxy-2-(trifluoromethyl)quinoline
(Step 2, 1.24 g, 4.45 mmo!, I eq.) in anhydrous tctrahydrofiiran (44 mL) was added
tris(dibenzylidencacctone)-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 cq.), 2-dicycIohexyl-phosphino-2'-(N,N-
dimethylamino)biphcnyl (CYMAP,0.054 g, 0.14 mmol, 0.03 cq.), and l,4-dioxo-8-
azaspiro-4,5-decanc (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 hcxane/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).

[0280] 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 tetrahydrofiiran (20 mL)
was added 2N aqueous HCl (6 mL). The resulting mixture was stirred at 70°C for 5
hours. The reaction was cooled to room temperature, poured into IN aqueous sodium
hydroxide and extracted with ethyl acetate. The combined 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 hcxane/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).

yl]piperidin-4-one (Step 4, 0.31 g, 0.9 mmol, 1 cq.) and 6-methoxy-8-(1-
piperazinyl)quinolinc (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/Et20 (I 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).
[0282] The free base of the compound synthesized in Part 5 of this Example was
isolated as 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 ºC and a colorless solution was formed.
Meanwhile, in a 3-L flask were charged 240 g of 5-FIuoro-4-methoxy-8-(4-(4-(6-
methoxy-quinolin-8-yl)-piperazin-1 -yl)-piperidin-1 -yl)-2-trifluoromethyl-quinoline and
2250g of THF. 5-Fluoro-4-methoxy-8-(4-(4-(6-methoxy-quinolin-8-yl)-piperazin-1-yl)-
piperidin-1-yl)-2-trifluoromet.hyl-quinoli[ie in THF mixture was heated to 50 ºC and a
yellow solution was achieved. This yellow solution was slowly (about 3 hours) charged
into the 12-L reactor while maintain both solution temperature at about 50 aC. The
resulting slurry was stirred over night at room temperature, and then cooled to 5-10 °C.
After stirred 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.
[0283] The weight of the 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-1-yl)-piperidin-1-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.
CLAIMS
What is claimed is:
1. A process for isolating a compound having Formula I:
or a pharmaceutically acceptable salt thereof,
wherein R1, R2, R3, 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, -
OSO2R25, -SR25, -SO2R25, -SO2N(R23)2. -N(R23)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, the process comprising:
(a) reacting a compound having Formula I with a dicarboxylic acid to form an
addition salt of the compound having Formula I:
(b) isolating the compound of Formula F from the addition salt of Formula I in the
presence of an organic solvent, a base, and CH2Cl2.
2. The process of claim 1, wherein the dicarboxylic acid is a (C3-C12)-alkyl
dicarboxylic acid.
3. The process of claim 2, wherein the (C3-C12)-alkyl dicarboxylic acid is adipic
acid.
4. The process according to any one of claims 1 to 3, wherein R1, R2, R3, R4, R5, and
Rb, are each independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-
C6)-alkynyl, halogen, -CF3, -NO2, -CN, or -OR25.
5. The process according to any one of claims 1 to 4, wherein R5 is -OR25, and R2s is
(C1-C6)-alkyl.
6. The process according to anyone of claims 1 to 5, wherein R5 is a methoxy.
7. The process according to any one of claims 1 to 6, wherein the organic solvent is
toluene.
8. The process according to any one of claims 1 to 7, wherein the base is NaOH or
KOH.
9. A process for synthesizing a compound comprising:

a) mixing an optionally substituted aniline compound having Formula II with and
glycerol and 4-nitrophenol to form a first solution solution:
wherein D is halogen, and
wherein 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, -
OSO2R25, -SR25, -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 (C2-C6)-alkynyl;
b) reacting the first solution with an acid to form a compound of Formula III:
wherein D is halogen, and wherein R7, R1, R9, R10, R11, and R12, are each
independently -H, (C1-C6)-alkyl, (C1-C6)-ha]oalkyl, (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,
and R25 is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or
(C2-C6)-alkynyl,
wherein the method comprises mixing the optionally substituted aniline
compound having Formula II, glycerol, and 4-nitrophenol to form a solution prior to
addition of acid.
10. The process of claim 9, wherein the acid is H2SO4.
11. The process of claim 9 or 10, wherein the temperature of the acid is greater than
about 50 °C.
12. The process of claim 9 or 10, wherein the temperature of the acid is greater than
about 100 °C.
13. The process of claim 9 or 10, wherein the temperature of the acid is greater than
about 120 °C.
14. The process of claim 9 or 10, wherein the temperature of the acid is between about
135 °C and about 145 °C.
15. The process of claim 9 or 10, wherein the temperature of the acid is less than
about 150°C.
16. The process according to any one of claims 9 to 15, wherein D is bromine or
chlorine.
17. The process according to claim 16, wherein D is bromine.
18. The process according to any one of claims 9 to 17, wherein R9 is halogen.
19. The process according to claim 18, wherein R9 is fluorine.
20. The process according to any one of claims 9 to 19, wherein R7 and R8 are each
independently hydrogen.
21. The process according to any one of claims 9 to 20, wherein R11 is hydrogen.
22. The process according to any one of claims 9 to 21, wherein R12 is hydrogen.
23. The process according to anyone of claims 9 to 17 and 20, wherein R9 is halogen,
R11 is hydrogen, and R12 is hydrogen.
24. The process according to claim 23, wherein D is bromine.

25. The process according to any one of claims 9 to 24further comprising heating a
mixture of the solution and H2SO4 to between 135 °C and 140 °C.
26. A process of synthesizing a compound comprising:
a) reacting an optionally substituted piperazino-quinoline compound of Formula I:
wherein R1, R2, R3, R4, R5, and R8, 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(R23)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 optionally substituted piperidin-4-one compound of Formula IV:
wherein 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, -OSO2R25, -SR25, -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)-alky], (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
in the presence of toluene and under conditions effective to bring about
reductive amination at the piperidine carbonyl, thereby providing an piperazine-piperidine
compound having the Formula V:
27. The process of claim 26, wherein R5 is -H, (C1-C6)-alkyl, OR25, halogen, or CF3.
28. The process of claim 26 or 27, wherein R9 is -H, (C1-C6)-alkyl, OR25, halogen,
CF3, -NO2, or -CN.
29. The process of any one of claims 26 to 28, wherein R10 is -H, (C1-C6)-alkyl, OR25,
halogen, CF3, -NO2, or -CN.
30. The process of any one of claims 26 to 29, wherein R12 is -H, (C1-C6)-alkyl, OR25,
halogen, CF3, -NO2, or -CN.
31. The process of any one of claims 26 to 30, wherein R5 is-H, (C1-C6)-alkyl, OR25,
halogen, or CF3; and R9 is -H, (Cl -C6)-alkyl, OR25, halogen, CF3, -NO2, or -CN.
32. The process of any one of claims 26 to 31, 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.
33. The process of any one of claims 26 to 32, wherein any one of R1, R2, R3, R4, R5,
and R6 is -H, (C1-C6)-alkyl, OR25, halogen, or CF3, and any three of R7, R8, R9, R10, R11,
and R12 is -H, (C1-C6)-alkyl, OR25, halogen, CF3, -NO2, or -CN.
34. The process of any one of claims 26 to 33, wherein R25 is (C1-C6)-alkyl.
35. The process of any one of claims 26 to 34, wherein n is 1.
36. The process according to any one of claims 26 to 35, wherein R5 is -OR25, R25
being linear or branched (C1-C6)-alkyl and R1, R2, R3, R4, and R5 are each -H.
37. The process according to claim 36, wherein R5 is methoxy.
38. The process according to claim 37, wherein Ra and Rb are each independently
hydrogen.
39. The process according to claim 38, wherein R9 is halogen, and R7, R8, R10, R11,
and R12, are each hydrogen.
40. The process according to claim 39, wherein R8 is halogen.
41. The process according to any one of claims 26 to 40further comprising reacting
the compound having Formula IV and the compound of Formula V in the presence of a
compound having the Formula VI:

42. The process of claim 41 further comprising
b) prcmixing toluene and the compound having Formula VII to form a first
organic solution;
c) premixing the compound having Formula IV with the compound having
Formula V in toluene to form a second organic solution; and
(d) mixing the first and second organic solutions under conditions effective for
reacting Formula IV and Formula V to produce Formula VI.
43. A process for isolating a compound comprising:
a) mixing a compound of Formula VII 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, -SR25, -SO2R25, -SO2N(R25)2, -N(R25)2, C(O), -COR25, -CO2R25,
-NR25CO2R25, -NR25COR25, -NR25CON(R25)2, or -CON(R25)2; and
R2s is -H; or linear or branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl,
or (C2-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 VII
from the mixture,
wherein the isolated dicarboxylic acid addition salt of the compound of Formula
VII contains less than 0.25 w% of each solvent used during the synthesis of the
compound of Formula VII.
44. The process of claim 43, wherein dicarboxylic acid is succinic acid.
45. The process of claim 43 or 44, wherein the first organic solvent is THF.
46. The process of any one of claims 43 to 45, wherein the second organic solvent is
acetone.
47. The process of claim 46, wherein the first organic solvent is THF, the second
organic solvent is acetone, and the dicarboxylic acid is succinic acid.
48. The process of any one of claims 43 to 47, wherein R1, R2, R1, and R4, are each
independently -H, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl,
halogen, -CF3, -NO2, -CN, or -OR25, and R25 is -H; or linear or branched (C1-C6)-alkyl,
(C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl.
49. The process of any one of claims 43 to 48, wherein R1, R2, R3, and R4, are each
independently -H, (C1-C6)-alkyl, halogen, -CF3, or -OR25, and R25 is -H; or linear or
branched (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl.
50. The process of any one of claims 43 to 49, wherein R1 and R3 are -H, or -OR25,
and R25 is -H or (C1-C6)-alkyl.
51. The process of claim 50, wherein R2 is -H or halogen and R4 is -H or -CF3.
52. The process of any one of claims 43 to 51, wherein the amount of each solvent is
less than 0.2 w%.
53. The process of any one of claims 43 to 51, wherein the amount of each solvent is
less than 0.15 w%.

54. The process of any one of claims 43 to 51, wherein the amount of each solvent is
less than 0.10 w%.
55. The process of any one of claims 43 to 51, wherein the amount of each solvent is
less than 0.05 w%.
56. The process of any one of claims 43 to 51, wherein the amount of each solvent is
less than 0.025 w%.
57. The process of any one of claims 43 to 51, wherein the amount of each solvent is
less than 0.02 w%.
58. The process of any one of claims 43 to 51, wherein the amount of each solvent is
less than 0.015 w%.
59 The process of any one of claims 43 to 51, wherein the amount of each solvent is
less than 0.01 w%.
The present invention relates to processes for synthesizing piperazine-piperidine compounds, and compounds useful
as 5-HT1A binding agents, particularly as 5-HT1A receptor antagonists and agonists. The processes also allow for safer and environmentally
tolerant production of these useful compounds.